When encountering negative AQP4 in nmosd patients, what diseases should you consider

Neuromyelitis optica spectrum disease (nmosd) is a group of immune-mediated central nervous system (CNS) inflammatory demyelinating diseases with optic nerve and spinal cord involvement. In 2015, the diagnostic criteria of nmosd formulated by the international NMO diagnostic group were divided into positive and negative groups based on anti AQP4 antibody. In fact, the diseases that may involve optic nerve and / or spinal cord also include anti myelin oligodendrocyte glycoprotein related diseases (mog-ad), autoimmune glial fibrillary acidic protein astrocytosis (GFAP), anti-n-methyl-m-aspartate receptor (NMDAR) encephalitis, anti glutamic acid decarboxylase related diseases (gad-ad), anti glycine receptor related diseases (GlyR AD), which play an important role in the diagnosis of anti AQP 4. Negative nmosd should be considered.

Nmosd is a group of CNS inflammatory demyelinating disease spectrum mediated by antigen antibody mainly involved in humoral immunity, with or without anti AQP4 positive. The majority of nmosd patients were young adults, the median age was 39 years old, and the ratio of male to female was 1:9-11. The clinical manifestations included optic neuritis, acute myelitis, posterior medullary syndrome, acute brainstem syndrome, acute diencephalon syndrome and brain syndrome. Among them, optic neuritis often involves the posterior segment of optic nerve and optic chiasm; while acute myelitis mostly involves more than three vertebral segments, and most of them are transverse injuries; in some early cases, the length of spinal cord involvement can be shorter than three vertebral segments or incomplete transverse involvement. It is not difficult to diagnose patients with positive anti AQP4, but it is still a challenge to diagnose patients with negative anti AQP4.

Mog-ad is an inflammatory demyelinating disease of CNS mediated by anti MOG antibody, which is more common in children than in adults, and the incidence ratio of male to female is 1:1-2. The main symptoms include optic neuritis, meningoencephalitis, brainstem encephalitis and myelitis. For AQP4 negative patients, the possibility of mog-ad should be considered. Optic neuritis in mog-ad can involve bilateral optic nerves, especially the anterior segment of optic nerve, which can lead to optic disc edema (90%); it is often associated with orbital connective tissue involvement, which leads to peripheral optic neuritis. Mog-ad myelitis can be long segment transverse myelitis, but also short segment myelitis, involving the lumbar spinal cord and conus.

GFAP astrocytosis is the first reported autoimmune disease of the nervous system in 2016, and it is related to GFAP autoantibodies. The median age of GFAP astrocytosis was 44-54 years old, and the proportion of female was slightly higher than that of male, about 55.1%. Based on the current research, about 50% of GFAP patients will have the manifestation of myelitis, and can show a wide range of T2 high signal changes in the longitudinal direction, all involving the central gray matter, showing linear, punctate or patchy enhancement of the central canal; spinal cord lesions mostly involve the thoracic spinal cord, and the lumbar spinal cord is not involved. In a study of 22 patients with GFAP astrocytosis, optic neuritis was also found in GFAP astrocytosis (1 / 22 cases), presenting with blurred vision but no significant change in imaging.

NMDAR encephalitis is an autoimmune encephalitis mediated by anti NMDAR antibody, which is more common in children and young people, and more common in women than in men. NMDAR encephalitis is characterized by mental symptoms, seizures, dyskinesia and cognitive impairment. However, recent studies have reported anti NMDAR antibody positive myelitis, which showed T2 hyperintense changes in the ventral gray matter of the spinal cord [6]. A recent study of 179 patients with transverse myelitis and optic neuritis found that 3.4% (3 / 89) of patients with transverse myelitis, 1.4% (1 / 71) of patients with optic neuritis and 11.1% (1 / 9) of patients with transverse myelitis and optic neuritis were anti NMDAR antibody positive and AQP4 and MOG negative.

GlyR ad was first reported in 2008. It is an autoimmune disease mediated by anti GlyR antibody. It is characterized by ankylosis and myoclonus, epilepsy, cerebellar ataxia, dyskinesia, demyelination and cognitive impairment. One study included 20 NMO patients for AQP4, MOG and GlyR antibody detection. The results showed that 2 patients with negative AQP4 and MOG were positive for GlyR antibody. This study showed that NMO patients with positive GlyR antibody often presented with simultaneous onset of optic neuritis and transverse myelitis.

Gad-ad is an autoimmune disease mediated by anti GAD antibody. Gad-ad often presents as stiff person syndrome, autoimmune cerebellar ataxia, brainstem encephalitis, autoimmune epilepsy, optic neuromyelitis, autoimmune rhabdomyopathy, myasthenia gravis, Lambert Eaton myasthenia syndrome and autonomic neuropathy. A study of 62 patients with positive anti GAD antibody showed that the median age of onset was 50 years old and 77% of them were female; most of the patients were initially considered neurodegenerative or inflammatory (multiple sclerosis or paraneoplastic tumor); the main manifestations were cerebellar ataxia (63%), brainstem involvement (29%), seizures (27%), stiff person syndrome (26%) and extrapyramidal system syndrome (16%), and only 40% of them were diagnosed Three patients had myelopathy and 53% had thyroid autoantibodies. Domestic scholars analyzed 390 serum samples of patients with myelitis, and found that only 1 case (0.26%) was positive for anti GAD antibody in serum and cerebrospinal fluid, while AQP4 and MOG were negative; the imaging findings were abnormal lesions in C5-C7 segment. Therefore, researchers believe that GAD antibody is very rare in myelitis demyelinating disease, and it is not recommended to routinely screen GAD antibody in patients with myelitis.

For the above diseases, the treatment measures may be similar, but the prognosis of different diseases may be different. In the diagnosis of AQP4 negative nmosd, the above diseases should be fully considered.

 

Cindy