PEDIATRICS Vol. 108 No. 2 August 2001, pp. 477-481

EXPERIENCE AND REASON:
Optic Neuropathy in Children With Lyme Disease

	ABSTRACT

Top Abstract Introduction Discussion References

Involvement of the optic nerve, either because of inflammation or increased intracranial pressure, is a rare manifestation of Lyme disease. Of the 4 children reported here with optic nerve abnormalities, 2 had decreased vision months after disease onset attributable to optic neuritis, and 1 had headache and diplopia early in the infection because of increased intracranial pressure associated with Lyme meningitis. In these 3 children, optic nerve involvement responded well to intravenous ceftriaxone therapy. The fourth child had headache and visual loss attributable to increased intracranial pressure and perhaps also to optic neuritis. Despite treatment with ceftriaxone and steroids, he had persistent increased intracranial pressure leading to permanent bilateral blindness. Clinicians should be aware that neuro-ophthalmologic involvement of Lyme disease may have significant consequences. If increased intracranial pressure persists despite antibiotic therapy, measures must be taken quickly to reduce the pressure.

Lyme disease is a multisystem illness affecting both children and adults.¹ In the United States, this infection is caused by the tick-transmitted spirochete Borrelia burgdorferi sensu stricto. The illness usually begins in summer with a characteristic skin lesion, erythema migrans, followed within days to weeks by dissemination of the spirochete to many possible sites, including the skin, nervous system, heart, or joints. Months to years later, patients may develop chronic manifestations of the illness.

The infection is associated with a wide variety of neurologic abnormalities.^2-5 Early neurologic manifestations include meningitis, encephalitis, cranial neuritis (most commonly facial palsy), radiculoneuritis, mononeuritis multiplex, cerebellar ataxia, or myelitis.^3,4 The eye may also be affected in Lyme disease, apparently because of direct infection, resulting in conjunctivitis, choroiditis, iritis, keratitis, neuroretinitis, or endophthalmitis.^6-12 Although rare, vision may also be affected in Lyme disease because of involvement of the optic nerve, either because of inflammation or increased intracranial pressure.^8,1013-27 However, descriptions of neuro-ophthalmologic manifestations of the disease are limited.

During the 25 years that we have conducted a Lyme disease clinic, we have evaluated 7 children and 4 adults who have had active optic nerve involvement associated with Lyme disease or a history of that manifestation of the illness. We report here the 4 cases in children for whom sufficient documentation of optic nerve involvement was available, including the first reported pediatric case of permanent, bilateral blindness resulting from Lyme disease.

	CASE REPORTS

The following 4 case reports demonstrate involvement of the optic nerve in Lyme disease; 2 patients had optic neuritis, 1 had increased intracranial pressure, and 1 may have had both of these abnormalities. A clinical summary of the 4 cases is given in Table 1.

Serologic testing for Lyme disease was done at New England Medical Center by enzyme-linked immunosorbent assay (ELISA) and Western blotting, as previously described²⁸; the results were interpreted according to the Centers for Disease Control/Association of State and Territorial and Public Health Laboratory Director's criteria.²⁹ An indeterminate immunoglobin M (IgM) response by ELISA was defined as 100 U and a positive response was 200 U; an indeterminate immunoglobin G (IgG) result was defined as 200 U or 400 U and a positive result was 800U. A positive IgM Western blot had at least 2 of the following 3 bands: 23, 39, or 41 kDa; and a positive IgG Western blot had at least 5 of the following 10 bands: 18, 23, 28, 30, 39, 41, 45, 58, 66, or 93 kDa. Spinal fluid was tested for intrathecal IgM, IgG, and immunoglobin A (IgA) antibody production to B burgdorferi by antibody capture enzyme assay, as previously described.³⁰ This test compares the amount of antibody of each isotype in serum and cerebrospinal fluid (CSF). In patients with positive responses, greater value in CSF than serum was defined as local synthesis of specific antibody in CSF.

