An 11-year-old previously healthy, fully vaccinated female, was admitted to the hospital at end of October with 8 weeks of bilateral hip pain, left lower extremity weakness and abnormal gait. The family reported visiting a lake house in east Texas on July 4th. Three days after the trip, she noted a circular “bull’s eye” rash over the left medial posterior knee. She denied any tick, flea or other insect bites. She was treated for presumed cellulitis with a 10-day course of cephalexin and topical mupirocin. The rash eventually resolved with topical steroids. In early August, she developed myalgias of both lower extremities followed by bilateral hip pain. Due to persistent pain, a contrast magnetic resonance imaging (MRI) of the hips was performed in early September, which was unremarkable. In mid-September, Lyme screening antibody (Ab) test (enzyme immunoassay) was positive (>12 with reference positive being >1.09) but the confirmatory Western immunoblot showed negative IGM for all 3 bands and positive IGG for 2/10 bands (+ for 18 kDa and 41 kDa) which did not meet Center for Disease Control and Prevention (CDC) criteria for diagnosis of Lyme borreliosis (LB).1,2 Ten days prior to admission (end of October), she developed low back pain and progressive left leg weakness with gait disturbance. A contrast MRI of the lumbar spine revealed florid enhancement of the ventral greater than dorsal lumbar nerve roots, the distal cord and conus, and she was admitted to the hospital for further management.
Infectious diseases and neurology were consulted. Her travel history was remarkable for living in Budapest, Hungary, for 2 years prior to returning to the United States in late June. Her review of systems was negative. She denied any other exposures except for having a pet dog who routinely received tick/flea medications. On further questioning, the patient vaguely recalled removing a tick from her left foot, a week before returning to the United States.
On examination, she was well appearing but in mild distress due to left thigh pain. Her vital signs were stable. Her neurologic examination was remarkable for moderate weakness of left lower extremity with reduced strength. Deep tendon reflexes and sensations were normal. There was a faint targetoid rash over the left posterior knee.
Her white blood cell count was 4.8 × 103/µL (59% neutrophils and 35% lymphocytes); platelets and hemoglobin were within normal limits. The C-reactive protein was < 0.5 mg/dL and erythrocyte sedimentation rate 6 mm/h. MRI of the brain and complete spine showed enhancement of the ventral greater than dorsal nerve roots extending from the T10-11 level to the conus. There was also enhancement of the right trigeminal nerve (Fig. 1A and 1B). There was no parenchymal brain involvement.
Cerebrospinal fluid (CSF) analysis revealed 59 white blood cells/mm3 (with predominant lymphocytosis), protein 321 mg/dL and glucose 47 mg/dL. The opening pressure was 16 cmH2O. Cytologic analysis was negative for malignancy. The CSF IgG and oligoclonal bands were increased. CSF bacterial cultures and bacterial polymerase chain reaction (PCR) were negative. CSF PCR studies were negative for herpes simplex virus 1/2, cytomegalovirus, varicella-zoster virus, Epstein-Barr virus, human herpes virus 6, enterovirus, West Nile and Borrelia spp. CSF West Nile IgG/IgM were negative as were serum arboviral Ab. Both serum and CSF Borrelia Western immunoblot was positive for 3/3 IGM bands (41, 39, 23 kDa) and 9/10 IGG bands (93, 66, 58, 45, 41, 39, 28, 23, 18 kDa) and was positive per CDC criteria.1,2 A C6 enzyme-linked immunosorbent assay serum Ab test also was positive. The CSF: serum Ab index could not be performed due to lack of CSF fluid. Plasma metagenomic next-generation sequencing (mNGS) for pathogens detected low levels of DNA sequencing reads for Borrelia afzelii.
The patient was diagnosed with Lyme neuroborreliosis (LNB) and treated with a 4-week course of intravenous (IV) ceftriaxone. She had complete resolution of her symptoms at the end of the course. At a 2-month follow-up visit, she was back in school without any residual pain or weakness.
We present a pediatric case of BWS, initially described by Garin, Bujadeux and Bannwarth with a classic triad of painful radiculopathy, cranial neuritis and CSF lymphocytic pleocytosis, seen in early LNB.3,4 LB is a tick-borne illness caused by the spirochete B. burgdorferi sensu lato complex. In the United States, the causative agent of LB is B. burgdorferi sensu stricto with the endemic regions being the upper Midwestern and northeastern United States. Ixodes scapularis is the most frequent vector in the United States. In Europe, the causative agents are primarily Borrelia garinii or B. afzelii with the predominant vector being Ixodes ricinus.
