Article Text

Lyme neuroborreliosis: a treatable cause of acute ocular motor disturbances in children
  1. M H Correll1,2,
  2. N Datta2,
  3. H S S Arvidsson1,
  4. H A Melsom1,
  5. A K Thielberg3,
  6. M Bjerager3,
  7. M C Brodsky4,
  8. J P Saunte1,2
  1. 1Department of Ophthalmology, Nordsjællands Hospital Hillerød, Hillerød, Denmark
  2. 2Department of Ophthalmology, Copenhagen University Hospital Glostrup, Glostrup, Denmark
  3. 3Department of Pediatrics, Nordsjællands Hospital Hillerød, Hillerød, Denmark
  4. 4Departments of Ophthalmology and Neurology, Mayo Clinic, Rochester, Minnesota, USA
  1. Correspondence to Dr Jon Peiter Saunte, Ophthalmology Dept., Copenhagen University Hospital Glostrup, Region H, Nordre Ringvej 57, Glostrup DK—2600, Denmark; jonpeiter{at}saunte.com

Abstract

Background Lyme neuroborreliosis (LNB) designates central nervous system involvement caused by the tick-borne spirochaete Borrelia burgdorferi (Bb). The present study describes a spectrum of acquired ocular motor disorders in children with LNB.

Methods Six paediatric patients (age 3–15 years) with ocular motor symptoms as first manifestations of LNB evaluated by a paediatrician and ophthalmologist are presented. Diagnosis was based on new onset ocular motor disturbances and detection of cerebrospinal fluid (CSF) pleocytosis and intrathecal synthesis of Bb IgM and/or IgG antibodies by lumbar puncture. The children were evaluated before and after antibiotic treatment with a follow-up time of 1–7 months. Videos were obtained both pre and post treatment in four patients.

Results Two children presented with acquired nystagmus, one with combined nystagmus and partial sixth nerve palsy, one with partial sixth nerve palsy, one with ptosis and one with Adie’s pupil. Five of the patients presented with severe fatigue, malaise, nausea, headache and fever. Four had recognised a tick bite recently, and two developed erythema migrans. Intrathecal synthesis of IgM and/or IgG antibodies specific for Bb was positive in all children, and five showed CSF pleocytosis. Cerebral MRI or CT of the brain were normal. Treatment with intravenous or oral antibiotics produced rapid clinical improvement in five of the six children.

Conclusions LNB can present as acute ocular motor disorders in conjunction with fatigue and other clinical manifestations. In endemic areas, children with unexplained, acquired ocular motor abnormalities should be evaluated for LNB, a treatable medical condition.

  • Child health (paediatrics)
  • Infection
  • Muscles
  • Pupil

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Introduction

Lyme neuroborreliosis (LNB), a disseminated form of tick-borne Lyme disease, is caused by the spirochaete Borrelia burgdorferi sensu lato (Bb) species. It occurs only in a temperate climate zone, with local variation in incidence and clinical presentation, depending on the specific Bb species. In Europe, where B afzelii and the neurotropic B garinii are predominant, B afzelii is associated with skin manifestations, while in North America, Borrelia burgdorferi sensu stricto is associated with arthritis.1 In Denmark, the annual incidence of LNB is three cases in 100 000 inhabitants.2–4 Seasonal variation is seen with peak incidence from June to October.2 The highest incidence is among children 1–14 years old (40% of LNB cases) and adults 50–59 years old (18% of LNB cases).3 LNB can present with a variety of neurological symptoms as acute peripheral facial palsy or meningitis, especially in children.5 More rarely, cerebral or cerebellar involvement may result in opsoclonus-myoclonus,6 ocular flutter,7 internuclear ophthalmoplegia8 or tonic pupil.9 ,10

LNB is diagnosed when two of the three following clinical criteria are fulfilled: neurological symptoms, cerebrospinal fluid (CSF) pleocytosis and intrathecal Bb-specific antibody synthesis.11 Intrathecal antibody synthesis is identified when analysis of the CSF and serum reveals a positive CSF/serum antibody index (AI): either Bb-specific immunoglobulin M (IgM) AI or Bb-specific IgG AI. We evaluted six children who displayed acute ocular motor system disturbances as the presenting clinical sign of LNB.

