orbital optic glioma on the basis of its neuroimaging characteristics (see Chap. 4). Optic nerve sheath meningioma is classically held to exhibit a more aggressive course in children than in adults, especially with regard to early intracranial extension.13,587 However, there is no evidence that it this has any significant effect on prognosis for life or vision in the contralateral eye. Children with optic nerve sheath meningioma should be evaluated by chromosome analysis for the possibility of occult NF-2 (see Chap. 11).

also precipitate optic neuritis in children. The delayed onset of pediatric optic neuritis after recent infection or immunization and the bilateral involvement in most cases of postinfectious optic neuritis suggest a generalized mechanism of injury (i.e., a systemic autoimmune demyelination) rather than random, viral invasion of each optic nerve.499 Hierons and Lyle240 noted that encephalomyelitis typically occurs in the wake of viral infections and suggested that optic neuritis in children be viewed as a localized form of encephalitis.

Pediatric optic neuritis is fundamentally different from adult optic neuritis in the following ways:

(1)Pediatric optic neuritis is commonly bilateral whereas adult optic neuritis is usually unilateral.294,375

When childhood optic neuritis is accompanied by multiple neurological signs, the primary diagnostic considerations are acute disseminated encephalomyelitis (ADE), MS, and Devic’s disease (Table 3.7). The terms postinfectious

often retrobulbar.375

(3)Pediatric optic neuritis is usually a postinfectious condition that does not presage multiple sclerosis (MS)375 whereas adult optic neuritis is usually a demyelinative event that augurs the onset of MS.460

History and Physical Examination

It is often difficult or impossible to obtain an accurate history of the onset of visual symptoms in children. Young children may not notice unilateral visual loss and may blithely accept bilateral visual loss until it is so severe as to be incapacitating.294 In older children, a sense of panic may lead to denial of symptoms.294 The vagaries of subjective symptoms in children detract from the overall reliability of the history. Headache appears to be more common in pediatric optic neuritis.294,317 As in adults, a history of pain with eye movements supports the diagnosis.

Postinfectious Optic Neuritis

A febrile or flu-like illness commonly precedes pediatric optic neuritis by days or weeks. Diseases that have been specifically associated with optic neuritis in children include measles, mumps, chickenpox, rubella, brucella, pertussis, infectious mononucleosis, cat scratch disease, toxoplasmosis462 Q fever, viral ebola virus, mycoplasma, enterovirus, herpes simplex,

and Lyme disease.57,131,264,374,389,390,399,427,453,458,470,484,485 Diphtheria,

pertussis, and tetanus vaccines or other immunizations may

inflammatory, demyelinating disease of the CNS that usually follows a viral illness or vaccination by days to weeks. Children 6–10 years of age are most commonly affected, presenting with acute onset of motor signs and symptoms, seizure activity, and sometimes, altered consciousness, headache, fever, and ataxia.33 CSF analysis may show pleocytosis The histopathological hallmark of ADE is a zone of demyelination (with relative sparing of axons) around veins in association with infiltration of vessel walls and perivascular spaces by lymphocytes, plasma cells, and monocytes.33 ADE is believed to result from an

Table 3.7  Differential diagnosis of optic disc swelling with visual loss in children

AMPEE acute multifocal placoid pigment epitheliopathy, MEWDS multiple evanescent white dot syndrome

autoimmune reaction to myelin triggered by a virus or vaccine, because no virus has consistently been isolated.33 Also, the temporal framework and pathological features of postinfectious encephalitis closely resemble those of experimental allergic encephalitis, a prototypical autoimmune demyelinating disease.499

MR imaging in ADE shows moderate to large areas of increased signal intensity on T2-weighted images corresponding to the inflammation and edema associated with demyelination (Fig. 3.18).20,33 These lesions involve subcortical white matter in a patchy distribution, but cortical and deep gray matter are also involved to a lesser extent. The lesions are bilateral but usually asymmetrical. Brain stem and cerebellar lesions are common.20

Despite the large size and subcortical location of the lesions, MR imaging findings in ADE show significant overlap with those of MS.33 Conclusive differentiation of ADE from the initial presentation of childhood MS is not possible, even when combining clinical features, CSF analysis, and MR imaging.33 Although ADE is classically considered to be a monophasic illness, a small but significant fraction of patients have relapses, establishing the diagnosis of MS.33 Recent reports suggest that thalamic involvement may be a useful neuroimaging sign of ADE, because it is rarely seen in children with MS.33,225 Acute disseminated encephalitis is an emergent condition, with mortality estimated at 10–20%. Systemic corticosteroids are the mainstay of treatment.