Case 1: Bilateral Optic Neuritis as the Primary Manifestation of Lyme Disease

In June 2000, after a trip to Southport, Connecticut, an 8-year-old boy developed headaches 3 to 4 times per week associated with fatigue (Table 1). The headache was primarily occipital but sometimes radiated to the orbits. In mid-August, he told his parents that he could not see well; he moved closer to the television to see the picture, and he became slow in his activities. He occasionally mentioned pain in his left thigh. He had no other signs or symptoms, and did not remember a tick bite.

On examination, he had only ophthalmologic abnormalities. Visual acuity was 20/200 in the right eye and 20/400 in the left. Goldmann visual field testing showed central scotomas in both eyes with intact peripheral fields. Both optic nerves were markedly swollen with patchy white exudates overlying the optic disk surfaces and peripapillary hemorrhages (Fig 1A and B). There was elevation of both peripapillary retinas extending into the macular regions. Optic coherence tomography, a technique that uses reflected light to create cross-sectional images of intraocular structures, showed evidence of subretinal fluid primarily in the central portions of the retinas. A magnetic resonance imaging (MRI) scan of the brain demonstrated no intracranial abnormalities. A lumbar puncture showed an opening pressure of 120 mm of water. Cerebrospinal fluid protein was 56 mg/dL and the glucose was 44 mg/dL. There were no white blood cells and only 1 red blood cell/mm³.

View larger version (96K): [in this window] [in a new window]   Fig. 1.   Fundus photographs are shown in an 8-year-old boy who had bilateral anterior optic neuritis as the only manifestation of Lyme disease. The right eye (A) showed optic disk edema, exudates and peripapillary hemorrhages, and the left eye (B) showed similar but more severe changes.

He was diagnosed with bilateral anterior optic neuritis or papillitis and was initially treated with intravenous methylprednisolone, 250 mg every 12 hours. Within 3 days, his visual acuities improved to 20/70 in the right eye and 20/100 in the left eye. Two weeks later, serologic testing for Lyme disease was found to be markedly positive. The serum IgM response by ELISA was 100 U and the IgG response was 25 600 U with 10 bands on western blot (Table 1). CSF was not examined for intrathecal antibody production to the spirochete. He was treated with intravenous ceftriaxone, 1.5 g once a day for 30 days. One month after the conclusion of treatment, the appearance of both optic nerves was almost normal, but there were residual striae in both maculas and mild optic atrophy on the left. Four months later, visual acuities had improved to 20/20 in the right eye and 20/30 in the left eye.

Case 2: Unilateral Optic Neuritis Following Months After Lyme Arthritis

In August 1994, after returning from a summer vacation at Cape Cod, Massachusetts, a 16-year-old boy developed a painful, swollen knee (Table 1). He had no recollection of a tick bite during the summer, nor did he remember a skin rash or flu-like illness. A Lyme antibody test was positive. He was treated with tetracycline, 1 g once a day for 10 days, and doxycycline, 100 mg twice a day for 20 days. The arthritis resolved during the course of treatment.

Six months later he awoke with blurred vision in his left eye. He had no other symptoms. Ophthalmologic evaluation of the right eye was normal, but examination of the left eye revealed a central scotoma, a swollen optic disk, and a visual acuity of 20/200. He was diagnosed with unilateral anterior optic neuritis. A MRI of the brain was normal, as was spinal fluid analysis, including a negative test for myelin basic protein and negative cultures for syphilis, tuberculosis, and other common bacteria. An antibody test for Lyme disease showed an IgG response of 1600 U by ELISA with 8 bands on Western blot (Table 1). He was treated with a 30-day course of intravenous ceftriaxone, 2 g daily. By the time the antibiotic course was completed, the optic neuritis had completely resolved and vision had improved to 20/30. Four months later his vision had normalized to 20/20. In the subsequent 6 years he has been well, with no recurrence of visual symptoms or arthritis.