Methods

Six paediatric patients (age 3–15 years, four boys, two girls) presenting with neuro-ophthalmological symptoms to one hospital (Nordsjællands Hospital Hillerød, Denmark) during a 3-year period are evaluated retrospectively. Epidemiological data, exposure to tick bites, duration of symptoms, clinical findings, laboratory data, treatment profile and outcomes are reported. The laboratory testing for Bb-specific antibodies on capture ELISA was performed using an in-house kit (Statens Serum Institute, Artillerivej 5, 2300 Copenhagen, Denmark) based on flagellin protein from B. afzelii strain DK1 as antigen. In accordance with European guidelines, no confirmatory immunoblot assays were performed.11 MRI of the brain was obtained in three patients and CT scanning of the brain was obtained in one patient. All procedures and collection of data were conducted in a manner compliant with Danish Data Protection Agency (Datatilsynet:approval 2013–41-2491), and conformed to local laws and principles of the Declaration of Helsinki.

Results

Clinical presentation, symptoms, CSF and serology testing, neuroimaging data and outcomes are presented for six paediatric patients with acquired LNB.

Case 1: sixth nerve palsy combined with horizontal nystagmus

An 8-year-old boy presented with horizontal diplopia in left gaze 6 weeks after removal of three ticks from his neck where an erythema had been observed (table 1). He denied symptoms of vertigo, imbalance or oscillopsia. Clinical evaluation revealed a left partial sixth nerve palsy with mild abduction deficit of the left eye. He was orthotropic at near and distance in primary position, but developed a small angle esotropia in left gaze. A conjugate left-beating nystagmus was noted on left gaze (see online supplementary video 1). The visual acuity was 20/20 in both eyes. There was no afferent pupillary defect (APD). Slit lamp biomicroscopy and optic disc and retinal examination by indirect ophthalmoscopy disclosed no abnormalities. Neurological examination showed no focal deficits. CSF antibody (ELISA) and PCR testing for herpes simplex virus (HSV) DNA and varicella zoster virus (VZV) DNA were negative. Lumbar puncture revealed CSF pleocytosis with mononuclear leucocyte count of 232×106/L and intrathecal synthesis of Bb-specific IgM (AI 1.8) and Bb-specific IgG (AI 41.9). He was diagnosed with early LNB, and intravenous antibiotic treatment with cephalosporine was initiated (table 2). His diplopia, abduction deficit and nystagmus gradually resolved over the following 2 weeks (see online supplementary video 2).

Table 1

Demographic data, symptoms and ocular findings

Table 2

Laboratory results, treatment profile and outcome

Case 2: horizontal nystagmus

A 15-year-old boy was admitted to hospital after 4 days of oscillopsia, nausea, vertigo and headache. The patient experienced a tick bite on the scrotum without subsequent erythema 4 months before the onset of symptoms (table 1). He presented with horizontal nystagmus in primary position which stayed horizontal in downgaze and upgaze, with higher amplitude on left gaze, explaining his left headturn (see online supplementary video 3). The visual acuity was 20/20 in both eyes. There was no APD and neurological examination showed no focal deficits. Slit lamp biomicroscopy and optic disc and retinal examination by indirect ophthalmoscopy disclosed no abnormalities. Lumbar puncture showed CSF pleocytosis with mononuclear leucocyte count of 250×106/L and intrathecal synthesis of Bb-specific IgM (AI 1.0) and Bb-specific IgG (AI 25.0) (table 2). MRI of the brain disclosed no abnormalities. CSF antibody (ELISA) and DNA (PCR) testing for HSV and VZV were negative. He was diagnosed with early LNB, and intravenous cephalosporine was initiated. Over the following 3 days, his nystagmus gradually decreased. Three months later he was asymptomatic but retained a mild horizontal nystagmus (see online supplementary video 4).

