Cerebral small vessel disease (CSVD) belongs to a group of diseases involving cerebral arterioles, venules and capillaries. CSVD accounts for about 25% of ischemic stroke, and its etiology remains unclear. The pathogenesis may be related to vascular endothelial injury, hypoperfusion and ischemia, and impaired blood-brain barrier function (1, 2). Currently, CSVD can be divided into 6 categories according to different pathological characteristics: atherosclerosis, cerebral amyloid angiopathy, hereditary vascular diseases [such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), Fabry disease, etc.], inflammatory vascular diseases (such as primary angiitis of the central nervous system (PACNS), Susac syndrome, etc.), venous collagen deposition lesion and other types (3, 4). The imaging features included recent small subcortical infarcts, lacune of presumed vascular origin, white matter hyperintensities of presumed vascular origin, perivascular space (PVS), cerebral microbleed (CMB) and brain atrophy. Some patients may obtain CSVD-related symptoms, but many patients lack symptom and the occurrence of such imaging features appears more problematic within individuals above the age of 50. However, after repeated small vessel events, patients often show abnormal gait, numbness of limbs, cognitive decline and etc., which can seriously result in cognitive dysfunction and physical disability. It has been reported that the etiology of 45% patients with dementia is CSVD, which ranks second only to Alzheimer's disease (3, 5). Therefore, a series of complications caused by CSVD bring immeasurable burden and cost to society.

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demyelination of white matter centered on the central nervous system. The etiology and pathogenesis of MS remains to be unknown. In terms of anatomical structure, MRI showed that the white matter lesions of MS were often distributed around the paracele, subcortex, thalamus, brainstem, and others, showing hyperintensity signal lesions on T2-weighted images (6). MS is an important cause of non-traumatic nervous system dysfunction in young people. Epidemiologically, the incidence of MS shows obvious differences in different regions of the world, and the incidence of MS in Europe and America is higher than that in Asia and Africa. The incidence of MS in females is higher than that in males. Usually, the clinical onset age ranges from 20 to 40 years old, and its clinical manifestations are non-specific. The main symptoms include limb numbness, limb weakness, dizziness, ataxia, blurred vision and others, which are often similar to the clinical manifestations of other inflammatory-related diseases and non-inflammatory-related diseases, thus making them difficult to be distinguished. If patients cannot be correctly diagnosed and treated in the early stage of MS progression, more than half of patients will lose their independent exercise ability after 20 years (7, 8). It not only seriously affects the quality of life of patients, but also brings more medical burden to all sectors of society.

In clinical work, CSVD and MS often have similar characteristics in clinical manifestations, imaging features and pathological changes, which brings many difficulties to the identification, early diagnosis and treatment intervention of clinical diseases, and further delays the effective treatment time window of patients. Therefore, it is helpful to improve our diagnosis, comprehensive evaluation and formulate treatment strategies in clinical work through in-depth understanding of the similarities and differences in clinical symptoms, imaging changes and pathological features of these two diseases. This review intends to summarize and discuss the similarities and differences between CSVD and MS from three aspects, such as clinical features, imaging changes, and pathological features, so as to provide a strong basis for the subsequent clinical diagnosis and treatment.