Case 3: Papilledema Associated With Lyme Meningitis

In August 1997, a 13-year-old girl developed headaches, nausea, low-grade fever, and neck pain (Table 1). The fevers and neck pain resolved within a few days, but the headaches continued and became severe enough to awaken her at night. After 3 weeks of continuing headaches, she developed eye pain with horizontal diplopia, and described the sound of "wind puffing" in her left ear. On admission to the hospital, ophthalmologic examination showed visual acuities of 20/25 in both the right and left eyes, moderate optic disk swelling in both eyes, as well as left lateral rectus dysfunction. Visual fields demonstrated moderate enlargement of the blindspots. Otherwise, her physical and neurologic examinations were normal, as was a head MRI. A lumbar puncture showed an opening pressure of 600 mm H₂0; 82 white cells, predominantly lymphocytes, a protein of 56 mg/dL and a glucose of 43 mg/dL. Sixteen milliliters of spinal fluid were removed. During the next several days, her symptoms improved without specific treatment, and a repeat lumbar puncture showed an opening pressure of 135 mm H₂O.

The results of testing for Lyme disease, which became available several days later, showed an elevated IgG antibody response to B burgdorferi of 3200 U by ELISA with 7 bands on Western blot. In addition, spinal fluid analysis showed selective concentration of both IgG and IgA antibody to B burgdorferi (Table 1). She was treated with a 1-month course of intravenous ceftriaxone therapy, 2-g daily. By the end of treatment, she had 20/20 vision, minimal crowding of the optic heads, and almost complete resolution of her lateral rectus dysfunction. Three months later, she was asymptomatic, and her examination was normal.

Case 4: Increased Intracranial Pressure and Optic Atrophy in Lyme Disease

In late summer of 1998, an 11-year-old boy developed severe headaches, nausea, vomiting, and low-grade fevers. Four days later, his pediatrician noted 3 annular lesions suggestive of erythema migrans on his thigh, chest, and back. Both the IgM and IgG responses to B burgdorferi were positive by ELISA and Western blot (Table 1). Treatment with doxycycline, 100-mg orally twice a day, was begun for Lyme disease, but his vomiting and headaches continued to worsen. Within the next week, he developed diplopia and was found to have bilateral sixth and seventh nerve palsies. In addition, his bicipital reflexes were absent, and knee and ankle reflexes were decreased. An MRI scan of the head with gadolinium was normal. He was treated with a 5-day course of methylprednisolone and a 1-month course of intravenous ceftriaxone, 2-g daily. His diplopia improved, but the headaches continued and he had transient hip pain.

On the 14th day of antibiotics, the patient lost vision in both eyes, maintaining only light perception. He also noted a whistling sound in his ears. Ophthalmologic examination revealed bilateral optic disk edema in addition to bilateral sixth nerve palsies. On admission to the hospital, he had nonreactive pupils, limited ocular motility, and bilateral optic disk swelling. An MRI scan showed increased gadolinium enhancement of the optic nerves, which was thought to be consistent with optic neuritis. A lumbar puncture showed 3 white blood cells, normal glucose and protein, and an opening pressure of 570 mm H₂O. After removal of 20 mL of fluid, the closing pressure was 200 mm H₂O. His headaches and nausea improved markedly after the spinal tap. Both serum IgM and IgG responses to B burgdorferi were again positive, and the IgM response had declined; he did not have evidence of intrathecal antibody production (Table 1). In addition to the antibiotics, he was again treated with a 5-day course of intravenous methylprednisolone. His vision did not improve, and on discharge 1 week later his visual evoked potential responses were flat. One week later, ophthalmologic examination revealed optic nerve atrophy and no improvement in vision.

He was evaluated at New England Medical Center on the 33rd and last day of ceftriaxone. He was blind in both eyes, and he had bilateral abducens palsies and decreased biceps and quadriceps reflexes. Fundoscopic examination showed optic atrophy in both eyes (Fig 2A and 2B). Serologic testing again demonstrated positive IgM and IgG antibody responses to B burgdorferi, and the IgM response had declined still more (Table 1). Spinal tap still showed an elevated opening pressure of 470 mm H₂O, but the CSF analysis was normal. A repeat MRI demonstrated increased size of the lateral and third ventricles. These findings suggested that in addition to previous optic neuritis, he now had obstructive, communicating hydrocephalus. A right frontal, ventriculoperitoneal shunt was placed to relieve pressure on the optic nerves, and a short course of prednisone was begun. He had improvement of his ocular palsies and reflexes, although his vision remained significantly impaired. During the next 6 months, he had complete resolution of all symptoms except for blindness. At follow-up evaluation 1 year later, he could find his way around a room and visual evoked potential responses showed some signal. On testing of visual acuities, he could only see hand motions.

