CASE

An immunocompetent 7-year-old boy presented to a community hospital emergency room with a 1-month history of headaches, dizziness, nausea, vomiting and arthralgias and a 1-week history of bilateral vision loss. He was given 1 g of intravenous ceftriaxone, then transferred to a tertiary care center. On arrival, he had a temperature was 37.7°C, heart rate of 70 beats per minute, blood pressure of 131/91, respiratory rate of 20 breaths per minute and oxygen saturation of 98% on room air. The patient was lethargic but arousable. His pupils measured 8 mm and were equally round and reactive to light and accommodation. He was only able to perceive hand motion. He was not able to differentiate colors. Ophthalmic examination confirmed the presence of bilateral papilledema and neuroretinitis (Fig. 1). His physical examination also revealed bilateral cranial nerve 6 palsy. There were no other cranial nerve deficits, and the remainder of the systemic examination was unremarkable.

FIGURE 1.:

Magnified view via handheld lens of bilateral papilledema and diffuse blurring of disk margins. OD indicates right eye; OS, left eye.

On laboratory analysis, a complete blood cell count and comprehensive metabolic panel were normal. C-reactive protein and procalcitonin were not elevated. However, erythrocyte sedimentation rate was 27 (normal range <15 mm/h). Serology for human immunodeficiency virus, syphilis, herpes simplex viruses 1 and 2, Epstein-Barr virus, varicella virus, toxoplasma and bartonella were negative. Coronavirus disease 2019 and respiratory viral panel polymerase chain reaction tests were negative. Opening pressure on lumbar puncture was 38 cm H2O. Cerebrospinal fluid (CSF) analysis showed a normal cell count, protein and glucose. A CSF pathogen panel for viral [cytomegalovirus (CMV) enterovirus, HSV-1, HSV-2, HSV-6, VZV] and bacterial (Haemophilus influenzae, Neisseria meningitidis, Escherichia coli, Listeria monocytogenes, Streptococcus agalactiae) causes of meningitis/encephalitis was negative. Serology for syphilis, neuromyelitis optica/aquaporin-4-IgG and myelin oligodendrocyte glycoprotein antibodies were negative. Computed tomography angiography of the head and neck and magnetic resonance imaging of the brain showed mild prominence of the ventricles and extra-axial spaces but were otherwise negative. Magnetic resonance imaging of the orbits was normal.

Empiric treatment with intravenous ceftriaxone 100 mg/kg/d was started as well as treatment with acetazolamide 1000 mg twice daily, and methylprednisolone 100 mg every 6 hours was started.

Additional history and laboratory analyses revealed the diagnosis.

DENOUEMENT

A detailed history of presenting illness revealed that the patient had previously presented to a community hospital emergency room with a 2-week history of headaches, fatigue, and elbow pain. He was diagnosed with Lyme disease and started on amoxicillin. Over the next week, the patient developed significant nausea, vomiting and polyarthralgia. One week after starting amoxicillin, he was evaluated by his primary care provider and switched to doxycycline. On follow up 1 week later, the patient reported bilateral blurry vision, color blindness and dizziness. Due to concern for doxycycline-induced vision change, amoxicillin was restarted, and doxycycline was stopped. The following day, the patient again presented to a community hospital emergency room. His symptoms included nuchal rigidity, dizziness, bilateral vision loss, polyarthralgia and fatigue. Due to the need for subspecialty evaluation, the patient was transferred to the tertiary care hospital.

Serological testing on admission was positive for Lyme IgM and IgG. Thus, optic neuritis and neuroretinitis secondary to Lyme meningitis was suspected. Lyme polymerase chain reaction (PCR) of the CSF was negative. However, studies question the diagnostic utility of this test as it is known to have a low sensitivity.1–3

The differential diagnosis for optic neuritis and neuroretinitis includes multiple infectious etiologies. While Lyme positivity suggested the most likely culprit of disease, bartonella, syphilis, toxoplasma, CMV, herpes simplex, varicella, rubella and measles are all known to cause vision loss related to posterior uveitis manifesting as neuroretinitis.4 Our patient was fully immunized and had no rash on examination to suggest rubella or measles infection. Both CMV IgG and IgM were mildly elevated to 1.41 (ISR) [normal range <0.91 (ISR)] and 48.5 AU/mL (normal range 0–29.9 AU/mL), respectively, suggesting possible infection versus cross reactivity. His Epstein-Barr virus IgG was also positive, indicating a previous infection. Furthermore, there is published evidence of neuroretinitis and intracranial hypertension (ICH) following mycoplasma pneumoniae infection.5 A single test yielded elevated mycoplasma IgM. Confirmatory testing was not conducted to rule out possibility of false positive testing. Lack of serological confirmation serves as a significant limitation to evaluating confounding infections.