Fig. 3.18  Acute disseminated encephalomyelitis. MR image shows patchy areas of prolonged T2 relaxation involving subcortical white matter and cortex. Courtesy of A. James Barkovich, M.D.

MS and Pediatric Optic Neuritis

Clinical and experimental evidence has demonstrated that the distinction between postinfectious childhood optic neuritis and MS may not be absolute. Riikonen458 believes that a combination of abnormal immunological responses, possibly precipitated by infectious agents in a genetically susceptible individual, may lead either to MS or to optic neuritis. Riikonen et al456 studied 18 children with optic neuritis, 10 of whom eventually developed MS. More than half of the children had suffered a bacterial or viral infection within 2 weeks prior to the first symptoms of optic neuritis. Vaccinations with live or attenuated viruses (e.g., polio, vaccinia, rubella, influenza) preceded the first episode of optic neuritis in six patients. Subsequent vaccinations caused exacerbations of optic neuritis in several cases. Five of the recently vaccinated children eventually developed MS.

Killed virus components, such as those used for influenza vaccines, do not produce this effect. Riikonen has recommended avoiding immunizations with live or attenuated viruses in children with MS. Bye et al73 described five similar children with chronic, recurrent optic neuritis, three of whom had encephalomyelitis with optic neuritis as their initial episode. These findings corroborate those from the Riikonen study and confirm that postinfectious optic neuritis, with or without encephalomyelitis, may be a harbinger of MS in some children.73 It is currently unclear whether concurrent encephalomyelitis affects the likelihood that MS will develop in the child with optic neuritis or whether the severity of the encephalomyelitis influences this prognosis.417

Controversy persists regarding the incidence of MS and its relative association with unilateral versus bilateral optic neuritis. Morales et al391 found that: (1) Children typically have bilateral involvement with papillitis following an antecedent viral illness; (2) Although visual prognosis is poorer in children than adults, the development of MS is less common in children; (3) Children who present with unilateral involvement have a better visual prognosis, however, they also develop MS at a greater frequency than children with bilateral involvement; and (4) Patients who developed MS were, on average, older than those who did not develop MS. Studies of childhood optic neuritis with long clinical observation periods show the rate of subsequent diagnosis of multiple diagnosis to be 26–56%.361,458 A second demyelinating event can occur more than 10 years following an initial episode of optic neuritis.361

Wilejto et al573 found that the risk of MS was high (36%) at 2 years in children with optic neuritis. This retrospective study found that 13 of 36 (36%) children with pediatric optic neuritis developed MS. Contrary to other studies,326,391 this study found that bilateral optic neuritis was associated with a greater likelihood of having or developing MS. MR imaging

abnormalities and the presence of clinical findings extrinsic to the visual system at baseline correlated with the diagnosis of MS. Morales et al391 and Wilejto et al573 found more MS in bilateral cases. Morales et al391 tried to debunk the notion that unilateral optic neuritis is supportive of the diagnosis of MS. In a retrospective analysis of 25 patients, Brady et al58 found that pediatric optic neuritis is usually associated with visual recovery, but a significant number (22%) remain visually disabled. The occasional poor visual outcome emphasizes the guarded prognosis of this disorder. Younger age at presentation and normal neuroimaging seem to impart a better visual prognosis, perhaps owing to a greater capacity for remyelination.79

Other studies have found that, compared with adults, the risk for development of MS after childhood optic neuritis is lower. In a 15-year follow-up of adult optic neuritis, the LONS found the cumulative probability of MS to be 50% at 15 years.416 Lucchinetti et al361 performed a life-table analysis of 79 patients and found that clinically or laboratory-suggested definite optic neuritis would develop in 13% after 10 years of follow-up. By 20 years, the risk rose to 19%. Not surprisingly, there was increased risk of development of MS in patients with sequential or recurrent optic neuritis compared with those who had unilateral or bilateral simultaneous involvement. Repka and Green454 described a 5-year-old girl who developed severe macular distortion due an epiretinal membrane in one eye following bilateral papillitis.221