View larger version (98K): [in this window] [in a new window]   Fig. 2.   Fundus photographs of an 11-year-old boy who developed increased intracranial pressure and optic atrophy early in the course of Lyme disease. Pallor and irregular optic disk borders suggestive of previous optic disk swelling (atrophic papilledema) are seen in both the right (A) and left (B) eyes.

	DISCUSSION

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The 4 cases reported here represent a spectrum of neuro-ophthalmologic involvement in Lyme disease. Two months after the onset of intermittent headache, the first patient developed bilateral anterior optic neuritis or papillitis, with accumulation of subretinal fluid and loss of central vision. Although this patient had visited an endemic area for Lyme disease in June, his clinical course was remarkable for the lack of other, more characteristic manifestations of the infection, such as erythema migrans, meningitis, or facial palsy. The second patient had unilateral anterior optic neuritis 6 months after oral antibiotic therapy for Lyme arthritis. We favor that his optic neuritis was a manifestation of Lyme disease because of its temporal relationship to well-documented Lyme arthritis, its anterior rather than posterior location, its prompt resolution with antibiotic treatment, and its lack of recurrence in the subsequent 6 years.

Optic neuritis in children may be caused by parainfectious or postinfectious processes or demyelinating diseases, or it may be idiopathic. The 2 children reported here had anterior optic neuritis or papillitis as opposed to posterior optic neuritis, as is seen in most cases of multiple sclerosis. The pathogenesis of optic neuritis in Lyme disease is not known; it may result from immune-mediated phenomena rather than direct infection of the optic nerve.

Six previous American patients have been reported with Lyme disease-associated optic neuritis, which occurred 1 to 9 months after initial infection.^1014-17 A Finnish study also reported 4 patients with optic neuritis occurring 2 to 4 years after initial infection,⁸ although the diagnosis of Lyme disease in these patients was not confirmed serologically.^8,11 All 6 American patients presented with blurred vision or visual loss. Two had been previously treated with antibiotics, 1 with oral doxycycline and the other with a 2-week course of intravenous ceftriaxone.^10,14,15 Four of the 6 patients had nearly full recovery after antibiotic treatment or retreatment. One of the other 2 cases was a 10-year-old girl who had developed optic atrophy by the time Lyme disease was diagnosed. Despite treatment with steroids and intravenous ceftriaxone, she had permanent loss of vision in the right eye.¹⁵ The other patient, a 23-year-old woman, had waxing and waning visual problems during a 1-year period despite antibiotic treatment. Despite one positive Western blot, she had neither a clear history of Lyme disease nor a positive ELISA test; therefore, her case is less clearly one of Lyme disease.¹⁷

The third patient in our series developed papilledema, diplopia, and decreased vision associated with unequivocal Lyme meningitis. She had a lymphocytic pleocytosis and intrathecal antibody production to B burgdorferi. The fourth patient presented with meningeal symptoms and was thought to have Lyme meningitis based on a positive serologic test for Lyme disease. Despite treatment with intravenous ceftriaxone, blindness developed and an MRI scan was thought to show optic neuritis. However, he also had signs and symptoms of increased intracranial pressure, and the opening pressure in cerebrospinal fluid was markedly elevated. Although he had only 3 white cells/mm³ in CSF, antibiotic therapy given before lumbar puncture might have cleared a CSF pleocytosis. Thus, both optic neuritis and postmeningitic obstructive, communicating hydrocephalus may have caused enlarged ventricles, optic atrophy and blindness. Although a few cases of unilateral visual loss attributable to Lyme disease have been reported in the literature,^9,12,15 this is the first reported case of bilateral permanent blindness.