Systemic autoimmune conditions such as Behcet Disease, sarcoidosis, systemic lupus erythematosus, multiple sclerosis and neuromyelitis optica are also included in the differential for causes of neuroretinitis.6 Serology and CSF testing did not reveal elevated levels of ANA, CRP, anti-centromere antibody (Ab), anti-dsDNA, anti-Histone, anti-Jo-1, NMO/AQ4 Ab, MOG Ab, RF, anti-RNP, anti-SCL-70, anti-Smith, anti-SSA and anti-SSB. Angiotensin-converting enzyme (ACE) and muramidase levels were normal. Thus, an autoimmune etiology for optic neuritis was unlikely. Although the patient did present with an elevated ESR, his age and absence of supporting symptomology made diagnosis of arteritic anterior ischemic optic neuropathy secondary to giant cell arteritis highly unlikely. Similarly, the patient’s age, bilateral papilledema, presence of eye pain, and absence of optic nerve splinter hemorrhages made nonarteritic anterior ischemic optic neuropathy unlikely.

Neuroborreliosis occurs in approximately 15% of patients diagnosed with Lyme disease and varies in its manifestation. In a study of pediatric patients in Pennsylvania, cranial nerve palsies were present in 12% of cases and neck stiffness in 11%.7 There are few reports of optic neuritis and vision loss associated with Lyme disease in the literature, especially in the pediatric population. Optic neuritis is a rare complication of Lyme neuroborreliosis and as such, there are few pediatric case reports in the literature. A single case series published by Rothermel et al8 indicates the presenting visual symptoms as well as the prognosis can vary. In this case series, all patients were treated with a prolonged course of ceftriaxone. Three children recovered their vision, while 1 suffered permanent blindness due to Lyme infection. Interestingly, as with our patient, the patient with permanent blindness was treated first with doxycycline and developed vision changes while on antibiotic therapy. An additional case of chiasmal optic neuritis due to Lyme disease was reported in a 10-year-old patient by Scott et al.9 This patient received a prolonged course of steroids and a combination of ceftriaxone and doxycycline. However, her vision did not improve, and she too suffered permanent vision loss. Although our patient’s vision improved, his visual acuity remained 20/50. Fundus imaging 6 months after hospital admission showed progressive resolution of papillary inflammation with residual retinal nerve fiber layer thinning. After 7 months, central visual acuity improved to 20/25 in the right eye and 20/30 in the left. However, patient was declared legally blind due to severe peripheral visual field restriction.

According to Infectious Disease Society of America guidelines, oral amoxicillin, doxycycline or cefuroxime axetil should be used to treat early Lyme disease; oral doxycycline, intravenous ceftriaxone, cefotaxime or penicillin G should be used to treat neuroborreliosis.10 Our patient was initially given amoxicillin but switched to doxycycline when his symptoms progressed. Shortly thereafter, he developed changes in vision. It is possible that the doxycycline exacerbated his neuro-ophthalmologic symptoms by causing or worsening his ICH. Several case reports have linked the use of doxycycline to ICH in patients with and without Lyme disease.11–13 Doxycycline-induced ICH has also been associated with mild to severe losses of visual acuity, especially in obese adults and/or women of child-bearing age.12 As a thin and young male, our patient does not fit this demographic. The role of doxycycline in inducing ICH becomes less clear when considering the direct effect that Lyme meningitis has on elevating intracranial pressure. Our patient’s opening pressure was elevated on admission and had increased to 56 cm H2O on hospital day 4. Additional research is needed to identify risk factors for doxycycline-induced ICH in pediatric patients with Lyme disease.

Further study is also needed to determine the optimal treatment for ICH in the setting of Lyme disease and secondary to antibiotic therapy. Two of Rothermel et al’s8 patients were given a short course of intravenous steroids. Vision in the first returned to 20/20. However, the second developed obstructive, communicating hydrocephalus and required placement of a ventriculoperitoneal shunt. Our patient’s ICH was initially treated with intravenous steroids and acetazolamide. As a result of acetazolamide therapy, he then developed multiple electrolyte derangements, including hypokalemia. The patient subsequently manifested worsening ICP, requiring temporary lumbar drain placement to provide symptom relief.

As our case and prior literature suggest, permanent visual decline is a notable outcome in pediatric Lyme optic neuritis. Despite prolonged antibiotic and steroid therapy, our patient was able to recover only a central island of vision bilaterally. It is therefore imperative that clinicians provide early ophthalmic evaluation for patients presenting with changes in visual acuity in the context of Lyme infection. Furthermore, it is vital that such patients be monitored for worsening neuro-ophthalmic complications when using doxycycline to treat the infection.

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