TOUCHED BY LYME: CDC ups cases to 329,000; some docs push back

The Centers for Disease Control and Prevention (CDC) now says there are about 329,000 cases of Lyme disease in the US every year. That’s up from the estimate of 300,000 that they gave in 2013. (The number of officially reported cases, those meeting the CDC’s strict surveillance guidelines, still hovers around 30,000.)
Yet, even this new bigger number is based on insurance claims–which only show up when people have been diagnosed with Lyme disease. We all know how hard it is to get diagnosed with Lyme. So how many people actually have it? Much higher than 329,000, I dare say.
“We’ve always had the understanding that cases are under-reported, so we always knew that surveillance doesn’t capture every case,” said one of the researchers. “This study helps capture and quantify this fact.”

Yet, according to Minnesota Public Radio, some infectious disease docs are pushing back about the new number:

Some Minnesota infectious disease experts say physicians and patients are often too quick to label a problem as Lyme disease, and that if that diagnosis turns out to be wrong, the insurance claims may not be corrected to reflect that.

Most Lyme disease cases are diagnosed based merely on a physician’s observations, said Dr. Gary Kravitz with AllinaHealth. 

That may produce an insurance claim for Lyme disease, but unless the diagnosis is eventually confirmed with a blood test, the problem could well be something else, he added.

Physicians are too quick to label a problem Lyme disease? What universe are those guys inhabiting? (Oh yeah, the one where Lyme is “hard to catch and easy to cure.” The one where joint pain, fatigue, and gastrointestinal distress are “all in your head.”)
In my ten years of communicating with Lyme patients, not ONE of them complained that their doctor was “too quick” to identify their problem as Lyme disease. And in a survey by LymeDisease.org, more than half of patients had to see seven or more physicians before finally being diagnosed with Lyme disease. Over a third saw 10 or more!
So the CDC is finally recognizing that 329,000 people get diagnosed with Lyme every year.  Maybe that’s a baby step in the right direction. But what about the suffering thousands who don’t get diagnosed and continue to be kicked to the curb by the medical establishment? When will our health officials step up and give them the help they deserve?

https://www.lymedisease.org/329000-lyme/

Borreliosis de Lyme: acercamiento a una enfermedad infecciosa emergente

Revista Cubana de Higiene y Epidemiología

versión On-line ISSN 1561-3003

Rev Cubana Hig Epidemiol v.35 n.2 Ciudad de la Habana ene.-ago. 1997 

RESUMEN

Se realizó una revisión de la evidencia científica disponible sobre la borreliosis de Lyme teniendo en cuenta la importancia actual de esta enfermedad emergente debido a su amplia distribución en el mundo, sus graves secuelas para la salud humana, difícil prevención y control. Se abordaron diferentes aspectos de la enfermedad, se enfatizó en la epidemiología, aspectos clínicos, diagnóstico y otros, a la luz de los conocimientos más actuales sobre el tema. Se evidenció que aún no existe acuerdo sobre el diagnóstico y el tratamiento antibiótico que se debe utilizar, mientras que en relación con su prevención y control, la educación sanitaria y evitar las áreas infestadas resultan ser las medidas más recomendadas hasta tanto existan vacunas eficaces disponibles.

Descriptores DeCS: ENFERMEDAD DE LYME/epidemiología; ENFERMEDAD DE LYME/etiología; ENFERMEDAD DE LYME/diagnóstico; ENFERMEDAD DE LYME/prevención y control; ENFERMEDAD DE LYME/quimioterapia.

ANTECEDENTES

Las enfermedades infecciosas emergentes son aquéllas que con un origen infeccioso, han incrementado su incidencia en los humanos en las 2 décadas pasadas o amenazan con hacerlo en el futuro próximo. Disímiles factores de forma independiente o combinados pueden contribuir a la emergencia de una enfermedad: cambios genéticos en un organismo, resistencia y adaptación microbiana, variación en las condiciones ecológicas, eventos sociales, fallas en las acciones de salud pública y otros.

La borreliosis o enfermedad de Lyme como entidad nosológica infecciosa transmitida por vectores resulta aparentemente nueva, pues existen antecedentes que ya en 1910 el dermatólogo sueco A. Afzelius¹ y 12 años después 2 médicos franceses C. Garin y R. Bujadoux reportan una enfermedad rara que afectaba la piel y otros órganos, causaba parálisis y al parecer era provocada por picadas de garrapatas.²

Cincuenta y tres años más tarde, en 1975, se produce la reemergencia de esta enfermedad como consecuencia de una epidemia de artritis que afectó a 39 niños y 12 adultos en la cual, la cuarta parte de los enfermos presentaba una lesión cutánea característica en forma de "ojo de buey" precedente a la aparición de la artritis. Los casos estaban agrupados en el lado este del río Connecticut y aparecieron durante el verano en áreas cercanas a zonas muy boscosas de poblados de Nueva Inglaterra, Estado de Connecticut en Estados Unidos (Old Lyme, Lyme y East Haddam).³ Esta epidemia fue estudiada por el epidemiológo Allen Steere de la Universidad de Yale, que sospechó inicialmente se debía a una enfermedad desconocida, de origen probablemente viral y transmitida por un artrópodo no identificado. El hecho de que uno de los pacientes, que era ecologista, aportara una garrapata (Ixodes dammini) que lo había picado previamente a la enfermedad, asociado al hecho de que algunos de los pacientes mencionaron un inusual eritema que apareció semanas antes de comenzar los síntomas, y que era similar a uno reportado en Europa al parecer causado por la picada de garrapata, permitió suponer que éste podría ser el vector de la enfermedad denominada inicialmente artritis de Lyme y posteriormente enfermedad de Lyme, por la población donde aparecieron los primeros casos.³

Hubo que esperar aún 7 años después de la epidemia de Connecticut para que en 1982, el entomólogo William Burgdorfer al disecar el tubo digestivo de una garrapata Ixodes damnini, recolectada en una región de Estados Unidos (Shelter Island, New York), lo encontrara repleto de espiroquetas que sospechó podrían ser el agente causal de la enfermedad; posteriormente demostró que estos microorganismos provocaban una lesión característica en los conejos picados por garrapatas infectadas. Espiroquetas similares se aislaron de la sangre y líquido cefalorraquídeo de enfermos de Lyme.⁴

En 1983, R.C. Johnson demostró que este microorganismo era una nueva especie de espiroqueta del género Borrelia y propone el nombre de Borrelia burgdorferi en honor a su descubridor.⁵

EPIDEMIOLOGÍA

La verdadera incidencia y distribución en el mundo de esta enfermedad es aún desconocida debido, fundamentalmente, a sus características epizootiológicas y dificultades en el diagnóstico. La mayoría de los reportes provienen de los países desarrollados y algunos en vías de desarrollo. La borreliosis de Lyme se ha convertido en la enfermedad transmitida por artrópodos más frecuente en Estados Unidos y Europa.^6,7 En EE.UU. el número de casos se ha incrementado de 491 en 1982 a 13 083 en 1994.⁸ En Europa ha sido reportada en casi todos los países: España, Francia, Inglaterra, Alemania, Austria, Serbia, Croacia, Eslovenia, Suiza, Suecia, Dinamarca, Holanda, República Checa, Eslovaquia, Italia, Rusia y otros.⁶ En Asia existen reportes en China⁹ y Japón,¹⁰ también se ha encontrado en Australia,¹¹ norte de África¹² y Brasil.¹³ Las tasas de incidencia en algunos países europeos, Japón y Estados Unidos fluctuaron entre 0,6 y 300 x 100 000 habitantes.⁸

Desde el punto de vista de su manifestación en grupos humanos, han ocurrido epidemias, aunque en la actualidad mantiene una endemia en los países que la vigilan y reportan, con una estacionalidad característica que comenzando en primavera, tiene picos en verano y otoño para finalizar en este último.^7,14

B. burgdorferi es transmitida de los animales al ser humano por garrapatas pertenecientes primariamente el complejo Ixodes (del griego ixos=pegarse, por lo tenazmente que se fijan a su huésped). La transmisión ocurre durante la alimentación, bien sea por salivación, regurgitación o ambos procesos.