Schilder disease is a severe form of MS that can present with cortical blindness and bilateral occipital lesions.327,495 The centrum semiovale is the typical location of the large plaque-like lesions of Schilder disease.434

Devic Disease (Neuromyelitis Optica)

The diagnosis of early neuromyelitis optica Devic disease should be considered in any child or adult who presents with acute bilateral optic neuritis. Such patients should be cautioned to return immediately if they develop a gait disturbance or bladder dysfunction. Unlike MS, Devic disease is usually an acute and often self-limiting disorder (a “once and for all” demyelination). Subsequent attacks of demyelination are rare. When relapses involve other neurological signs, the patient must be considered to have MS. The relative incidence of Devic disease to MS is much higher in Asia, particularly in Japan.320 It is most common in young adults but may appear at any age from 5 to 60 years.375 Most cases start with bilateral visual symptoms. Visual loss occurs acutely and becomes severe within a few days.324 The optic discs may be normal or swollen.375 Pediatric Neuromyelitis Optic (PMO) may be difficult to distinguish from multiple sclerois

in the early stages of the disease.357a Although many adults remain permanently blind after an attack of Devic disease, Jeffery and Buncic found that children with Devic disease have an excellent prognosis for visual and neurological recovery with no recurrences or long-term sequelae.263 However, a recent report of a 23-month-old child with Devic disease described severe sequelae with a poor outcome.589 Occasionally, visual system and spinal cord involvement are separated by months or years.364 Rarely, positive NMO antibodies are found in patients with recurrent optic neuritis without clear evidence of transverse myelitis.113

Neurological involvement consists of a progressive and often ascending sensorimotor myelitis affecting either the lower limbs or all four limbs and sometimes causing a complete transverse lesion of the cord.375 Urinary retention or incontinence are common. The CSF typically shows a pleocytosis and increased total protein. Patients with Devic disease have a high CSF albumin level with a low serum/CSF albumin ratio, suggesting a permeability defect in the blood-brain barrier. Most affected individuals are found to have absent oligoclonal bands, in contrast to the increased daily CSF IgG synthesis and oligoclonal bands that typify MS.364 Devic disease is fatal in approximately 20% of cases.320 Immunosuppressive therapies generally fail to benefit patients.364

Until recently, the clinical diagnosis of Devic disease was predicated on the diagnosis of concurrent acute optic neuritis and spinal cord dysfunction, with absence of brain white matter signal abnormalities on MR imaging.199 MR imaging in Devic disease typically demonstrates a normalappearing brain with enlargement and cavitation of the spinal cord.364 Unlike in MS, the cerebral hemispheres, brain stem, and cerebellum are generally unaffected in Devic disease.364 The usual absence of white matter MR signal abnormalities within the brain hemispheres in Devic disease helps to distinguish it from MS.364 The final diagnosis is established by finding antiNMO antibodies within the CSF (reference from below).

Recently, a serum antibody that targets the aquaporin-4 molecule has been identified in adults with Devic disease.341 Devic disease, which is now considered to be an aquaporin channelopathy, may represent the first molecularly defined autoimmune optic neuropathy. Researchers at Mayo Clinic have identified an immunoglobulin marker of neuromyelitis optica (the “NMO antibody”) that binds selectively to the aquaporin-4 water channel and may play a causative role.114 NMO-IgG is a serum autoantibody marker that is both sensitive and specific for NMO and is generally absent in patients whose clinical course is otherwise indistinguishable from prototypical MS. This marker has also been found in Japanese patients with opticospinal MS, prompting the suggestion that neuromyelitis optica and Japanese opticospinal MS are the same disorder.340

The NMO antibody, which predicts frequent relapse of myelopathy and optic neuritis, is also found in patients with lupus erythematosus and Sjögren’s syndrome who also have severe optic neuritis and longitudinally extensive myelitis. Because this antibody is also found in patients with optic neuritis and myelitis who have brain signal abnormalities atypical of MS, the diagnosis of NMO has been revised to allow inclusion of these brain imaging abnormalities. However, a positive marker is not universal in patients who have classic Devic disease. It continues to be a subject of debate whether NMO is a separate disease or merely a form of MS and whether the natural history of NMO is always worse than that of conventional MS.202 No single clinical characteristic is adequate for defining NMO.