Case 3: sixth nerve palsy

A 15-year-old boy presented with horizontal diplopia during 10 days (table 1). Six weeks prior to hospital admission, he had discovered a tick bite on the left shoulder without subsequent erythema. He had a moderate abduction limitation in the right eye and a right headturn (see online supplementary video 5). In primary position, prism and alternate cover testing showed 30 PD esotropia at distance and 10 PD esophoria at near. Visual acuity was 20/20 in each eye and no APD was found. MRI of the brain, slit lamp biomicroscopy and optic disc and retinal examination by indirect ophthalmoscopy disclosed no abnormalities. CSF antibody (ELISA) and DNA (PCR) testing for HSV and VZV were negative. Antibodies against Bb were detected in serum, and analysis of CSF showed intrathecal synthesis of Bb-specific IgG (AI 3.0) and CSF pleocytosis as well as a mononuclear leucocyte count of 34×106/L (table 2). He was diagnosed with early LNB and treated with oral doxycycline for 14 days. Two months later, the patient presented no symptoms of diplopia, with full abduction of both eyes, and was found orthotropic in primary position.

Case 4: horizontal nystagmus

A 7-year-old boy presented with fever, headache, neck pain, nausea, fatigue and acquired horizontal nystagmus (table 1). He had left-beating nystagmus which increased on left gaze and decreased on right gaze, and maintained a left compensatory headturn (see online supplementary video 6). At a previous ophthalmological examination at the age of 4 years, he had bilateral astigmatism and meridional amblyopia with best corrected visual acuity of 20/40 in each eye. However, no binocular misalignment had been detected. At actual presentation, cycloplegic refraction revealed untreated refractive error of OD: +1.0 sphere cc +3.5 cylinder at 115°, OS: +0.75 sphere cc +2.0 cylinder at 97°. His best corrected visual acuity was 20/40 in both eyes. Pupillary responses were normal with no APD. Slit lamp biomicroscopy and optic disc and retinal examination by indirect ophthalmoscopy disclosed no abnormalities. Symptoms of fatigue, headache and nausea increased during the following days. Neurological examination showed no focal deficits. Lumbar puncture showed CSF pleocytosis with mononuclear leucocyte count of 396×106/L and intrathecal synthesis of Bb-specific IgM (AI 10.0) and Bb-specific IgG (AI 27.8) (table 2). CSF antibody (ELISA) and DNA (PCR) testing for HSV and VZV were negative. He was diagnosed with early LNB, and treated with intravenous cephalosporine. The nystagmus dampened the next day, the fatigue improved within 3 days, and the other symptoms resolved after 10 days. The visual acuity remained unchanged and 7 months later the nystagmus had resolved (see online supplementary video 7).

Case 5: partial third nerve palsy

A 3-year-old girl was treated for 2 weeks with 1% fucidin acid eyedrops by the general physician for a red, swollen upper right eyelid. No trauma was reported. The parents suspected a tick bite on the eyelid, but no tick had been identified. The redness and swelling diminished gradually, but right upper eyelid ptosis developed and she was admitted to hospital. At presentation 39 days after onset of symptoms, the parents reported increasing fatigue and nausea. The child had been sleeping several hours in the middle of the day during the previous week (table 1). On examination, a right upper eyelid ptosis was noted. She was able to follow optokinetic targets and had normal pupillary response to light with no APD. Ocular rotations were full with no signs of aberrant regeneration. Slit lamp biomicroscopy and optic disc and retinal examination by indirect ophthalmoscopy disclosed no abnormalities. Lumbar puncture revealed CSF pleocytosis with mononuclear leucocyte count of 75 x106/L and intrathecal synthesis of Bb-specific IgM (AI 41.9) and Bb-specific IgG (AI 70.8). CSF antibody (ELISA) and DNA (PCR) testing for HSV and VZV were negative. She was diagnosed with early LNB, and the day after initiation of intravenous antibiotic treatment with cephalosporine her lassitude resolved. The ptosis resolved after ten days of treatment (table 2).