Se ha reportado también la transmisión transplacentaria madre-feto en madres infectadas durante el primer trimestre del embarazo.¹⁵ Existen reportes de la posibilidad de transmisión a través de la sangre o sus productos, pues los procedimientos habituales de selección de donantes no son efectivos al 100 %.¹⁶

Por último, se plantea la posibilidad, de acuerdo con recientes hallazgos, de la transmisión oral en animales de laboratorio, por lo que al ingerir partes crudas o poco cocinadas de animales infectados se pudiera producir la transmisión.¹⁷

La borreliosis de Lyme es causada por una espiroqueta, Borrelia burgdorferi, identificada en 1982 y clasificada en el orden Spirochaetales. Su estructura cromosomal es lineal. Entre las distintas cepas las diferencias conciernen esencialmente a proteínas de la membrana externa de las cuales están identificadas la A, B, C, E y F.¹⁸ Este organismo en su interacción con los distintos huéspedes debe adaptarse a disímiles y variados ambientes en su ciclo de vida, por lo que su capacidad de resistencia es alta, puede permanecer viable en los tejidos hasta 10 años. Recientemente se han demostrado diferencias antigénicas entre las cepas de borrelias americanas y europeas por lo que se propone el reconocimiento de nuevas especies: Borrelia garinii y Borrelia afzelii.¹⁹

Dos especies de Ixodes eurasiáticos (Ixodes ricinus e Ixodes persulcatus) y 3 norteamericanas (Ixodes dammini, Ixodes scapularis e Ixodes pacificus) son vectores de Borrelia burgdorferi al humano. Todas se alimentan de 3 animales diferentes durante su vida (2 a 7 años) y cada especie puede parasitar a un gran número de animales: el I. ricinus es capaz de alimentarse de 300 diferentes clases de mamíferos, pájaros y reptiles. Los roedores del género Peromyscus y Apodemus son importantes reservorios en Norteamérica y Europa. Los pájaros pueden constituir medios naturales de distribución de garrapatas infectadas a largas distancias durante sus vuelos migratorios. Las ninfas y los adultos son el estadio en que hay una mayor proporción de elementos infectantes.²⁰

El principal y más importante factor de riesgo para esta enfermedad es la permanencia por cualquier razón en zonas boscosas,^14,21 lo que ha motivado que algunos países declaren la enfermedad de Lyme una enfermedad profesional en actividades tales como las realizadas por leñadores y guardabosques,¹⁹ y en la agricultura y la ganadería.^21,22

PATOGENIA

Algunas características de B.burgdorferi tienen una función crucial en la patogenia de la enfermedad de Lyme, que resulta ser un complejo proceso resultante de inflamación, liberación de citotocinas, diseminación y adherencia del microorganismo a los diferentes tejidos.

B. burgdorferi estimula a diversas citocinas inflamatorias (interleukina 1 y 6) y al factor de necrosis tumoral alfa (FNT-alfa) que pudieran desempeñar alguna función en la reacción inflamatoria que acompaña a la enfermedad.²³ La diseminación del microorganismo se facilita por la alta permeabilidad de los vasos sanguíneos y la activa penetración de la bacteria a través de las membranas endoteliales. La invasión de los diferentes tipos de tejidos se produce como resultado de la adherencia del germen a distintos tipos de células (fibroblastos y células endoteliales)²⁴ y estructuras ampliamente distribuidas en el huésped humano. La respuesta inmunitaria, normalmente protectora, no resulta eficaz para erradicar los microorganismos y puede contribuir a la enfermedad al desarrollar un proceso autorreactivo. Esta reacción está basada en la reactividad cruzada antigénica entre epitopes comunes al agente y al huésped, especialmente localizados en las llamadas "proteínas de estrés o choque térmico"²⁵ de las cuales en B. burgdorferi se han detectado de 5 a 7. Estas proteínas protegen a la bacteria del daño producido por componentes bactericidas (calor, radicales oxígeno reactivos y otros). Una de ellas, la GroEl se cree presente en todas las células vivientes y son las responsables de la respuesta al estrés, tiene una importante función en la supervivencia de la espiroqueta en el huésped durante la transición del vector (con baja temperatura corporal) a los animales de sangre caliente.²⁶

El éxito de la invasión de un organismo patógeno depende en gran medida de varios factores citoplasmáticos, asociados a la superficie del germen y secretados. Las dificultades técnicas de manipulación de las espiroquetas hacen difícil el reconocimiento de los factores específicos implicados en la entrada y larga supervivencia de este microorganismo en el huésped. Evidencias indirectas sugieren que la producción de GroEL modifica la capacidad de la espiroqueta de sobrevivir en el medio hostil del huésped infectado. ²⁶

Estudios realizados sobre las proteínas de la superficie externa (Osp) sugieren que son muy importantes también para la interacción parásito-huésped. Esto ha sido sustentado por estudios de un anticuerpo monoclonal (9B3D) contra Osp A que es capaz de bloquear el aco-plamiento de B. burgdorferi a la célula.

Parece ser que la disminución de la infectividad por el germen está relacionada con la pérdida de proteínas y plásmidos especifícos. El gen especificante de una de esas proteínas ha sido identificado y es una lipoproteína (Lap 30) especificada por un plásmido de 38 kilodalton (kDa).²⁶

MANIFESTACIONES CLÍNICAS

La borreliosis de Lyme es una enfermedad multisistémica y proteiforme caracterizada por lesiones en la piel, síntomas catarrales, fatiga, dolores músculo-esqueléticos, trastornos neurológicos, articulares y cardíacos que pueden aparecer semanas, meses o años más

tarde.⁶ Puede simular o parecerse a otras entidades tanto infecciosas como no infecciosas, por lo que su diagnóstico clínico en ocasiones resulta difícil.

En general se distinguen 3 estadios evolutivos de la enfermedad: reciente, diseminado y tardío, los cuales aparecen resumidos en la tabla 1.

Las manifestaciones dermatológicas más frecuentemente encontradas son: eritema crónico migratriz (ECM), linfocitoma borrélico y acrodermatitis crónica atrófica. El ECM es una lesión eritematosa macular o papulosa, aunque a veces puede resultar vesicular, que aparece en el sitio de la inoculación borrélica y que tiene una coloración roja homogénea, a veces más clara en el centro, con extensión centrífuga, anula, aunque pueden existir variantes atípicas.²⁷ Su tamaño es variable pero con mucha frecuencia es igual o mayor de 5 cm. Es con frecuencia un signo temprano de la enfermedad y permite establecer el diagnóstico de ésta aun en el primer estadio.²⁷ En los casos en que se puede establecer el antecedente de la picada claramente se ha observado un período de incubación de 5 a 6 d entre la picada y la aparición de la lesión. Los sitios más comúnmente afectados son los miembros inferiores, el tronco y el cuello.²² Durante la infección temprana también puede ocurrir la aparición de múltiples lesiones semejantes a ECM como resultado de la diseminación hematógena de la infección y puede constituir un marcador importante de ésta.²⁷ El linfocitoma borrélico o linfadenosis benigna cutis comúnmente se presenta como un nódulo eritematoso rojo-azulado en el sitio de la picada, lóbulo de la oreja y región del pecho secundariamente al ECM o como primera manifestación de borreliosis de Lyme. La acrodermatitis crónica atrófica es una lesión crónica de la piel que comienza con una fase inflamatoria con decoloración azul-rojiza de la piel en las extremidades y años después puede ser seguida de una fase atrófica.²⁷
TABLA 1. Estadios o fases de la borreliosis de Lyme  

