When a laboratory test becomes available for a disorder previously diagnosed solely on clinical grounds, the spectrum of that disorder is apt to be expanded. With the discovery of a blood test (the NMO antibody) that has an estimated sensitivity of 76% and a specificity of 94%,1Devic disease is proving to be such an example. Devic recurrent neuromyelitis optica was considered a demyelinating disease in which the cardinal features were a bilateral optic neuropathy and a cervical myelopathy without other clinical or magnetic resonance imaging (MRI) evidence of involvement elsewhere in the nervous system and with a poor prognosis for recovery. With the advent of the NMO-antibody test, the picture of the syndrome is expanding.2We report on the cases of 3 women who suffered from recurrent optic neuritis (ON) in association with the NMO antibody but who never developed clear evidence of a transverse myelitis in approximately a decade of follow-up.
A 43-year-old woman was seen in October 1994 with a severe bifrontal headache and left eye pain with eye movement. Over the next week visual acuity declined to 20/50 OS. Dyschromatopsia, a superior altitudinal visual field defect, and an afferent pupillary defect were all present in the left eye. Her fundi, general neurological examination results, and findings from contrast MRI of the brain were unremarkable. Her vision did not improve and optic atrophy developed. She was stable until late 2001 when the visual acuity OS decreased painlessly to the level of counting fingers. Brain MRI findings were again normal. She was observed without any improvement. In the spring of 2002, she had similar symptoms in the right eye attributed to ON and was not treated; details of her examination findings at that time were not available to us. We first evaluated her condition in July 2002 by which time her best-corrected visual acuity had recovered to 20/20 OD with normal color and full visual fields. Her visual acuity OS was 1/200 and her remaining visual field was a small inferonasal island. Both optic discs were pale. Contrast MRI of the brain and cervical spine showed no lesion and she was not treated. Results of a repeated contrast MRI of the brain and cervicothoracic cord in April 2003 were normal. She was well until June 2005 when she developed “blotchy” vision in her right eye that was accompanied by discomfort with eye movement. Visual acuities were 20/400 OD and hand motion perception OS. There was an inferior altitudinal visual field defect in the right eye. An MRI of the brain and orbits showed only 1 small T2-weighted hyperintense lesion in the subcortical white matter of each parietal lobe. She was treated with intravenous (IV) methylprednisolone sodium succinate, 1g/d, for 5 days, and 2 months later visual acuity OD improved to 20/20 and the inferior altitudinal visual field defect improved. The NMO-antibody test at that time was positive. She also complained of intermittent, fleeting paresthesias that could occur anywhere in her body, including the face and head. Findings from a neurological examination were normal except for a left Hoffman sign. Results from a contrast MRI of the total spine were normal (Figure 1).
Patient 1. T2-weighted sagittal magnetic resonance image of the total spine (cervical spine is shown here) showed no white matter hyperintensities 12 years after her index event.
In July 1997, a 39-year-old woman had 2 episodes of blurry vision in both eyes that appeared like “wavy water” after taking a hot shower. Four months later, vision in her left eye declined over 5 days, ac companied by pain on eye movement and occasional photopsias. Best-corrected visual acuities were 20/10 OD and 8/200 OS and she could only correctly identify the control Ishihara plate with her left eye. There was a large central scotoma and a relative afferent pupillary defect in the left eye. The right fundus was unremarkable and the nasal portion of the left optic disc was swollen without hemorrhages or exudates. Findings from neurological examination were normal. An MRI of the orbits showed increased inversion recovery signal and enhancement of the left optic nerve that extended through the optic canal but spared the optic chiasm. The brain parenchyma was unremarkable. Based on a history of an abdominal rash several months earlier and an antinuclear antibody titer positive at 1:5120, she was treated with IV methylprednisolone for presumed lupus optic neuropathy. However, there was no other clinical evidence of systemic lupus and findings for double-stranded DNA were negative. One month later, the acuity OS decreased to hand motion perception, but it improved to 20/40 by 8 months after her first visit. She was then unchanged until 7 years later when she experienced pain with eye movements in the left eye that was followed by a progressive loss of visual acuity to no light perception (NLP) over 2 days. Acuity OD was 20/20, but a temporal field defect was found. An MRI showed enhancement of the left optic nerve to the chiasm but no white matter lesions in the brain parenchyma (Figure 2). The visual acuity OS improved to 8/200 over 8 months, but the acuity OD dropped to 20/25 prompting another course of IV methylprednisolone. In February 2005, she saw a yellow band across the center of her left eye accompanied by pain in each eye. She improved with another course of IV methylprednisolone.