Case 6: unilateral tonic pupil

A 4-year-old girl presented with an acquired anisocoria, present for approximately 3 months. The only symptom was mild photophobia (table 1). The dilated left pupil was poorly reactive to light (figure 1) and showed a sustained contraction in convergence (light-near dissociation) with slow redilatation. On slitlamp biomicroscopy, a left partial iridoplegia and vermiform pupil movements to intense light was noted. Indirect ophthalmoscopy of the optic disc and retinal examination disclosed no further abnormalities. Bilateral instillation of diluted pilocarpine 0.125% resulted in left pupillary miosis, confirming the diagnosis of left Adie’s tonic pupil (figure 2). Visual acuity was 20/20 in both eyes. General examination revealed left ankle areflexia. MRI of the brain disclosed no abnormalities. CSF antibody (ELISA) and DNA (PCR) testing for HSV and VZV were negative. Lumbar puncture revealed intrathecal synthesis of Bb-specific IgG (AI 5.0), but no pleocytosis (table 2). She was diagnosed with Adie’s pupil, possibly due to LNB, and treated with 10 days of intravenous cephalosporine, but without improvement in the pupillary function during 6 months of follow-up.

Figure 1

Case 6. Adie’s syndrome: anisocoria, the left pupil is dilated and unresponsive to light.

Figure 2

Case 6. Adie’s syndrome: installation of diluted pilocarpine discloses supersensitivity and miosis in the left eye.

Discussion

We present six paediatric patients with diverse acquired acute ocular motor disturbances as nystagmus, sixth nerve palsy, ptosis or Adie’s pupil as the first manifestation of LNB.

LNB is rarely listed in the differential diagnosis of unexplained, acquired ocular motor disturbances in children.12 A few cases of LNB affecting the third, fourth and sixth nerve, either alone or in combination, have been reported both in adults and children.3 ,9 ,13–17 Nystagmus as the presenting sign of LNB was previously reported in only one paediatric case.18 Bilateral or unilateral ptosis due to orbital inflammation related to borreliosis has been reported in few cases, but without information on intrathecal synthesis of Bb antibodies; hence, it remains unknown whether these patients simply had borreliosis with eyelid/orbital inflammation, or LNB with partial third nerve palsy.19 ,20 Adie’s tonic pupil secondary to LNB was previously reported in the literature in three adults and one 13-year-old child only; in the latter case the pupillary changes persisted after antibiotic treatment.9 ,10

In our LNB series, the condition in the patient with sixth nerve palsy accompanied by nystagmus (case 1), has not previously been described in the literature. The child with horizontal nystagmus (case 2) resembled infantile nystagmus in that it stayed horizontal in upgaze, but differed in that it resolved after antibiotic treatment. In the child with an acquired unilateral tonic pupil with vermiform contractions to light (case 6), the associated ankle hyporeflexia established the diagnosis of Adie’s syndrome.

The diagnosis of LNB in our patients was provided by intrathecal synthesis of Bb-specific antibodies in all six children in combination with elevated cell count in the CSF and unexplained, acute ocular motor disturbances in five of six children. In all but one patient, the clinical clue towards the diagnosis of LNB was symptoms of fatigue, and in some patients combined with a history of tick bite and skin rash, absence of antecedent illness or immunisations. Two patients had symptoms of central vestibular dysfunction.