Estadio	Síntomas	Período de incubación	Duración
Reciente (I)  (< 1 año)	Eritema crónico  migratiz y síntomas catarrales	Pocos días (5 a 6)  después de la picada	Días-semanas  (>21 días)
Diseminado (II)	Fatiga pronunciada fiebre, dolores músculares, esqueléticos, desórdenes cardiovasculares y neurológicos	Semanas o meses	Semanas o meses
Tardío (III)  (> 1 año)	Artritis en las grandes articulaciones con algunas complicaciones neurológicas y cardíacas graves que existían o se adicionaron	Meses o años	Crónico

Una de las manifestaciones clínicas más importantes en esta enfermedad lo constituye la artritis. La sucesión o coexistencia de ataques intermitentes de artralgias y artritis puede ser un indicador importante de enfermedad de Lyme. Esta manifestación generalmente se atribuye al estadio más avanzado de la enfermedad (III) y su localización patognómonica es en las rodillas. En los niños se presenta típicamente como artritis intermitente y unilateral de la rodilla, la cual debe ser tratada cuanto antes con antibióticos para evitar secuelas.²⁸ Durante los accesos, la inflamación franca de la articulación puede ser signo de la presencia de la espiroqueta en el líquido sinovial.^29-30 Estudios inmunogenéticos sugieren que los pacientes con el antígeno de histocompatibilidad leucocitaria humana DR 4 y/o DR 2 pueden estar predispuestos a desarrollar artritis crónica a pesar del tratamiento antibiótico.

La neuroborreliosis es un conjunto de manifestaciones clínicas y síndromes que responden a la misma causa: borreliosis de Lyme, y se puede presentar en cualquier fase de la enfermedad, aunque con mayor frecuencia en la diseminada y tardía. La persistencia de Borrelia burgdorferi en el sistema nervioso central puede ocasionar daños neurológicos irreversibles. Los reportes europeos enfatizan en las formas graves como el síndrome Garin-Bujadoux-Bannwarth (radiculitis dolorosa) y la paraparesia espástica progresiva crónica. En Norteamérica parecen desarrollarse formas menores de afectación del sistema nervioso pero con un rango amplio de variaciones: desde un ligero estado confusional hasta una severa encefalitis o meningoencefalitis. Las manifestaciones de los nervios periféricos van desde los síntomas intermitentes sensoriales hasta la típica radiculitis dolorosa.³¹ En los niños los síntomas tienen un amplio diapasón: desde cambios de conducta, papiledema, diplopia, trastornos del sueño hasta aumento de la presión intracraneal, parálisis facial (tipo Bell) y meningitis.³²

Las manifestaciones cardiovasculares de la borreliosis de Lyme son abundantes y pueden ir desde pericarditis, miocarditis y endocarditis en la fase aguda hasta cardiomiopatías con cardiomegalia, endocarditis crónica y bloqueo aurículo- -ventricular (A-V) de tercer grado de pronóstico reservado.¹⁹ En Europa suelen reportarse de 3 a 8 % de carditis borrélicas.^19,33

Dentro de los trastornos músculo-esquéleticos la fibrositis o fibromialgia es otra manifestación asociada a la borreliosis de Lyme y se caracteriza por dolores difusos, rigidez, fatiga generalizada, sueño no restaurador y puntos sensibles en la musculatura profunda. Este trastorno ha sido identificado hasta en un 25 % de casos con diagnóstico de Lyme.³⁴

Otras manifestaciones de esta enfermedad pueden ocurrir al nivel de otros órganos y aparatos: manifestaciones otolaringológicas, oftalmológicas, psiquiátricas y otras.

DIAGNÓSTICO

En el caso de la borreliosis de Lyme las pruebas serológicas en vez de aclarar los problemas diagnósticos pueden crear dudas y cuando el médico recurre al laboratorio para confirmar la sospecha clínica puede resultar decepcionado. La confirmación del diagnóstico clínico por métodos de laboratorio resulta, por lo tanto, una cuestión delicada y difícil por la ocurrencia de resultados falsos positivos debido a la existencia de alguna enfermedad de base autoinmune (lupus eritematoso, artritis reumatoidea y otras), la mononucleosis infecciosa y la sífilis.

Para el diagnóstico de borreliosis de Lyme el antecedente de la exposición a la picadura por garrapatas en áreas infestadas, unido a manifestaciones clínicas y resultados serológicos positivos pueden ser suficientes.³⁵ Aún así se mantiene un amplio debate internacional sobre la utilidad diagnóstica de las diferentes pruebas serológicas para el diagnóstico de borreliosis de Lyme. Las opciones pudieran ser:

- El examen directo en campo oscuro basado en la morfología de Borrelias y su movilidad con giro de las espirales en contra de las manecillas del reloj puede ser una opción en lugares con pocos recursos. - Las pruebas serológicas más comunes son: inmunofluorescencia indirecta, hemaglutinación y ELISA y permiten detectar anticuerpos específicos contra B.burgdorferi entre 3 y 6 semanas después de la infección (anticuerpos IgM después de la infección inicial y anticuerpos IgG durante años).¹⁴ En general, en la literatura internacional se recomienda analizar los resultados de estas pruebas con precaución por los falsos positivos y las dificultades en la estandarización de las técnicas.^14,36 El método confirmatorio por excelencia de las pruebas serológicas es el inmunoblotting (Western Blotting),³⁷ se considera como positivo durante la fase reciente (IgM) la detección de 2 de 3 bandas de 24, 39 y 41 kDa de polipéptidos espiroquetales, y en la fase tardía (IgG) 5 de las 10 bandas de 18, 21, 28, 30, 39, 41, 45, 58, 66 y kDa. - La detección directa de la bacteria por el cultivo en medio Barbour-Stuenner-Kelly del material de biopsias de la piel de lesiones de ECM, liquido sinovial o cefalorraquídeo, puede resultar un método engorroso aunque útil para el diagnóstico definitivo de la enfermedad.³⁸ - Pueden emplearse investigaciones como la coloración y demostración de partes del genoma por técnicas de amplificación de fragmentos de ADN de B. burgdorferi (in vitro pueden detectar hasta un solo microorganismo) mediante la reacción en cadena de la polimerasa (RCP) en líquidos corporales del individuo.^14,39. Las pruebas de reacción de las células T-proliferativas también brindan información de la exposición al germen y pueden resultar positivas aun con un ELISA negativo, tal vez por la formación de inmunocomplejos.³⁴ pero en general resultan costosas, toman mucho tiempo y son poco accesibles.