To date, 23 patients with Lyme neuroborreliosis and increased intracranial pressure have been reported in the medical literature, all in children.^{1018-22,25,27} The children presented with headache a few weeks after the onset of infection frequently accompanied by meningeal signs such as nausea and vomiting, and 18 had mild CSF pleocytoses. Our patients also had pulsatile tinnitus, a sensation associated with increased intracranial pressure. The previous 23 children were sometimes reported to have pseudotumor cerebri, or idiopathic intracranial hypertension, but this terminology is probably not correct.³¹ Increased intracranial pressure is rarely an idiopathic phenomenon in children; a cause can usually be identified, be it steroids, growth hormone, venous sinus thrombosis, or infection. Among patients with Lyme meningitis, CSF outflow from the arachnoid villi may become blocked with inflammatory cells and necrotic cellular debris leading to increased intracranial pressure, as may occur with any type of meningitis. In addition, increased intracranial pressure is seen in immune-mediated diseases, such as lupus, in which deposition of immune complexes in the arachnoid villi may be responsible for increased intracranial pressure,¹⁸ and this may be a factor in neuroborreliosis. Venous sinus thrombosis secondary to infection may also cause this complication, but this has not been documented in Lyme disease.

How frequent are neuro-opthalmologic abnormalities in Lyme disease? In an analysis of 18 patients with early neurologic abnormalities of Lyme disease,³ 7 patients had ocular symptoms. Two had diplopia associated with oculomotor palsies, and 5 patients with meningitis had transient blurred vision suggestive of increased intracranial pressure. On examination, only 2 of these 5 cases had papilledema, and only 1 had a documented increase in spinal fluid pressure. In a recent study of children in which the presentations of Lyme meningitis and viral meningitis were compared, the presence of papilledema, lower temperature, longer duration of symptoms, and milder pleocytosis favored the diagnosis of Lyme disease.¹⁹

Clinicians should be aware that optic nerve involvement may be a manifestation of Lyme disease, either because of inflammation or increased intracranial pressure, or both. Among patients with symptoms suggestive of Lyme disease, decreased vision suggests the possibility of optic neuritis, whereas the presence of headache, visual symptoms, pulsatile tinnitus, sixth nerve palsy, or papilledema are important clues to the possibility of increased intracranial pressure. In such patients, treatment with intravenous antibiotic therapy is indicated. Among those with increased intracranial pressure, corticosteroids or acetozolamide may be considered in individual cases, although experience is limited. Opening and closing pressures should be monitored sequentially. Shunting may be warranted if visual loss is marked or if other treatments do not lead to a reduction in intracranial pressure.

	ACKNOWLEDGMENTS

Support for this work was provided by National Institutes of Health Grant AR-20358, CDC Cooperative Agreement CCU110291, the Eshe fund, and a gift from Jeanette Rohatyn. Dr Rothermel received support from training Grant AR-07570.

We thank Drs Laurie Douglass, Alan Richman, Mark Hughes, Taraneth Shetty, and William Brown for providing information about patients; Bernadette Muldoon for help with patient care; Gail McHugh and Jason Hoitt for laboratory support in Lyme disease testing; and Colleen Fitzpatrick for help with preparation of the manuscript.

Holly Rothermel, MD^*,
Thomas R. Hedges III, MD^§
Allen C. Steere, MD^*
* Division of Rheumatology/Immunology
 Division of Pediatric Rheumatology
^§ Departments of Neurology and Ophthalmology
Tufts University School of Medicine
New England Medical Center
Boston, MA 02111

	FOOTNOTES

Received for publication Aug 7, 2000; accepted Jan 29, 2001.

Reprint requests to (A.C.S.) New England Medical Center, #406, 750 Washington St, Boston, MA 02111. E-mail: asteere{at}lifespan.org

	ABBREVIATIONS

ELISA, enzyme-linked immunosorbent assay; IgM, immunoglobin M; IgG, immunoglobin G; IgA, immunoglobin A; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging.

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