NMO is an inflammatory disease of the central nervous system characterized by severe optic neuritis and the onset of long segment transverse myelitis (LETM). Our understanding of NMO has progressed tremendously over the past few decades. This has been largely due to the discovery of the disease-specific autoantibody, NMO-IgG, and subsequently its primary auto-target antigen, antibodies to aquaporin 4 (AQP-4), which have allowed NMO to be distinguished from MS as a separate disease.
The current diagnostic criteria (referring to the 2006 diagnostic criteria) still require the presence of optic neuritis and myelitis for the diagnosis of NMO. However, the discovery of AQP-4 antibodies has led to the recognition of a more diverse group of clinical phenotypes in addition to the classic NMO, the so-called “optic neuromyelitis optica spectrum disorders (NMOSD)”, which encompass not only serum AQP4-positive limited forms of NMO with specific brain abnormalities (limited forms of NMO) or transmissible NMO. NMOSD includes not only limited forms of NMO or classic NMO with specific brain abnormalities, but also patients with other autoimmune diseases (e.g., SLE, dry syndrome, etc.) who are seropositive for AQP4 antibodies. In this context, MRI plays an increasingly important role in the differentiation of NMOSD from other inflammatory diseases of the central nervous system, especially MS. It is crucial to differentiate the above-mentioned diseases because of the different treatments. In addition, current evolving MRI techniques may help to identify more specific markers that can help to elucidate the underlying pathogenic mechanisms of NMOSD.
Early cranial MRI studies of NMO patients have revealed unexplained clinically asymptomatic, nonspecific white matter lesions, and the advent of AQP4-IgG testing has updated our understanding that a large proportion of NMOSD patients actually have brain MRI abnormalities, often located in areas of high AQP4 expression. However, brain abnormalities can also be present in areas with low AQP4 expression. Although nonspecific punctate or patchy high signal on T2WI/FLAIR is the most common imaging manifestation of NMOSD, certain lesions in NMOSD still have site- or morphologic-specific features.
Prior to the discovery of the AQP4 antibody, reported MR abnormalities of the brain were seen in only 13-46% of patients with NMOSD. However, when cranial MRI criteria were not considered, cranial MRI abnormalities were seen in up to 50-85% (refer to the revised 2006 NMO diagnostic criteria) and 51-89% (NMOSD seropositive patients). In addition, cranial MRI abnormalities have been reported in approximately 43-70% of patients with NMOSD at the initial onset of NMOSD. One possible explanation for the wide variation in the proportion of cranial MRI abnormalities reported in different literatures is that the probability of cranial MRI abnormalities becomes higher as the disease progresses. In a group containing 88 reports of seropositive children, 68% of children who underwent cranial MRI had cranial abnormalities, with lesions more pronounced in the periventricular region of the third ventricle (mesencephalon), periventricular region of the fourth ventricle (brainstem), supratentorial and subretinal white matter, midbrain, and cerebellum. This is consistent with the observation that 45-55% of children with NMOSD have episodic brain symptoms, including oculomotor paralysis, intractable vomiting and eructations, altered state of consciousness, severe behavioral changes, somnolence, ataxia, and seizures.
Classification of cranial MRI manifestations of NMOSD
1. Periventricular lesions surrounding the ventricular system
(1) Mesencephalic lesions surrounding the third ventricle and aqueduct: The sites of mesencephalic lesions surrounding the third ventricle and aqueduct include the thalamus, hypothalamus, and anterior border of the midbrain, which have been reported in NMOSD (Figure 1A). These lesions are usually asymptomatic, but some patients may present with abnormal antidiuretic hormone secretion, narcolepsy episodes, hypothermia, hypotension, hypersomnia, obesity, hypothyroidism, hyperprolactinemia, secondary amenorrhea, overflow of breast milk, and behavioral changes.
(2) Dorsal brainstem lesions adjacent to the four ventricles: lesions in the dorsal brainstem adjacent to the four ventricles, including the area postrema and the solitary nucleus, are among the most specific cranial MRI findings in NMOSD patients. It is seen in 7-46% of NMOSD patients and is highly correlated with intractable eructation, nausea, and vomiting. MRI and clinical evidence suggest that the posterior pole region is an important area of NMOSD susceptibility, and subsequent studies have identified this region as an important pathway for circulating IgG to enter the CNS. 40% of NMOSD patients have pathological changes in this region, but no definite neuronal, axonal, or myelin deficits. The medulla oblongata lesions are often contiguous with the cervical medulla lesions and are mostly linear (Figure 1B.b). These lesions are often associated with the first symptoms of the disease or predict acute deterioration. Brainstem lesions can present with a variety of different clinical manifestations, such as nystagmus, dysarthria, dysphagia, ataxia, and oculomotor palsy.
(3) Periventricular lesions surrounding the lateral ventricles: corpus callosum lesions are seen in 12-40% of NMOSD patients. Because corpus callosum lesions are frequently seen in both NMO and MS patients, this site does not serve as a specific point of differentiation between NMO and MS. However, corpus callosum lesions in MS are often discontinuous, ovoid, perpendicular to the lateral ventricles, and mostly involve the lower part of the corpus callosum (Figure 2A). In contrast, in NMOSD, the location of the lesion is very close to the lateral ventricle, immediately adjacent to the inner layer of the ventricular canal (Figure 1C.a). The corpus callosum lesions in the acute phase of NMOSD are often markedly edematous and polymorphic, forming a “marbled pattern”, sometimes involving the entirety of the corpus callosum pressure, with a distinctive Sometimes the entire corpus callosum is involved, and a unique “arch bridge pattern” appears (Figure 1C.b and C.c). Sometimes, the corpus callosum lesions continue into the cerebral hemispheres, forming extensive, fused white matter lesions. In the chronic phase of NMOSD, the corpus callosum lesions may gradually shrink, diminish in signal, and may even disappear; however, both capsular degeneration and corpus callosum atrophy have been reported. Certain clinical manifestations, such as impaired cognitive function and motor coordination, may be related to damage to the corpus callosum, but the evidence is not very strong.