PREVENCIÓN Y CONTROL

El conocimiento de las determinantes ambientales resulta esencial para evaluar el riesgo humano y recomendar estrategias de prevención. La prevención y control de esta entidad nosológica resulta muy difícil por varias razones: el vector tiene una amplia difusión en el mundo, durante su ciclo de vida pasa una parte en la tierra o sobre las hierbas aguardando la llegada de un huésped, la duración de su vida puede ser entre 2 y 7 años, transita alternativamente por 3 huéspedes diferentes, algunos de los cuales pueden trasladarlo a grandes distancias y su picadura puede pasar inadvertida; además, el agente causal es resistente y adaptable a diferentes medios con un largo tiempo de supervivencia, produciendo un cuadro clínico proteiforme. En general, el control químico de estos vectores resulta un método caro, temporal y necesariamente reiterativo,⁴⁰ por lo que se recomienda utilizarlo con otras medidas entre las que sobresalen: autoprotección, autoeliminación de garrapatas de la piel, acaricidas para la piel y vestidos, control de vectores, modificación de hábitats y educación sanitaria. El humano susceptible parece ser, hasta ahora, sobre quien las medidas de prevención parecen ser más eficaces. A menudo la recomendación del uso de vestimentas cerradas en las extremidades tiene una eficacia incierta, pues estos insectos hematófagos pueden posarse y caminar por los vestidos hasta encontrar una vía de acceso a la piel. La picada es generalmente indolora por lo que se recomienda siempre que después de un paseo por zonas boscosas deben buscarse las garrapatas en la piel y extraerlas lo más rápidamente posible luego de haberlas anestesiado con éter, se debe evitar que queden adheridos restos de la boca a la piel: a mayor tiempo de permanencia de la garrapata en ésta, mayor el riesgo de infectarse. Si existe alguna lesión cutánea sospechosa de ser provocada por la garrapata, debe acudirse cuanto antes al médico.¹⁴ También puede ser recomendable la utilización de repelentes contra garrapatas: para la piel (N,N-dietil-metatoluamisa:DEET, 2-etil-1,3-hexanediol y dimetil ftalato) o sobre los vestidos (Permethrin), el uso de ambos a la vez es lo más recomendable aunque tienen como incoveniente que su aplicación debe realizarse cada 1 ó 2 horas.⁴¹ Otras medidas tales como evitar las zonas boscosas infestadas, usar ropas claras para poder identificar las garrapatas fácilmente, revisarse el cuerpo periódicamente así como el de los animales domésticos, pueden ser útiles, pero casi todos los autores coinciden en recomendar la educación sanitaria como la medida fundamental en la prevención de esta enfermedad. La quimioprofilaxis antimicrobiana en los individuos expuestos no se recomienda por cuanto el riesgo de enfermar después de la exposición al vector puede ser bajo. La inmunización aún no es posible dada la inexistencia de una vacuna efectiva para los humanos. Un preparado vacunal que utiliza una forma recombinante de las proteínas Osp A y Osp B de Borrelia burgdorferi ya ha sido probado en modelos animales y pudiera ser uno de los candidatos más cercanos a incluir en una vacuna polipeptídica protectora contra las principales especies de B. burgdorferi patógenas para el hombre y los animales.^42,43

TRATAMIENTO

Antes de conocerse el origen de las borreliosis de Lyme sus manifestaciones a menudo eran tratadas con penicilina, tratamiento que resultó casi siempre exitoso.⁴⁴ Después han sido probados otros antibióticos con más o menos éxito pero todavía no hay consenso sobre cuál, si es que lo hay, es superior al resto o de cuál manifestación de la enfermedad puede ser mejor tratada por un antibiótico en particular⁴⁵ lo que también está influido por el estadio de la enfermedad y el criterio médico.^46,47 TABLA 2. Esquema de tratamiento para la borreliosis de Lyme en personas adultas

Enfermedad reciente o temprana	Dosis
Doxiciclina	100 mg 2 veces al día
Amoxicilina con o sin probenecid	500 mg 3 veces al día
Tetraciclina	500 mg 4 veces al día
Artritis y carditis de Lyme	Dosis
Penicilina G 20	20 millones U (i.v.)* 2 a 3 veces al día durante 10 a 14 d
Rocephin (ceftriaxone)	2 g (i.v.) diario durante 14 d
Neuroborreliosis	Dosis
	Si solo hay parálisis facial usar el tratamiento para la fase reciente si hay otras complicaciones usar el tratamiento para la artritis durante 14 a 30 d
Cefotaxine sódica	2 g (i.v.) cada 8 h
Doxiciclina	100 mg (i.v.) cada 12 h
Cloramfenicol	1 g (i.v.) cada 6 h
Embarazo	Dosis
Amoxicilina	1 500 mg 3 veces al día
Peniclina G	20millones (U) (i.v.) 2 a veces al día durante 10 a 14 d
Rocephin	2 g (i.v.) diario durante 14 d

* i.v.: intravenoso. TABLA 3.Esquema de tratamiento para la borreliosis de Lyme en niños enfermos
 

Enfermedad temprana	Dosis
Tetraciclina*	250 mg 4 veces al día
Doxiciclina*	100 mg 2 veces al día
Penicilina V (< 9 años)	25 a 50 mg por kg por día repartidos en 3 dosis
Enfermedad tardía	Dosis
Parálisis de Bell, artritis y carditis ligera	Esquema igual al anteriordurante 10 a 30 d
Artritis persistente y carditis severa	Ceftriaxone 75-100 mg por kg1 vez al día por vía parenteral durante 14 a 21 d
Meningitis o encefalitispor día por vía parenteraldurante 14 a 21d.	Penicilina G 300000 U por kg

* No recomendable a niños menores de 9 años. La decisión del tratamiento antibiótico debe hacerse sobre las bases de la du-ración, extensión y estadio de la enfermedad. Existen autores que opinan que no es necesario continuar el tratamiento antibiótico hasta que desaparezcan todos los síntomas porque muchos de los sín-tomas son el resultado de una respuesta inflamatoria con un componente inmunológico. Otros argumentan que la persistencia de los síntomas denota infección por lo que se debe mantener el tratamiento hasta que se demuestre la negativización ulterior con cultivo o RCP.⁴⁸ Un tratamiento oral temprano y oportuno con antibióticos está preconizado para prevenir las variadas complicaciones, pero generalmente la antibioticoterapia no es prescrita hasta que se desarrollan⁴⁹ el ECM u otros síntomas y signos característicos. Para algunos autores, el ECM puede tratarse con éxito a base de tetraciclinas, macrólidos o minocycline.^22,50,51 Los tratamientos experimentales más recientes incluyen a antibióticos como clarithromycin⁵² con buenos resultados en hámsters; y vancomycin, un glicopéptido efectivo en ensayos in vitro.⁵³ Existen reportes que recomiendan no emplear roxitrthromycin por su poca eficacia contra las manifestaciones de la enfermedad.⁵⁴ Los esquemas de tratamiento antimicrobiano que proponemos utilizar se sintetizan en las tablas 2 y 3.

SUMMARY

A review on the available scientific evidence on Lyme borreliosis was made taking into account the present importance of this disease due to its wide distribution worldwide, its severe sequelae for human health, and the difficult prevention and control. Different aspects of this disease were approached placing emphasis on the epidemiology, clinical aspects, diagnosis, and others, in the light of the current knowledge about the subject. It was evidenced that there is no agreement yet about the diagnosis and the antibiotic treatment that should be used, while regarding its prevention and control, health education as well as to avoid infested areas seem to be the most important and recommended measures until effective vaccines are available. Subject headings: LYME DISEASE/epidemiology; LYME DISEASE/etiology; LYME DISEASE/diagnosis; LYME DISEASE/prevention & control; LYME DISEASE/drug therapy.