Patient 2. A, Axial T1-weighted magnetic resonance image of the orbits with contrast in 1997 showed enhancement of the left optic nerve. B, Sagittal fluid-attenuated inversion recovery still did not show any white matter hyperintensities in 2004.
In January 2006, vision in the left eye became totally black and she experienced superior blurriness in the right eye, with acuity OD dropping to 20/30. She also complained of left facial and tongue numbness. She received another course of IV methylprednisolone. Neurological examination findings showed symmetric brisk reflexes. Her antinuclear antibody titer was positive at a dilution of 1:320 and the angiotensin-converting enzyme level was normal. A contrast MRI of the brain and cervical spine showed no abnormalities. Cerebrospinal fluid analysis showed normal contents, including negative oligoclonal bands and IgG levels. Tests for serum Lyme, anticardiolipin, and lupus anticoagulant antibodies were negative and serum rapid plasma reagin testing was nonreactive. The NMO-antibody titer was positive at 1:15 360 (normal <1:120). She was started on daily azathioprine treatment and has had no further visual symptoms; however, at one visit she complained of intermittent left face, tongue, and limb numbness. Contrast MRI of the brain and cervicothoracic spine in November 2006 again showned no white matter abnormalities.
In August 1995, a 31-year-old woman experienced blurring of vision in her right eye that was accompanied by headache, rhinorrhea, and right eye pain. Over 2 days, visual acuity deteriorated to NLP and an MRI showed enhancement of the right optic nerve without brain abnormalities. She was treated with 1 week of IV methylprednisolone and her vision returned to normal within 1 month. She was well until June 1999, when she experienced the same symptoms. Visual acuities were 20/400 OD and 20/20 OS, and there was a relative afferent pupillary defect, a large central scotoma, and optic nerve pallor in the right eye. There were minimal patchy paracentral defects in the left eye. An MRI revealed right prechiasmal optic nerve enhancement, as well as mild enhancement of the left optic nerve. A new T2-weighted hyperintense lesion was seen in the body of the corpus callosum. A course of IV methylprednisolone was given, but vision did not improve. Findings from neurological examination in November were normal except for hyperreflexia of the left biceps and brachioradialis. Results from a cervical spine MRI were normal and reflexes were symmetric in February 2000. A lumbar puncture showed normal contents, including negative oligoclonal bands and IgG. Erythrocyte sedimentation rate, angiotension-converting enzyme, and serum protein electrophoresis values were normal. During a pregnancy in 2001, she experienced fleeting bilateral hand numbness when fatigued, but her neurological examination findings were normal. In July 2004, she began to experience 1- to 2-minute episodes of pain across her pelvis and thighs without bowel or bladder symptoms. Apart from 4+/5 right psoas strength, findings from her neurological examination were normal. A cervicothoracic MRI with contrast showed no abnormalities and the sensory episodes subsided within several months and her strength normalized.
In July 2005, visual acuity OD rapidly deteriorated to NLP. Extensive intracanalicular enhancement of the optic nerve was seen on MRI. She received 5 days of treatment with IV methylprednisolone and her visual acuity improved to 20/400 within 10 days. Test results for serum rapid plasma reagin, Lyme antibody, and anti-Ro, anti-LA, and SM antibodies were negative. In November 2005, she complained of left arm numbness that resolved in 3 days. Neurological examination showed subtle left-sided weakness and a subtly diminished sensitivity to pinprick on the left-sided extensor surface of the forearm. An MRI of the brain showed only a left-sided developmental venous anomaly. By February 2006, her neurological examination results were completely normal. In July 2006, she noted an inferior visual field defect in the left eye. Visual acuities were 20/400 OD and 20/40 OS. She could identify no color plates OD and OS the color plate acuity was 6.5/8 and there was a new inferior arcuate defect in the left eye. The patient received another course of IV methylprednisolone. Testing for the NMO-IgG antibody marker was positive at 1:480. The patient was treated with plasmapharesis in August. By November 2006, acuity OS had improved slightly to 20/30−1.