2. White matter lesions of the cerebral hemispheres
Extensive, fused white matter lesions in the cerebral hemispheres are often verrucous (the maximum radius can be >3 cm) or long fusiform or radial along the white matter fiber alignment (Figure 1D). There is usually no occupancy effect. increased diffusion coefficient of the lesion on ADC suggests a possible acute inflammation-related vasogenic edema (Figure 1D.c), which may be confused with reversible posterior encephalopathy syndrome (PRES) or Balo disease. These extensive lesions are more common in patients with positive AQP4 antibodies compared to those with negative AQP4 antibodies. In the chronic phase of the disease, these large lesions tend to shrink or even disappear, but some patients may develop cystic or cavernous changes. The above lesions can cause various symptoms such as hemiparesis, encephalopathy, and visual field defects depending on the area they involve. Large fused white matter lesions of the cerebral hemispheres are more common in children with NMOSD. Tumor-like lesions accompanied by perifocal edema and varying degrees of occupying effects may resemble acute disseminated encephalomyelitis (ADEM) or CNS malignancies.
3. Lesions involving the corticospinal tract cortex
Spinal tract involvement may be unilateral or bilateral, and lesions may extend from the deep white matter of the cerebral hemispheres through the posterior limb of the internal capsule to the cerebral peduncle or pons of the midbrain (Figure 1E). These lesions are continuous, often long-segmented, and distributed along the pyramidal tracts (Figure 1E.c). Several cohort studies of patients with NMOSD have reported the presence of foci in the corticospinal tract in approximately 23-44% of patients, and they have been occasionally found in other studies. Interestingly, unlike the periventricular area, the corticospinal tract is not a region of high AQP4 expression, so it is unclear why this region is frequently involved in NMOSD patients.
4. Non-specific lesions
On T2WI/FLAIR, small non-specific punctate (<3mm) or lamellar high signal is often observed in subcortical areas or deep white matter areas, which is the most common cranial MRI abnormality in NMOSD (35-84%), usually without clinical symptoms.
5. Reinforcing lesions
Some previous studies have reported that 9-36% of NMOSD patients may have enhancing lesions on cranial MRI, but the exact percentage is not known. Most of the lesions show indistinct, blurred, multilamellar enhancement, which is called “cloudy enhancement” (Figure 1F.a). This cloudy intensification pattern is helpful to differentiate from well-defined ovoid or annular/open-ring lesions (Figure 2), which are more typical features of MS. Linear enhancement of the ventricular canal surface of the lateral ventricles (pencil-like lesions) has also been reported (Figure 1F.b). Well-defined nodular enhancement or meningeal enhancement is also seen in patients with NMOSD, but is rare.
(Aa: mesencephalic lesion surrounding the third ventricle and aqueduct; Ab: thalamic and hypothalamic involvement; Ac: anterior border of the midbrain; Ba: dorsal brainstem lesion adjacent to the four ventricles; Bb: medullary linear lesion continuous with the cervical medullary lesion; Bc: swollen diffuse dorsal brainstem lesion involving the cerebellar peduncle; Ca: corpus callosum lesion adjacent to the lateral ventricles and immediately adjacent to the inner layer of the ventricular canal; Cb: corpus callosum lesion in a “marble-like pattern”; Cc: corpus callosum lesion with “arch bridge pattern”; Da: tumor-like cerebral hemisphere white matter lesion; Db: long fusiform lesion; Dc: increased diffusion coefficient of the lesion on ADC, suggesting vasogenic edema; Dd: chronic phase cystic lesions in the cerebral hemispheres; Ea: lesions in the corticospinal tracts of the posterior limb of the internal capsule; Eb: lesions in the cerebral peduncle of the midbrain; Ec: long segmental lesions along the pyramidal tracts; Fa: cloudy enhancement; Fb: linear enhancement of the ventricular surface of the lateral ventricles; Fc: meningeal enhancement)
(A: discontinuous, ovoid, perpendicular lesions visible in the lateral ventricles and corpus callosum; B: lesions with oval or open-loop enhancement and clear borders)
MRI manifestation of the optic nerve in NMOSD
It has been reported that nonspecific optic nerve sheath thickening and optic nerve high signal are seen in T2WI and T1WI enhancement sequences during the acute optic neuritis phase. However, because similar changes can be seen in MS patients with optic neuritis, this feature cannot be used as a diagnostic support point for NMOSD. Studies at this stage have focused on the different features of MRI of optic nerve injury in MS and NMOSD. In patients with NMOSD, the lesions tend to involve the posterior part of the optic nerve, including the optic cross, often with simultaneous bilateral optic nerve involvement. Therefore, in clinical practice, NMOSD should be considered when there is inflammation of the long segment of the optic nerve, especially when there is simultaneous bilateral involvement and posterior extension of the lesion involving the optic cross.
(A: right posterior optic nerve enhancing lesion; B: bilateral posterior optic nerve/optical cross diffusely enhancing lesion)