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20. Anderson JF. Epizootiology of Lyme borreliosis. Scand J Infect Dis Suppl 1991;77:23-34.
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24. Comstock LE, Thomas DD. Penetration of endothelial cell monolayers by Borrelia burgdorferi. Infect Immun 1989;57:1626-8.
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26. Hinderson P, Thomas D, Stamm L, Penn C, Norris S, Joens LA, Interaction of spirochetes with the host. Res Microbiol 1992;143(6):629-39.
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28. Lawrence SJ. Lyme disease: an orthopedic perspective. Orthopedics 1992;15(11):1331-5.
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32. Belman AL, Coyle PK, Roque C, Cantos E. MRI findings in children infected by Borrelia burgdorferi. Pediatr Neurol 1992;8(6):428-31.
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34. Schned ES, Williams DN. Special concerns in Lyme disease: seropositivity with vague symptoms and development of fibrositis. Postgrad Med 1992;91(7):65-70.
35. Banyas GT. Difficulties with Lyme serology. J Am Otom Assoc 1992;63(2):135-9.
36. Bakken LL, Case KL, Callister SM, Bourdeau NJ, Schell RF. Performance of 45 laboratory participation in a proficiency testing program for Lyme disease serology. JAMA 1992;268(7):891-5.
37. Zoller L, Cremer J, Fauide M. Westernblotting as a tool in the diagnosis of Lyme borreliosis. Electrophoresis 1993;14(9):937-44.
38. Melski JW, Reed KD, Mitchell PD, Barth GD. Primary and secundary erythema migrans in central Wisconsin. Arch Dermatol 1993;129(6):709-16.
39. Schutzer SE, Schwartz RA. Diagnosing Lyme disease: often simple, often difficult. Cutis 1991;47(4):229-32.
40. Ginsberg HS. Transmission risk of Lyme disease and implications for tick management. Am J Epidemiol 1993;138(1):65-73.
41. Couch P, Johnson CE. Prevention of Lyme disease. Am J Hosp Pharm 1992;49(5):1164-73.
42. Edelman R. Perspective on the development of vaccines against Lyme disease. Vaccine 1991;9(8):531-2.
43. Simon MM, Mildward F, Lefebvre R, Schools L, Frikig E, Wasmoen T, et al. Spirochete: vaccine animal models and diagnostics. Res Microbiol 1992;143(6):641-7.
44. Niksic S. Therapy of Lyme disease. Glas Srp Akad Nauka Med 1993;43:271-5.
45. Philipson A. Antibiotic treatment in Lyme borreliosis. Scand J Inf Dis Suppl 1991;77:145-50.
46. Hercogova J, Tomankova M, Batak P. Contributions to the treatment of dermatologic manifestations of Lyme borreliosis. Cutis 1992;49(6):409-11.
47. Bemasconi E, Nadal D, Vogt H. Suspected Lyme borreliosis: how to diagnose, whom to treat? Ther Umsch 1992;49(4):257-62.
48. Pachner AR. The new great imitator. Ann NY Acad Sci 1988;539:58-64.
49. Magid D, Schwartz B, Craft J, Schwartz JS. Prevention of Lyme disease after tick bites. A cost effectiveness analysis. N Engl J Med 1992;327(8):534-41.
50. Liegner KB, Shapiro JR, Ramsay D, Halperin AJ, Hogrefe W, Kong L. Recurrent erythema migrans despite extended antibiotic treatment with minocycline in a patient with persisting Borrelia burgdorferi infectin. J Am Acad Dermatol 1993;28:312-4.
51. Peters DH, Friedel HA, Mc Tavish D. Azithromycin. A review of its antimicrobiologic activity. Drugs 1992;44(5):750-99.
52. Alder J, Mitten M, Jarvis K, Gupta P, Clement J. Efficacy of clarithromycin for treatment of experimental Lyme disease in vivo. Antimicrob Agents Chemother 1993;37(6):1329-33.
53. Dever LL, Ingersen JH, Barbour AG. In vitro activity of vancomycin against the spirochete Borrelia burgdorferi. Antimicrob Agents Chemother 1993;37(5):1115-21.
54. Hansen K, Hovmark K, Hovmark A, Lebech AM, Lebech K, Olsson I, et al. Roxithromycin in Lyme borreliosis: discrepant results of an in vitro and in vivo animal susceptibility study and a clinical trial in patients with erythema migrans. Acta Derm Venereo Stockh 1992;72(4):297-300.

     http://scielo.sld.cu/scielo.php?pid=S1561-30031997000200005&script=sci_arttext
Recibido: 6 de enero de 1997. Aprobado: 30 de julio de 1997.

Lyme Neuroborreliosis: Manifestations of a Rapidly Emerging Zoonosis

  Lyme disease has a worldwide distribution and is the most common vector-borne disease in the United States. Incidence, clinical manifestations, and presentations vary by geography, season, and recreational habits. Lyme neuroborreliosis (LNB) is neurologic involvement secondary to systemic infection by the spirochete Borrelia burgdorferi in the United States and by Borrelia garinii or Borrelia afzelii species in Europe. Enhanced awareness of the clinical presentation of Lyme disease allows inclusion of LNB in the imaging differential diagnosis of facial neuritis, multiple enhancing cranial nerves, enhancing noncompressive radiculitis, and pediatric leptomeningitis with white matter hyperintensities on MR imaging. The MR imaging white matter appearance of successfully treated LNB and multiple sclerosis display sufficient similarity to suggest a common autoimmune pathogenesis for both. This review highlights differences in the epidemiology, clinical manifestations, diagnosis, and management of Lyme disease in the United States, Europe, and Asia, with an emphasis on neurologic manifestation and neuroimaging.                  

Lyme borreliosis is a tick-transmitted multisystem inflammatory disease caused by the spirochete Borrelia burgdorferi sensu stricto, in the United States and Borrelia garinii and Borrelia afzelii in Europe.^1,2 With approximately 20,000 new cases reported each year, Lyme disease has become the most common vector-borne disease in the United States.³

The Lyme disease syndrome, manifest as erythema migrans, meningopolyneuritis, and acrodermatitis chronica atrophicans, was first described in the early and mid-20th century in Europe and later recognized in the United States in Old Lyme, Connecticut, in 1976.^4,5 Lyme disease was subsequently linked to the recovery of a previously unrecognized spirochete, B. burgdorferi, which is transmitted by the bite of the Ixodes tick (Fig 1). After sustained attachment of the infected tick to the host, the spirochete is transmitted to the human host in the tick salivary secretions.^6,7

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Fig 1.

Blacklegged tick (I Scapularis): adult female, adult male, nymph, and larva. Reprinted with permission from the Centers for Disease Control and Prevention.

This review will highlight the differences in the epidemiology, clinical manifestations, diagnosis, and management of Lyme disease in the United States, Europe, and Asia. Emphasis is placed on the diagnosis and clinical spectrum of Lyme neuroborreliosis (LNB), with special attention to the varying features of corroborative diagnostic neuroimaging.

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Epidemiology and Clinical Presentation

More than 200,000 cases of Lyme disease in the United States have been reported to the Centers for Disease Control, resulting in a national incidence of 9.7 cases per 100 000 population. The prevalence of Lyme disease varies significantly by geography and has a seasonal incidence (Fig 2A, -B). More than 93% of Lyme disease cases in the United States have been reported in high endemic Midatlantic states, Michigan, and Minnesota.³ Lyme disease occurrence peaks during summer months, reflecting the enhanced transmission by the nymphal tick vectors during May and June. Since Lyme disease became nationally notifiable in 1991, the annual number of reported cases has more than doubled.³

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Fig 2.