LNB occurs in 10%-15% of patients infected with LB in both Europe and the United States.3 Facial nerve palsy (FNP) with or without lymphocytic meningitis is the most common presentation in children.5,6 Erythema migrans (EM) is present in 13%–16% of European children presenting with LNB.7,8 LNB was shown to be present in 12.5% of patients in the United States with confirmed LB in a surveillance data from the CDC.9 One-fourth of the reported cases of LB occurred in children less than 14 years of age. LB, including LNB, had a bimodal peak being highest among children 5–9 years and the 50–55 years age group.9 In a pediatric study (n = 201) done in the United States, majority presented with either a single EM (66%) or multiple EM (23%), or arthritis (6%).10 FNP was present in 3% and aseptic meningitis in 2% of cases.10
Benign intracranial hypertension has also been reported in children with LNB.3 BWS has been rarely reported in children, hence the true incidence is unknown. One Polish study (Table 1) reported an incidence of 10.5% in children in that geographic area but was less common than adults (36%).11Table 1 lists the pediatric studies and case reports of BWS or if “radiculopathy” was one of the presenting symptoms.7,11–17 BWS have not been reported in other pediatric studies.6–10,18 In a study of 77 adults with BWS in Europe, the most frequent signs and symptoms included radicular pain (100%), EM (59.7%), headache (46.8%), fatigue (44.2%), malaise (39%), paresthesias (32.5%), FNP (36.4%), meningeal signs (19.5%) and paresis (7.8%).19 CSF analyses in these patients revealed pleocytosis with a lymphocytic or monocytic predominance, elevated CSF protein concentration, increased CSF anti-Borrelial IgM/IGG levels.19 The median duration of illness at presentation in this adult cohort was 30 days (interquartile range of 14–60 days). Except for one study from the United States which described a cluster of 5 adult patients presenting with BWS, there is a paucity of data about this syndrome in the United States.20 In this study, all patients had a recent exposure to ticks but only 2 had EM. All presented with lower back pain, lower extremity paresthesia and weakness.20 All patients except one showed CSF lymphocytic pleocytosis, and all had positive serum and CSF LB Ab.20 It is possible that B. burgdorferi sensu stricto may be less likely to cause BWS than B. afzelii/garinii especially in children. However, under-recognition of this condition in children might also have contributed to the sparse reporting in the United States.
TABLE 1. -
Studies of Confirmed or Suspected Pediatric BWS
|Oymar et al15/2008 (N = 143)
|CN VII palsy
|Knudtzen et al 17/2017 (N = 126)
||Not specified for children
|Gordillo-Perez et al 14/2018 (N = 71)
||CN VII palsy*
|Rozic7/2019 (N = 153)
|Facial nerve palsy
|Krawczuk et al11/2020 (N = 57)
||Third generation cephalosporin-approx 21 d, max 30 d
|CN VII palsy
|Triad of BWS
|Baumann et al12/2009 (N = 1), CR
||Triad of BWS (CN affected: not mentioned)
|Walker et al16/2010 (N = 1), CR
||United States (Ohio)
||Triad of BWS (CN affected: CN VI)
|Doxycycline PO-16 d
|Makhani et al18/2011 (N = 1), CR
||Triad of BWS (CN affected: CN VII)
|Ewers et al13/2014 (N = 1), CR
||United States (Philadelphia)
||Triad of BWS (CN affected: CNs III, V, VII, VIII, and X)
*Most common presentation.
Approx indicates approximately; CN, cranial nerve; CR, case report; d, days; Max: maximum; N/A, not applicable; PO, per oral.
In the United States, the diagnosis of LNB is dependent on clinical presentation and epidemiology consistent with LB, diagnostic imaging studies and laboratory data. Serologic testing on LB has greatly improved with the adoption of the 2-tier testing as recommended by the CDC.1,2,9,21 The Infectious Diseases Society of America (IDSA) and the European Federation of Neurological Sciences guidelines recommend LB Ab testing and CSF cell count and chemistries but not PCR or culture of either the CSF or serum.22,23 Additionally, it is recommended to obtain simultaneous samples of CSF and serum for determination of LB Ab: serum Ab index.22,23 Intrathecal Ab production in conjunction with an elevated CSF: serum Ab index is very specific for LNB. Branda et al24 recently reported their experience using plasma mNGS in the diagnosis of early LB specifically in laboratory-confirmed EM. When Borrelia burgdorferi cell-free DNA detection was combined with the modified 2-tier LB testing, it increased the diagnostic sensitivity to 86%, which was significantly higher than either approach alone.24 However, whether this can be applicable to patients with LNB is not known and more studies are needed to investigate the utility of plasma mNGS in BWS. In our patient, given the low endemicity of LB in Texas, plasma mNGS helped identify the LB species and further supported our suspicion for LNB imported from Europe. The presence of oligoclonal bands indicating intrathecal IgG synthesis has been observed in other studies with LNB and was also present in our patient.25 Although MRI is not considered diagnostic of LNB or BWS, it does reveal abnormalities including leptomeningeal enhancement, cranial neuritis, myelitis, encephalitis and importantly helps exclude other causes of radiculopathy.26
The IDSA and European Federation of Neurological Sciences guidelines recommend that patients with LNB and any peripheral nervous system involvement be treated with oral doxycycline or intravenous ceftriaxone, cefotaxime or penicillin G.22,23 In the absence of any brain parenchymal disease, a 14-day course of oral doxycycline is as effective as IV ceftriaxone.22,23 Treatment of LNB in the United States is extrapolated from European studies, especially in children. Currently, the IDSA recommends a 2–4-week course of IV antibiotics in patients with central nervous system involvement.22 We treated our patient for 4 weeks with IV ceftriaxone, given the lack of data in pediatric LNB. We do acknowledge, however, that a shorter course with oral doxycycline would have been equally effective.
BWS is a rare clinical manifestation of LNB in children but should be suspected when the triad of painful radiculopathy, cranial neuropathy and lymphocytic pleocytosis are present in a patient with recent or suspected tick bite in a LB-endemic region. Diagnostic imaging serum and CSF LB IgM/IgG and CSF: serum Ab index aid in the diagnosis of LNB. Plasma mNGS may provide additional insight on the species of LB causing infection.
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