Our understanding of the clinical spectrum of Devic neuromyelitis optica has evolved substantially since Devic's 1894 review of 16 patients with visual loss and spinal cord disease.3The original description was that of an acute, monophasic, severe myelitis and simultaneous or sequential bilateral ON occurring in close succession and resulting in blindness and paraplegia. Over the years, however, patients were described who had only unilateral ON, whose episodes were separated by months or years, and who had recurrent disease.4A retrospective review in 1999 of 71 patients with NMO antibody revealed that most of them (48 of 71) had the recurrent form.5Based on that review, criteria were formulated for the diagnosis of Devic disease (Table).
In 2004, an IgG autoantibody was identified that appeared to differentiate patients with clinically definite NMO from patients with multiple sclerosis or other neurological disorders.7Further investigation revealed that NMO-IgG binds to aquaporin-4,8the principal water channel involved in fluid homeostasis in the central nervous system and that recognizes epitopes on astrocytic foot processes in the blood-brain barrier.9Using this antibody test against a criterion standard of clinically definite NMO by the 1999 Wingerchuk et al5criteria, its sensitivity and specificity were determined to be 73% and 91%, respectively.7Interestingly, among patients considered at high risk for Devic disease, (defined as having either recurrent isolated ON or isolated transverse myelitis extending more than 3 vertebral segments without imaging evidence of brain parenchymal lesions satisfying the criteria for multiple sclerosis), 46% were seropositive for NMO-IgG antibody. Of the subgroup with recurrent isolated ON, 2 of 8 were seropositive (25%), but it is not clear whether these patients went on to develop NMO antibody by diagnostic criteria.
A more recent study found that 36 of 60 patients (60%) with suspected or definite NMO antibody had abnormalities on brain MRI.10At the time of onset, 24 of these patients already had nonspecific changes on MRI. This finding, along with the discovery of the NMO antibody, led to a revision of the criteria1that included NMO-IgG antibody status as a supportive criterion and permitted brain lesions on MRI, as long as they did not fit the criteria of Paty et al6for multiple sclerosis (≥4 white matter lesions or 3 lesions when 1 is periventricular).
Using these criteria (Table), patients would no longer be excluded because of clinical evidence of disease beyond the spinal cord and optic nerves. Using a criterion standard of the study neurologist's final diagnosis based on clinical, imaging, and laboratory data, these criteria resulted in a 99% sensitivity and 90% specificity (P < .001).1Interestingly, using the new criterion standard of “final diagnosis” rather than the 1999 criteria, the sensitivity and specificity of the NMO-IgG antibody increased to 76% and 94%, respectively.
Even these more inclusive parameters still required both an ON and a transverse myelitis for the diagnosis. However, one prospective study showed that of 9 patients who experienced an acute attack of transverse myelitis extending to 3 or more vertebral segments and who were also seropositive for the NMO antibody, only 1 went on to have ON at 1 year, although 4 had a recurrence of their transverse myelitis.11A more recent study found that 6 of 6 patients with longitudinally extensive transverse myelitis were positive for the NMO antibody.12Together, these results suggested that there was a group of patients with only transverse myelitis for at least a year who are positive for NMO antibody and might have a disease with a similar pathologic course to those with clinical NMO antibody.