A, Summary of reported cases of Lyme disease in the United States. There is 1 dot within the county of residence for each reported case. Note the widespread diversity of cases correlating with the prevalence of infected Ixodes species in different geographic areas. Courtesy of the Centers for Disease Control. B, The beige-shaded areas indicate the geographic distribution of recorded clinical cases of Lyme borreliosis. The colored ellipses indicate the distribution of the various Borrelia subspecies. Fig 2B is reprinted with permission from Nature Publishing Group.¹⁰⁸

Tick-borne diseases, such as Lyme disease, are dynamic and rapidly evolving in the United States, due in part to climate change.³ B. burgdorferi is a zoonosis maintained at high levels in animals, such as field mice and white-tailed deer.^8–11 Song birds and waterfowl also appear to play a major role in the dispersion of infected ticks.⁹ Borrelia species are transmitted by the bite of infected Ixodes ticks, namely Ixodes scapularis in the United States and predominantly Ixodes ricinus in Europe.^3,11–14 Transmission of B. burgdorferi requires at least 24–48 hours of tick attachment.¹⁵ Unfortunately, most adult patients do not recall the tick bite because the dominant nymphal Ixodes ticks are very small and often unrecognized when attached to the skin or may fall off after feeding.⁸

As with other spirochetal infections such as syphilis, Lyme disease occurs in stages, with a wide spectrum of clinical signs and symptoms at each stage. Incubation varies from 3 to 32 days, after which a characteristic enlarging target-like rash, known as erythema migrans (Fig 3), may be evident and accompanied by flulike symptoms of fever, headache, malaise, and myalgias (stage 1).¹⁶ After several weeks to months, neurologic abnormalities and cardiac involvement may be seen in 15% and 8% of patients, respectively (stage 2). Migrating very transitory musculoskeletal pain in limited joints, bursae, tendons, muscle, or bone is a common feature of early Lyme disease.¹⁷ Within 2–4 weeks after the onset of infection, untreated patients develop a marked cellular and humoral immune response to the spirochete. In stage 3, patients may develop chronic monoarticular or oligoarticular Lyme arthritis, which commonly involves large joints, particularly the knee.^18,19

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Fig 3.

Erythema migrans rash with the typical target appearance that is virtually diagnostic of Lyme disease.

As shown in the Table, worldwide clinical manifestations of Lyme disease vary as a function of different subspecies but invariably include systemic symptoms and involvement of the dermatologic, neurologic, cardiac, and/or musculoskeletal systems.^{1,8,14,19–21} In the United States, erythema migrans rash, arthritis, and carditis are common presentations. In Europe and Asia, radiculitis and acrodermatitis chronica atrophicans are more common presenting signs. Generalized lymphadenopathy is not a classic feature of Lyme disease, but a Borrelial lymphocytoma may develop at the site of antecedent tick bite. There is a predilection for the ear, nipple, and scrotum.²² A weak association with primary cutaneous marginal zone B-cell lymphoma has been observed in Europe.²³

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Comparison of clinical differences between American and European LNB^*

The characteristic erythema migrans rash (Fig 3) is a hallmark of the disease and manifests as an area of expanding erythema >5 cm in diameter. It is commonly raised and sometimes pruritic. This circular or elliptic red area spreads centrifugally, reflecting movement of spirochetes through lymphatics of the skin. Subsequent central clearing gives the appearance of a “target.”⁸ In some patients, there are multiple lesions, suggesting dissemination of the spirochete. The erythematous rash should not be confused with the small area of erythema around other tick bites, which reflects a host reaction to the bite. The erythema migrans rash is commonly recalled by the patient at the later time of presentation with LNB.⁸

I scapularis ticks may also transmit other infectious agents, such as Anaplasma phagocytophilum (anaplasmosis) or human granulocytic ehrlichiosis, human monocytic ehrlichiosis, Babesia microti (babesiosis), and, less commonly, Franciscella tularensis (tularemia). Southern tick-associated rash illness (STARI) and Master disease are transmitted by the lone star tick (Amblyomma americanum) in the southern United States and may have a clinical presentation similar to that of Lyme disease due to the transmitted bacterium (Borrelia lonestari).

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Diagnostic Tests for Lyme Disease

The diagnosis of Lyme disease should be based on a history of tick exposure, epidemiology, clinical signs and symptoms at different stages of the disease (Table), and the use of serologic tests. Early Lyme disease in a patient with erythema migrans is virtually 100% specific and more sensitive (57%–86%) than serology.²⁴ Adults at risk for tick-borne disease who develop persistent “summer flu” symptoms should increase the clinical suspicion of tick-borne illnesses, such as Lyme disease.

A definitive diagnosis of LNB requires evidence of possible exposure, signs and symptoms of nervous system disease, and supportive laboratory data. Because LNB frequently has clinical overlap with other medical illnesses, there are many obstacles and pitfalls to securing the diagnosis with laboratory confirmation. B burgdorferi can be identified by direct microscopy in tissue biopsies, electron microscopy, and by culture, but these methodologies are not readily available.²⁵ Polymerase chain reaction (PCR) for clinical samples has had a low sensitivity for blood and CSF in Lyme disease but has been useful on synovial fluid specimens in patients with Lyme arthritis.^8,25

Most patients with suspected Lyme disease are currently tested for evidence of antibodies against B burgdorferi. However, B burgdorferi has extremely complex antigenic composition, which may vary by host and stage of the infection. Therefore, the use of indirect methods to detect serum antibodies to B burgdorferi, based on a 2-step method by using an initial enzyme immunoassay (EIA) or an enzyme-linked immunosorbent assay or indirect florescent antibody assay, followed by confirmation of a positive or equivocal initial test by immunoblot or Western blot is commonly used.²⁵ The 2-step method has advantages, such as ease of testing, better standardization, and greater diagnostic sensitivity than PCR but lacks sensitivity in early disease.^16,24 Current standards for the diagnosis of Lyme disease include a sensitive EIA, followed by Western blot (or immunoblot) with findings of abnormal immunoglobulin M (IgM) (at least 2 bands) and immunoglobulin G (IgG) antibodies (at least 5 bands).

Patients with suspected LNB may have evidence of IgG synthesis against B burgdorferi antigens in the CSF and elevated CSF inflammatory cells (usually lymphocytes, monocytes, or plasma cells), elevated protein, Borrelia-specific intrathecal antibodies, or PCR-detectable Borrelia species antigens (in early cases of Lyme disease). CSF Lyme antibodies (IgM, IgG, and immunoglobulin A) in the absence of inflammatory cells suggest previous infection. Tests developed for the detection of Lyme disease in Europe may not detect high antibody values in infections in the United States and vice versa.¹⁶

The use of an EIA with recombinant chimeric proteins, such as the C6 peptide, appears sensitive and has been suggested for use as a single assay, rather than the current 2-tier EIA and Western blot assays. Clearly, further studies are needed to elucidate the advantages and limitations of Lyme disease testing, especially for patients at different stages of neuroborreliosis and in different countries. The use of commercial laboratories that offer Lyme diagnostic tests that have not been professionally validated should be discouraged and prohibited for clinical use.^26–28

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LNB

LNB results when systemic infection with the spirochete B burgdorferi leads to neurologic involvement.^6,8,29,30 Approximately 10%–15% of patients with untreated Lyme disease will develop neurologic manifestations.^{8,14,19,31–34} The enhanced recognition and surveillance for LNB has generated a plethora of recent outstanding clinical review manuscripts.^{8,14,16,19,31–34}

The likelihood of a person developing LNB is dependent on the Borrelia species, geography, recreational habits of the individual, and season of the year. Because the spirochetes are transmitted to human beings only by the bite of infected ticks, individuals who do not frequent endemic areas or have not been in a situation predisposing to an infected tick bite cannot have LNB.⁸ The presentation of LNB can vary from weeks to months after exposure.

