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BJO Online First, published on April 13, 2015 as 10.1136/bjophthalmol-2015-306855 Clinical science
Lyme neuroborreliosis: a treatable cause of acute ocular motor disturbances in children M H Correll,1,2 N Datta,2 H S S Arvidsson,1 H A Melsom,1 A K Thielberg,3 M Bjerager,3 M C Brodsky,4 J P Saunte1,2 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ bjophthalmol-2015-306855). 1
Department of Ophthalmology, Nordsjællands Hospital Hillerød, Hillerød, Denmark 2 Department of Ophthalmology, Copenhagen University Hospital Glostrup, Glostrup, Denmark 3 Department of Pediatrics, Nordsjællands Hospital Hillerød, Hillerød, Denmark 4 Departments of Ophthalmology and Neurology, Mayo Clinic, Rochester, Minnesota, USA Correspondence to Dr Jon Peiter Saunte, Ophthalmology Dept., Copenhagen University Hospital Glostrup, Region H, Nordre Ringvej 57, Glostrup DK—2600, Denmark; [email protected] Each of the coauthors has seen and agrees to the manuscript and to the way his or her name is listed. Received 11 March 2015 Accepted 20 March 2015
ABSTRACT Background Lyme neuroborreliosis (LNB) designates central nervous system involvement caused by the tickborne 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.
INTRODUCTION
To cite: Correll MH, Datta N, Arvidsson HSS, et al. Br J Ophthalmol Published Online First: [please include Day Month Year] doi:10.1136/ bjophthalmol-2015-306855
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
Correll MH, et al. Br J Ophthalmol 2015;0:1–4. doi:10.1136/bjophthalmol-2015-306855
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd under licence.
1
Downloaded from http://bjo.bmj.com/ on August 13, 2015 - Published by group.bmj.com
Clinical science Table 1 Demographic data, symptoms and ocular findings Age at diagnosis (years)
Pt. no
Sex
1
M
8
2 3
M M
15 15
4 5 6
M F F
7 3 4
Headache
Fatigue
Nausea
Highest measured body temperature (0 Celsius)
Reported tick bite /location
Reported skin rash
Duration from tick bite until onset of symptoms (weeks)
Yes /neck
Yes
12
No
Yes
Yes
36.8
Yes /scrotum Yes /shoulder
No No
16 6
Yes No
Yes Yes
Yes No
Fever 37.9
No Yes /eyelid No
No Yes No
N/A 1 N/A
Yes No No
Yes Yes N/A
Yes Yes N/A
38.9 37.0 37.0
Ocular symptoms Left sixth nerve palsy, nystagmus Nystagmus, left head turn Right sixth nerve palsy, right head turn Nystagmus, left head turn Right ptosis Left Adie’s pupil, photophobia
F, female; M, male; N/A, not available.
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).
developed a small angle esotropia in left gaze. A conjugate leftbeating 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).
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 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
Table 2 Laboratory results, treatment profile and outcome
Pt. no
MRI/CT scan of cerebrum
1 2 3 4 5 6
Not performed MRI normal MRI normal CT normal Not performed MRI normal
Bb-specific IgM AI
Bb-specific IgG AI
White blood cell count in CSF (*106/L)
Duration from onset of symptoms until treatment (days)
Antibotic treatment
Antibiotic treatment duration (days)
Ocular persisting symptoms after treatment
1.8 1
BJO Online First, published on April 13, 2015 as 10.1136/bjophthalmol-2015-306855 Clinical science
Lyme neuroborreliosis: a treatable cause of acute ocular motor disturbances in children M H Correll,1,2 N Datta,2 H S S Arvidsson,1 H A Melsom,1 A K Thielberg,3 M Bjerager,3 M C Brodsky,4 J P Saunte1,2 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ bjophthalmol-2015-306855). 1
Department of Ophthalmology, Nordsjællands Hospital Hillerød, Hillerød, Denmark 2 Department of Ophthalmology, Copenhagen University Hospital Glostrup, Glostrup, Denmark 3 Department of Pediatrics, Nordsjællands Hospital Hillerød, Hillerød, Denmark 4 Departments of Ophthalmology and Neurology, Mayo Clinic, Rochester, Minnesota, USA Correspondence to Dr Jon Peiter Saunte, Ophthalmology Dept., Copenhagen University Hospital Glostrup, Region H, Nordre Ringvej 57, Glostrup DK—2600, Denmark; [email protected] Each of the coauthors has seen and agrees to the manuscript and to the way his or her name is listed. Received 11 March 2015 Accepted 20 March 2015
ABSTRACT Background Lyme neuroborreliosis (LNB) designates central nervous system involvement caused by the tickborne 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.
INTRODUCTION
To cite: Correll MH, Datta N, Arvidsson HSS, et al. Br J Ophthalmol Published Online First: [please include Day Month Year] doi:10.1136/ bjophthalmol-2015-306855
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
Correll MH, et al. Br J Ophthalmol 2015;0:1–4. doi:10.1136/bjophthalmol-2015-306855
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd under licence.
1
Downloaded from http://bjo.bmj.com/ on August 13, 2015 - Published by group.bmj.com
Clinical science Table 1 Demographic data, symptoms and ocular findings Age at diagnosis (years)
Pt. no
Sex
1
M
8
2 3
M M
15 15
4 5 6
M F F
7 3 4
Headache
Fatigue
Nausea
Highest measured body temperature (0 Celsius)
Reported tick bite /location
Reported skin rash
Duration from tick bite until onset of symptoms (weeks)
Yes /neck
Yes
12
No
Yes
Yes
36.8
Yes /scrotum Yes /shoulder
No No
16 6
Yes No
Yes Yes
Yes No
Fever 37.9
No Yes /eyelid No
No Yes No
N/A 1 N/A
Yes No No
Yes Yes N/A
Yes Yes N/A
38.9 37.0 37.0
Ocular symptoms Left sixth nerve palsy, nystagmus Nystagmus, left head turn Right sixth nerve palsy, right head turn Nystagmus, left head turn Right ptosis Left Adie’s pupil, photophobia
F, female; M, male; N/A, not available.
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).
developed a small angle esotropia in left gaze. A conjugate leftbeating 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).
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 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
Table 2 Laboratory results, treatment profile and outcome
Pt. no
MRI/CT scan of cerebrum
1 2 3 4 5 6
Not performed MRI normal MRI normal CT normal Not performed MRI normal
Bb-specific IgM AI
Bb-specific IgG AI
White blood cell count in CSF (*106/L)
Duration from onset of symptoms until treatment (days)
Antibotic treatment
Antibiotic treatment duration (days)
Ocular persisting symptoms after treatment
1.8 1
