Uncommon Non-MS Demyelinating Disorders of the Central Nervous System.

Publication date: Jul 01, 2025

Definitive diagnosis of multiple sclerosis (MS) requires exclusion of other central nervous system (CNS) disorders sharing similar clinical, pathological and radiological features. In this review we discuss some relatively uncommon disorders with special emphasis on their differentiation from MS clinically and radiologically. While most conditions have a demyelinating pathology, a few very important mimics may have a non-demyelinating pathology to merit some discussion. Two major areas of diagnostic advances have been made in recent times, the recognition of neuromyelitis optica spectrum disorder (NMOSD), and the myelin oligodendrocyte antibody mediated disorder (MOGAD). These two entities are mediated by completely different antibodies detectable in peripheral blood samples by enzyme-linked immunosorbent assay (ELISA) or cell-based assays and produce clinical disorders could be differentiated from MS by their clinical features, disease course, prognosis, and imaging features. NMOSD is a rare CNS autoimmune disease that predominantly targets the spinal cord, optic nerves and brainstem. In sixty to eighty% of cases of NMOSD, optic neuritis (ON) and/or longitudinally extensive transverse myelitis (LETM) result in blindness and paralysis. In NMOSD these are associated with a serological antibody to aquaporin-4 (AQP4). AQP4 is a water channel protein found in many organs, but in the CNS, AQP4 is expressed in a perivascular distribution on astrocytic foot processes around blood vessels and the glia limitans (glymphatic). Comparative studies of AQP4-seropositive and AQP4- seronegative NMOSD cohorts note that some of the seronegative NMOSD cases tend to differ from the seropositive cases in several aspects: bilateral optic neuritis, simultaneous optic neuritis and transverse myelitis, younger age at onset, and an apparently monophasic course. This prompted search for putative antibodies other than AQP4. MOG antibody disease is a CNS autoimmune disease associated with a serological antibody against myelin oligodendrocyte glycoprotein (MDG). MOG is a glycoprotein expressed on the outer membrane of myelin and solely found within the CNS, including the brain, optic nerves and spinal cord. Clinically, the disease resembles NMOSD in its predilection for relapses of optic neuritis and transverse myelitis. In addition, acute disseminated encephalomyelitis (ADEM) is a well-recognized phenotype of MOG antibody disease in children. About 42% of NMOSD patients who test seronegative for the AQP4 antibody test positive for MOG antibodies. MOG antibody disease has thus recently emerged as a distinct entity in a sizable portion of the patient population diagnosed with NMOSD or even MS. The second field where significant progress has been made is the recently modified McDonald criteria proposed at the ECTRIMS (European Committee (2024) for Treatment and Research in Multiple Sclerosis) which includes three new features – the central vein sign (CVS) and the paramagnetic ring lesions (PRL), along with CSF kappa free light chains (kFLC). The CVS refers to a blood vessel in the middle of MS lesions, visible on MRI. The PRL refers to rings of iron around the edges of active MS lesions, also detectable by MRI. Lastly, kFLC are molecules produced by white blood cells, now considered a diagnostic biomarker equivalent to CSF oligoclonal bands. This new criterion refines doing an MRI mandatory for making a diagnosis of MS. The list of non-MS demyelinating disorders of the CNS is vast. Most of the conditions are immunologically mediated. In the present review, diagnosis and management of NMOSD and MOGAD are discussed, along with a brief discussion on ADEM. Stress has been given also to some rarer conditions like antiphospholipid syndrome, Behcet disease, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS), and Susac syndrome, which can mimic MS. The auto inflammatory syndromes, a newly described group of conditions, which are being increasingly recognized as conditions which can cause systemic as well as neurological disease, are briefly discussed. There is aberrant activation of the innate immune system, as against autoimmune diseases where the adaptive immune system is involved. Non-immune mediated conditions can also cause or mimic demyelination. The causes include drugs, toxins, infections, and neoplastic conditions. CNS lymphomas, both primary and secondary, may mimic MS plaques. Infections including bacterial, viral and parasitic, may also produce white matter signal abnormalities mimicking MS. COVID 19 related CNS lesions and PML are also discussed. The ready availability of genetic testing, including whole exome sequencing, have resulted in expansion of the phenotypic spectrum of leukodystrophies, and in some cases of atypical MS the diagnosis is being revised to some form of leukodystrophy. The types of leukodystrophy which can mimic MS have been discussed. Longitudinally extensive spinal cord lesions (LECL) can occur in demyelinating (LETM) as well as other conditions, and are extremely important to differentiate from each other, so that appropriate management can be provided. Lastly commonly encountered vascular lesions like lacunes resulting from lipohyalinosis may also mimic MS plaques and in this category more extensive lesion like in CADASIL, an autosomal dominant disorder with a specific genetic marker, needs differentiation.

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