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Pathology

Pachner and Steiner⁸ observed that LNB inflammation in the nervous system in rhesus macaques was primarily localized to dorsal root ganglia, nerve roots, and leptomeninges. T-lymphocytes and plasma cells were the predominant inflammatory cell markers. Significantly increased amounts of immunoglobulin (IgG, IgM) and complement (C1q) are found in inflamed spinal cords. Spirochetes can be visualized by immunohistochemistry in the leptomeninges, nerve roots, and dorsal root ganglia, but not in the central nervous system (CNS) parenchyma.⁸ This predisposition correlates well with classic clinical LNB manifested by a predominant meningitis and radiculitis and the rare presence of intra-axial parenchymal brain and spinal cord involvement.⁸

Borrelia subspecies are responsible for significant differences in the clinical presentations of LNB observed in North America and Europe. European case reports of a painful radiculitis (Garin-Bujadoux-Bannwarth syndrome) and chronic progressive spastic paraparesis suggest a greater neurotropism to B garinii, which has not been found in the United States.^35,16

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Peripheral Nervous System Manifestations

Peripheral nervous system (PNS) manifestations of LNB are variable and may range from mild-to-severe intermittent sensory symptoms to a typical constant dermatomal painful radiculitis. The latter is a prominent feature of European LNB but is less commonly recognized in the United States. Approximately 85% of European disease presents with Bannwarth syndrome, a painful lymphocytic meningoradiculitis with or without paresis. The pain is frequently sharp, may display nocturnal exacerbations, and may last weeks to months.⁸ The European presentations are further confounded by a lower incidence of recognized erythema migrans. In the absence of a compressive etiology, Bannwarth syndrome may be a unique clinical hallmark of B garinii LNB. This form of LNB is rarely seen in North American LNB.^8,36 Enhancement of spinal nerve roots has been observed on postcontrast T1-weighted sequences in the lower spinal cord and cauda equina more than in cervical cord and roots associated with a lymphocytic meningitis.³⁷

North American LNB usually presents as a subacute meningitis within weeks to months of an antecedent untreated erythema migrans rash.⁸ Unilateral more than bilateral cranial nerve palsy occurs frequently. The seventh cranial nerve is most frequently involved (Fig 4).³² Lyme disease is an infrequent cause of isolated facial palsy in patients without constitutional symptoms or additional neurologic findings. However, in endemic areas, it may be responsible for ≥25% of new-onset Bell palsy.^38,39

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Fig 4.

Facial neuritis. A 48-year-old woman with headache and peripheral right facial palsy. Prominent enhancement of the fundal tuft and labyrinthine segment of the seventh cranial nerve on postinfusion axial T1 (A) and coronal spoiled gradient-recalled sequences (B). The patient had CSF pleocytosis, Lyme-positive EIA, and Western blot (IgM and IgG) in serum and CSF. Resolution occurred with intravenous ceftriaxone therapy.

There are no neurologic or imaging findings specific for LNB. In the appropriate geographic and seasonal setting, facial diplegia is highly suggestive of LNB as is headache and facial palsy, especially when coupled with a history of erythema migrans. Because erythema migrans may be absent and is usually not present at time of the clinical presentation of neurologic symptoms, suspicion of LNB should be confirmed by serum or CSF antibodies for Borrelia species.⁸ Sarcoidosis may have a similar neurologic presentation and should be considered in the differential diagnosis.

The role of imaging in the assessment of peripheral Lyme disease is enhanced awareness of LNB in the differential diagnosis of cranial neuritis and/or radiculitis in both endemic populations and in patients with a travel history to endemic areas. To our knowledge, there are no published prospective studies citing the incidence of cranial or radicular nerve enhancement in the clinical setting of Lyme disease. Similarly, the described pattern of contrast enhancement has been restricted to case series.^18,40,41 Third, fifth, and seventh cranial nerve enhancements have all been reported (Fig 5).^42,43 We have observed enhancement predominantly of the seventh cranial nerve with combined involvement of the fundal tuft and labyrinthine and tympanic segments more than generalized fundal tuft-to-mastoid involvement. The higher incidence of meningoradiculoneuritis (Bannwarth syndrome) in Europe is characterized by specific MR imaging findings of cervical, thoracic, and lumbar nerve root contrast enhancement.^37,40,44 Of note is the frequent absence of a correlation between multiple enhancing cranial or radicular nerves and neurologic symptoms.⁴⁰

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Fig 5.

Evolving cranial neuritis. A 71-year-old woman with headache, malaise, fever, and diplopia. Initial coronal postcontrast T1 MR imaging (A and B) with enhancing bilateral third and fifth cranial nerves. C, Nine days later, she developed left facial palsy with enhancing fundal tuft and labyrinthine and tympanic segments of the seventh cranial nerve. The patient had CSF pleocytosis with positive Lyme-EIA and Western blot in both serum and CSF and CSF Lyme PCR-negative findings. Resolution occurred with intravenous ceftriaxone therapy.

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CNS LNB

Despite the significant increased awareness of LNB and emphasis directed at its diagnosis and treatment, its neuropathology is incompletely understood. Subsequent to the tick bite inoculation, Borrelia species most likely reach the CNS either hematogenously or retrogradely via the peripheral nerves.³¹ In the United States, dissemination is predominantly hematogenous, leading to meningoencephalitis.^31,45 This feature contrasts with the European variant of predominant nerve root involvement (Bannwarth syndrome), wherein dissemination of endemic B garinii and B afzelii mainly occurs through the peripheral nerves. The putative mechanisms for LNB CNS injury include vasculitis, cytotoxicity, neurotoxic mediators, or autoimmune reaction via molecular mimicry.³¹

Direct CNS symptoms vary widely, ranging from a mild confusional state to severe encephalitis. Cranial neuropathies and motor or sensory radiculoneuritis have their highest incidence in children and adolescents.⁴⁶ The intrathecal production of anti-B burgdorferi antibodies or a positive PCR are the most reliable indicators of CNS infection. The CSF typically demonstrates a lymphocytic meningitis, with increased protein and increased CSF-to-serum-antibody ratios.

Encephalomyelitis is a very rare complication of borreliosis, with a few reports of progressive and severe courses of the disease.^47–51 In most cases of encephalomyelitis, MR imaging is very helpful in assessing the presence of rare tumefactive white matter lesions that may mimic a neoplastic process.^47,48,51 Tumefactive lesion biopsies are characterized by microgliosis and spirochetes morphologically compatible with B burgdorferi yet paradoxically without an inflammatory infiltrate.^48,52–54 Very rarely, MR imaging has documented reversal of LNB encephalitis subsequent to antibiotic management.^49,55 The imaging resolution, however, lagged years behind the rapid clinical response to intravenous antibiotics.

Approximately half of the patients with LNB demonstrate nonspecific abnormal imaging findings predominantly within the frontal cortex white matter arcuate fibers.^53,56 Despite successful clinical resolution with antibiotic management, white matter involvement often persists on MR imaging (Fig 6).⁴⁶

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Fig 6.

A 50-year-old woman with a history of tick bite and erythema migrans rash treated with doxycycline, who had recurrent erythema migrans rash with headache, fever, nausea, and nuchal rigidity. The patient had CSF pleocytosis with positive Lyme serum EIA and IgM Western blot and negative Lyme antibodies in the CSF. Gradual symptomatic improvement occurred following intravenous ceftriaxone therapy. There has been stable MR imaging for 5 years. Sagittal (A and B) and axial (C) fluid-attenuated inversion recovery images show arcuate and confluent subcortical white matter involvement and callososeptal interface involvement remarkably similar to that in MS, but without involvement of the periventricular white matter.

The distribution of involvement including the callososeptal interface fuels speculation as to a secondary autoimmune mechanism with imaging features mimicking primary demyelinating disease (Fig 7).^{40,46,48,57–65} Similar mechanisms of molecular mimicry and antigen-specific T-cell response have been recognized in both multiple sclerosis (MS) and chronic LNB.⁶⁶ Yet, T-cell lines demonstrate only weak cross-reactivity between myelin basic protein and B burgdorferi.⁶⁷

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Fig 7.

A 74-year-old man with 2-year cognitive decline and memory loss. The patient had Lyme-positive serum EIA and Western blot (IgG and IgM) and CSF pleocytosis with CSF positive Lyme IgM and IgG antibodies. The patient improved with intravenous ceftriaxone therapy. The “dot-dash” callososeptal interface (A) and periventricular distribution of involvement (B) would be routinely ascribed to a demyelinating process.