Five of the presented children were diagnosed with early-phase LNB, and they experienced remission of symptoms only days after initiated treatment with either intravenous or oral antibiotics (table 2). In case 6 (Adie’s pupil), the findings of intrathecal synthesis of Bb-specific IgG antibodies, with a lack of intrathecal synthesis of Bb-specific IgM antibodies, supports the history of symptoms present for more than 3 months and raises a high suspicion of previous LNB infection. In this child, the symptoms did not improve during intravenous antibiotic treatment, suggesting that a longer duration of symptoms may induce a higher risk of permanent sequelae in LNB.11 Adie’s tonic pupil is usually irreversible presumably caused by denervation of parasympathetic fibres in the ciliary ganglion, although the pupil often gradually becomes miotic over time.21

None of the children in our cohort had structural or vascular abnormalities on neuroimaging studies to explain their ocular motor abnormalities. Acute disseminated encephalomyelitis (ADEM) can give rise to similar symptoms as in the present cases, but lesions typical for ADEM would be visible on MRI.22 No patients had symptoms of elevated intracranial pressure, papilloedema or neuroretinitis. Severe malaise can also accompany fever, lymphadenopathy, skin rash and neuroretinitis in the setting of cat scratch disease (caused by Bartonella hensalae), but isolated ocular motor disturbances have not been associated with this condition.23

In early LNB, the Bb antibodies may be detected earlier in CSF than in serum, especially in children.24 Two weeks after infection by Bb, 85% of patients with LNB demonstrate increased CSF IgM and/or IgG levels. Several years after the Bb infection is cleared, raised IgG levels in both CSF and serum can be detected.25 If the treatment algorithm for LNB is based upon serum antibody testing in combination with neurological symptoms alone, a child with CSF Bb antibodies but without serological Bb antibodies would allow the diagnosis to be potentially missed. If children with neurological symptoms have positive serological Bb antibody tests, the lumbar puncture may then be unnecessary except to fortify the specific diagnosis of LNB.

Rapid diagnosis and treatment of LNB is important, as patients with untreated LNB for more than 6 months can progress to post-Lyme syndrome characterised by cerebral vasculitis, spastic-ataxic walking disturbances, spastic bladder, progressive encephalitis and/or hemiplegic palsy, and show no response to antibiotic treatment.11

The limitations to this study include its retrospective nature and the small sample size as well as the possibility that some clinical signs were not causally related to acute LNB. However, the concurrence of their clinical resolution with antibiotic therapy makes the latter possibility unlikely. Because all patients were treated with antibiotic therapy, it is unclear whether our patients would have experienced similar recovery without treatment. For example, the neurological manifestations of cat scratch disease can resolve with or without antibiotic treatment.23 Finally, neuroimaging was not performed in all patients.

In conclusion, LNB can produce a spectrum of ocular motor disturbances which can present in conjunction with severe malaise or fatigue. The rapid and persistent resolution with antibiotic therapy suggests an infectious rather than an inflammatory or autoimmune origin for the associated ocular motor symptoms. Early diagnosis and treatment are important to reduce morbidity and sequelae.11 During the summer and autumn months when the peak incidence of Lyme disease occurs in areas endemic of ticks carrying Bb spirochaetes, general practitioners, paediatricians, neurologists and ophthalmologists should consider LNB in the differential diagnosis of acute ocular motor abnormalities in children and include exposure questioning and travel history in the patient review.

References

Footnotes

  • Each of the coauthors has seen and agrees to the manuscript and to the way his or her name is listed.

  • Correction notice This article has been corrected since it was published Online First. The provenance and peer review statement has been corrected.

  • Contributors The authors were involved in the design and conduct of the study (MHC, ND, HSSA, JPS), collection, management, analysis and interpretation of the data (MHC, ND, HSSA, HAM, AKT, MB, MCB, JPS), preparation of the manuscript (MHC, ND, HSSA, HAM, JPS), critical revision and final approval of the manuscript (MHC, ND, HSSA, HAM, AKT, MB, MCB, JPS).

  • Competing interests None.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; internally peer reviewed.

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