Diagnostic confirmation using antiNMO antibody testing has led to revised diagnostic criteria by demonstrating the occasional presence of additional MR signal abnormalities in the brain is still compatible with the diagnosis of neuromyelitis optica196,578 Thus, while the presence of CNS symptoms outside the optic nerves and spinal cord formerly excluded the diagnosis of Devic disease,110,364,413 such lesions are now recognized as compatible with Devic disease. Similarly, the term NMO was applied to patients who experienced a monophasic event consisting of bilateral simultaneous optic neuritis and acute myelitis.122 The NMO spectrum is now recognized to typically evolve as a relapsing disorder that also includes patients with unilateral optic neuritis with index events of optic neuritis and myelitis occurring weeks or even years apart.577

A relapsing type of NMO is clinically characterized by two index events (optic neuritis and transverse myelitis) separated by an interval of days, weeks, months, or even years, with variable remission followed by new clinical events restricted to the optic nerve and spinal cord.421,422,577

Currently recommended diagnostic criteria for Devic disease require optic neuritis, myelitis, and at least two of three supportive criteria: MRI evidence of a contiguous spinal cord lesion three or more segments in length, onset brain MRI nondiagnostic for MS, or NMO-IgG seropositivity.578

A necrotizing (rather than demyelinating) myelopathy is the histopathological hallmark of Devic disease.364 Autopsy examination of the optic nerves and chiasm shows demyelination, with gliosis and cavitation in some cases.364 The remainder of the brain is normal. Autopsy examination of the spinal cord shows a severe necrotizing myelopathy with involvement of both gray and white matter, thickening of blood vessels walls, and no lymphocytic infiltrate.364 These findings contrast sharply with those of MS, in which multiple demarcated plaques are scattered throughout white matter in the brain and spinal cord.

Prognosis and Treatment

Proper distinction between NMO and MS is important both prognostically and therapeutically, as NMO has a worse prognosis than MS. Within 5 years of onset, 50% of patients are blind in both eyes and cannot walk unassisted, and 20% die of respiratory failure due to cervical myelitis.577 The visual prognosis for Devic’s disease optic neuritis is also worse than that for patients with MS.378 Therapeutically, the two disorders may respond differently to immune modulatory therapy and to plasmapheresis, whereas the currently promoted treatment of MS includes immune-modulating agents such as interferon b.114 Mitoxantrone, which potentially suppresses both T-helper lymphocytes and the humoral immune system via both macrophage and B-cell attenuation, shows promise in the clinical treatment of this devastating condition.566

Course of Visual Loss and Visual Recovery

Initial visual loss in pediatric optic neuritis is often profound; acuities of light perception and no light perception are not unusual. Despite the severity of visual loss, the prognosis for visual recovery is generally regarded as excellent.294,317,375,499 Kennedy and Carroll294 noted that “in most instances, improvement begins before the end of the third week after onset and reaches a maximum by 6 months”.21

Kriss et al317 found the pattern-evoked VEP latency to be normal in 55% of children with recovered optic neuritis, as compared to a previously established figure of 10% in adults and suggested that the greater potential for remyelination in the young than in the old may account for these findings. In most children, vision spontaneously recovers to 20/20, but some degree of optic disc pallor usually persists.

Meadows375 stated that “the slower and more insidious the loss of function, the less the likelihood of visual improvement, and if this does occur, it tends to be equally slow. In contrast, a more abrupt and catastrophic onset is sometimes followed by surprising recovery.” In offering an optimistic prognosis to the parents and child, it should be kept in mind that most series include descriptions of a few children whose vision either failed to improve or improved minimally.234 Some children in the older series may have had a mutation for Leber hereditary neuroretinopathy. It is not known whether children who sustain permanent visual loss have a distinct form of optic neuritis or whether their failure to improve represents the low end in a broad spectrum of recovery.