Unlike MS, occult brain and cervical cord pathology in normal-appearing white matter, as assessed by magnetization transfer ratios and diffusion tensor imaging, are infrequent findings in patients with LNB.⁵⁸ A classic clinical presentation with exposure history, meningitis, CSF pleocytosis, and elevated Lyme disease antibody titers aids in discrimination from MS. However, when the characteristic prodrome of erythema migrans, exposure history, or arthritis is lacking, the multifocal clinical findings on neurologic examination and positive oligoclonal bands and white matter patterns on MR imaging may confuse the diagnosis with that of MS.^57,63

Borrelia species are very difficult to culture as exemplified by individual case reports of rare strokelike presentations, wherein brain biopsies merely demonstrated a nonspecific perivascular or vasculitic lymphocytic inflammation.⁴⁸ In the appropriate clinical and geographic setting, rare instances of LNB vasculitis with ischemic stroke, subarachnoid hemorrhage, and intracerebral hemorrhage have been reported.^48,68–75 Single-photon emission CT may provide indirect manifestations of LNB antibiotic-reversible frontal hypoperfusion.^65,76,77

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Spinal Cord LNB

Spinal cord involvement by B burgdorferi is very rare. As a function of geography, LNB would be a rare differential consideration in the evaluation of transverse myelitis. MR imaging findings with LNB myelopathy are characterized by diffuse or multifocal T2-weighted cord lesions. In contrast to the classic cervical spinal cord MR imaging abnormalities seen in MS, most patients with LNB do not have macroscopic lesions or magnetization-transfer ratio changes.⁵⁸ Nerve root involvement is best seen on postcontrast T1-weighted sequences.⁴⁰ Spinal involvement has demonstrated diffuse or multifocal T2-weighted cord lesions and nerve root enhancement on postcontrast T1-weighted sequences (Fig 8).⁴⁰

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Fig 8.

A 56-year-old woman with neck, bilateral shoulder, and bilateral arm pain. In 2 weeks, she subsequently developed left facial palsy and positive serum EIA and Western blot (IgM and IgG) and CSF Lyme IgG and IgM antibodies. Complete resolution of symptoms occurred with oral doxycycline. Postcontrast sagittal and axial T1-weighted MR images show diffuse thin uniform cervical spinal cord leptomeningeal enhancement without apparent root or ganglion enhancement.

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Orbital and Ocular Lyme Disease

Rare ocular LNB may occur at all 3 stages of the disease. Uveitis and optic neuritis are the most common ocular complications.⁷⁸ Conjunctivitis and episcleritis are the most frequent manifestations of the early stage. Neuro-ophthalmic disorders and uveitis occur in the second stage, whereas keratitis, chronic intraocular inflammation, and orbital myositis are seen in the third stage of Lyme disease.⁷⁹ A nonspecific follicular conjunctivitis occurs in approximately 10% of patients with Lyme disease.³⁹ Direct ocular infection and a delayed hypersensitivity mechanism may be involved at different disease stages.

Borrelial orbital myositis is most probably an immunologically mediated response subsequent to hematogenous dissemination of Borrelia species.⁸⁰ The clinical and imaging manifestations of orbital myositis Lyme disease closely mimic those of orbital pseudotumor (Fig 9). The differential diagnosis includes lymphoma or possibly thyroid dysorbitopathy. Criteria for orbital and ocular Lyme disease include the lack of evidence of other diseases, occurrence in patients living in an endemic area, positive serology, and, in most cases, response to treatment.³⁹

View larger versión Fig 9.                        

A 17-year-old boy with right papilledema and orbital pain and rule out pseudotumor. The patient had positive serum EIA and Western blot (IgM and IgG) and CSF Lyme IgM and IgG antibodies. Lyme PCR in the CSF was negative. Complete resolution of symptoms occurred after intravenous ceftriaxone therapy. Right optic nerve edema on fat-saturated T2-weighted fast spin-echo images (A) and right-greater-than-left optic nerve enhancement on coronal fat-saturated contrast-enhanced T1-weighted images (B). C, Bilateral third cranial nerve enhancement (arrowheads) and bilateral retrobulbar compartment congestion (arrow). Note the generalized extraocular muscle enlargement and enhancement, including the insertions. Additional imaging findings included enhancement of right fifth cranial nerve, optic chiasm, and intracanalicular right seventh nerve, all of which were occult to neurologic examination.

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Pediatric LNB

Thirty percent of Lyme disease cases occur in children.³ The presence of erythema migrans in 89% of children significantly aids the clinical diagnosis.⁸¹ It is speculated that the CNS lesions in children represent a spirochete-triggered autoimmune process.⁸² Headache is the most frequent neurologic symptom; the most common neurologic signs of pediatric LNB include facial nerve palsy (3%–5%) and meningitis (1%). Less common manifestations are sleep disturbance and papilledema associated with increased intracranial pressure.^83,84 Ataxia, chorea, myelitis, pseudotumor cerebri, meningitis, and encephalopathy are very uncommon.^84–90 Peripheral neuropathies, radiculopathies, and Bannwarth syndrome are other rare pediatric LNB manifestations.

Brain MR imaging findings in pediatric LNB include the presence of prominent Virchow-Robin spaces, T2 bright white matter lesions, pial and cranial nerve enhancement, and treatment-responsive lesion enhancement.^18,82

Despite having a greater incidence of LNB, the clinical course in most children is milder and shorter than that reported for adults.⁸⁹ Facial nerve palsy resolves in 95% of pediatric patients irrespective of treatment.⁹⁰ The use of doxycycline for the primary therapy of Lyme disease is restricted due to side effects in this population of patients.

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Chronic Lyme Disease

The clinical presence of a chronic form of neuroborreliosis subsequent to classic verified objective manifestations and rigorous antibiotic management remains a focus of ongoing conjecture and controversy.^{34,46,91–96} The inflammatory reaction of neuroborreliosis is postulated by some to be one of the etiologies for a very broad spectrum of neurologic disorders. These include the amyloid deposition of Alzheimer disease, MS, autism, and neuropsychiatric illness.^{65,95,97–106} The diagnosis of chronic LNB is predicated on characteristic symptoms, specific serum antibodies, CSF pleocytosis, and intrathecal Lyme antibody production. The utility of brain MR imaging in confirming diagnostic suspicion of chronic LNB is very limited, due to the overlap with age-related basal ganglionic and subcortical white matter lesions and persistence subsequent to successful treatment of LNB. Conversely, LNB is a diagnostic consideration in a young patient with subependymal white matter lesions, a history of geographic/seasonal risk factors, and neurologic symptoms.¹⁰⁷

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Conclusions

LNB is an insidious infectious neurologic disease caused by the spirochete B burgdorferi. The mechanism of neurologic injury probably includes vasculitis, cytotoxicity, neurotoxic mediators, or autoimmune reaction via molecular mimicry. Although there are no neurologic or imaging findings specific for the diagnosis of LNB, an enhanced level of surveillance is required as a function of geography, recreational/travel history of the patient, and season of the year. In the at-risk patient population, LNB should be included in the imaging differential diagnosis of facial neuritis, multiple enhancing cranial nerves, enhancing noncompressive radiculitis, pediatric leptomeningitis with white matter hyperintensities, and symmetric orbital myositis with cranial neuritis. There is an overlap in the CNS MR imaging appearance of LNB and MS; however, unlike MS, cervical cord pathology and occult brain involvement in normal-appearing white matter are infrequent findings in patients with LNB. Further refinements and ongoing research in serum and CSF serologic tests will be required for better detection of active acute and chronic manifestations of Lyme disease.

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