We report 3 cases of patients who had isolated recurrent ON or chiasmitis and were found to be positive for the NMO antibody. None of them demonstrated definite clinical or radiological signs of transverse myelitis throughout their course of 9 years or more (9, 12, and 12 years). These cases suggest the existence of a group of patients with recurrent ON with incomplete recovery but without full-blown cases of transverse myelitis who fall within the spectrum of Devic disease. Their inclusion in an NMO spectrum is supported by the profound visual loss that resulted in all 3 cases and a brain MRI that showed no white matter disease in patients 2 and 3 and did not meet criteria for multiple sclerosis in patient 1. In the 2 patients who underwent lumbar puncture, the lack of oligoclonal bands is consistent with NMO antibody; however, the lack of a pleocytosis of more than 50 white blood cells is less typical. The presence in the second patient of antinuclear antibody when first seen by us is interesting since 1 study found an associated vasculitis (systemic lupus erythematosus or Sjögren disease) in 6 of 16 patients (37.5%)with Devic disease that was diagnosed by clinical criteria.13
The third patient experienced serial episodes of ON over an 11-year period with little improvement after the second episode despite treatment with methylprednisolone. Interestingly, she had 1 lesion in the corpus callosum on MRI. Brain lesions in patients with NMO antibody tend to occur in areas with a high aquaporin channel density, which include the hypothalamus, the periventricular and periaqueductal regions, the cerebellar hemispheres, and the fornix.14Although corpus callosum lesions are not typical, at least one other lesion in a patient with NMO antibody has been reported.14
All 3 of our patients may have experienced subclinical, subradiological spinal cord disease, as evidenced by the fleeting full-body paresthesias experienced by patient 1, intermittent left body numbness by patient 2, and several days of mild left arm numbness by patient 3. Although myelitis was not found by MRI in any of these cases, in retrospect it would have been useful to examine patients like this with somatosensory evoked potentials. However, in the first 2 cases, prominent involvement of the face, head, or tongue was more supportive of brainstem involvement than of spinal cord. If these subtle findings did represent spinal cord disease in these patients, the latency between the index ON and the myelits would not meet the original cut-off period of 2 years5(9, 7, and 6 years, respectively) or the original criteria for myelitis extending over 3 vertebral levels. In the 1999 study by Wingerchuk et al,5patients with an interval of more than 2 years between ON and transverse myelitis were excluded, producing a mean interval of 166 days.5In a recent study15of 30 patients with clinical NMO antibody where a 2-year criterion was not adhered to, the mean “optico-medullary time” was 2.3 +/−3.4 years.
In large series of patients with ON, there are always some patients who fail to recover, show no brain lesions to begin with, and do not develop multiple sclerosis or transverse myelitis. The 3 patients herein fall into that category. We suggest that they are part of a subset of patients with isolated, severe ON who have a monosymptomatic form of Devic disease. Of the 457 patients in the Optic Neuritis Treatment Trial who had acute unilateral ON, 3% were left with visual acuities less than 20/200 10 years after first being seen.16Evidence of isolated ON associated with NMO-antibody seropositivity in our's and others' studies (14.3% of patients with recurrent ON were positive for NMO antibody in a recent study17) raises the question of whether some of the Optic Neuritis Treatment Trial patients with poor recovery might harbor the NMO antibody. Patients with idiopathic ON, normal findings onbrain MRI, and poor visual recovery should be tested for the presence of the NMO-IgG antibody considering that its presence indicates a pathogenesis and prognosis different from those of multiple sclerosis, and the ultimate visual outcome could potentially be improved with the use of immuno modulatory treatments. The extent of eosinophilic infiltration, complement activation, and perivascular deposition of IgM found in pathological series of NMO lesions, along with the discovery of the NMO antibody, supports a humoral mechanism in the pathogenesis of the disease and the use of medications that are appropriately targeted.18It would appear that patients with multiple sclerosis and patients with Devic disease should be treated differently and every effort must be made to differentiate those patients who have ON from those who have the initial manifestation of Devic disease. Testing for NMO-IgG antibody, even in patients with isolated acute ON with no other signs of NMO antibody, could potentially help identify this group and lead to earlier focused intervention and better clinical outcomes.
Correspondence:Dr Dinkin, Department of Neurology, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115 (email@example.com).
Financial Disclosure:None reported.
Dinkin MJ, Cestari DM, Stein MC, Brass SD, Lessell S. NMO Antibody–Positive Recurrent Optic Neuritis Without Clear Evidence of Transverse Myelitis. Arch Ophthalmol. 2008;126(4):566-570. doi:10.1001/archopht.126.4.566