Currently, it is thought that there may be interaction between CSVD and MS, because the progression of CSVD and MS is positively correlated with age. Advanced age means that glial cells may have hypoxia (59), mitochondrial dysfunction (60), iron deposition (61) and other dysfunctions. These changes are obviously related to neurodegenerative changes. Recently, Geraldes et al. summarized that CSVD shares some features with MS and has been shown to contribute to the neuronal damage seen in vascular cognitive impairment (62). In addition, CSVD (35) has been found to be associated with neurodegeneration in young people with VRFs (63), which may also promote age-related neurodegeneration in MS. Therefore, we summarized the main possible reasons for the interaction value between MS and age-related CSVD: (i) the life expectancy of MS patients is longer (64), over 60 years old (65), and the risk of vascular complications is higher; (ii) vascular complications can promote the disease progression of MS (66), shorten the expected survival time (67–69), aggravate WML load and brain atrophy (70); (iii) the focal demyelination lesions in the watershed area of MS (71) are characterized by hypoperfusion and hypoxia (72–74), suggesting that there is an important relationship between the pathology of MS and cerebral artery perfusion. In addition, Lucchinetti et al. previously reported MS lesions divided into four patterns, in which two patterns (I and II) showed close similarities to T-cell-mediated or T-cell plus antibody-mediated autoimmune encephalomyelitis, and the other patterns (III and IV) were highly suggestive of a primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity. The pattern III is distal oligodendrogliopathy which means oligodendrocytic apoptosis due to hypoxia or viral infection (75, 76). Similar observations are reported independent researchers (77, 78). Santiago Martinez Sosa et al. also reported that The deep and periventricular white matter is preferentially affected in several neurological disorders, including CSVD and MS, suggesting that common pathogenic mechanisms may be involved in this injury and considered the potential pathogenic role of tissue hypoxia in lesion development, arising partly from the vascular anatomy of the affected white matter (1); (iv) chronic inflammatory microenvironment of MS can promote CSVD, furthermore, Robin et al. found that shared mechanism of white matter damage in ischemia and MS and reported that inflammation acts in distinct pathways because of the differing nature of the primary insult (79); (v) some MS patients benefit from using drugs targeting microvascular system (80–82). Furthermore, Chitnis et al. reported a case of Balo's concentric sclerosis, a variant of MS, with CADASIL mutation and suggested systematic testing for the CADASIL mutation in patients with a demyelinating presentation consistent with Balo concentric sclerosis or significant restricted diffusion on MRI (83) (Table 1).

The influencing mechanism of CSVD on the imaging features of MS remains to be unclear. It is possible that the increased load of T2 phase lesions in MS patients with VRFs is due to the superposition effect of paraventricular vascular WML, lacuna and microhemorrhage. Similarly, the more severe brain atrophy associated with VRFs in MS patients may also be due to the superposition of VRFs on MS basis (84). Although the previous understanding of MS is that multiple demyelination areas are found in pathological sections, and axons in these areas are relatively preserved, imaging and pathological studies have found that neuron/axon damage can occur at an early stage and is related to active inflammatory activity and demyelination (85, 86). However, age and duration of disease can affect the inflammatory response of WM and gray matter (GM) in lesion and non-lesion areas of MS, and the inflammatory response seems to decrease in elderly patients with longer course of disease (87, 88). In these patients, neurodegeneration may be related not only to persistent low-intensity inflammatory activity, but also to various mechanisms such as energy deficiency, oxidative damage, hypoxia, and energy reserve failure (72). Energy failure is an important concept for MS pathogenesis. Glucose and lactate transporters and connexin gap junctions have a crucial roles for energy transport among glial cells in MS (89–93). Recently, Philips et al. summarized oligodendrocytes transfer energy metabolites to neurons through cytoplasmic “myelinic” channels and monocarboxylate transporters, which allow for the fast delivery of short-carbon-chain energy metabolites like pyruvate and lactate to neurons. These substrates are metabolized and contribute to ATP synthesis in neurons (93). But this deficient process may be a cause of pathogenesis for MS. Age-related pathological processes, such as AD or vascular disease, may amplify the effects of these mechanisms and lead to increased neuronal damage (87).

The presence of CSVD in MS patients may mean an additional blow to the compensatory mechanism. In this case, chronic hypoxia caused by vascular dysfunction and hypoperfusion can cause neuron death and aggravate neurological dysfunction. In neurodegenerative diseases such as AD (94, 95) and vascular cognitive impairment (96), cerebral vascular lesions promote neuronal damage, aggravate pericyte and astrocyte dysfunction caused by chronic hypoperfusion and BBB permeability changes, oxidative stress, inflammation and mitochondrial damage (97). The theory of “blood vessel-neuron-inflammation” centered on NVU dysfunction in neurodegenerative diseases is also applicable to MS (95). Energy deficiency and tissue hypoxia caused by mitochondrial dysfunction in MS will lead to ion disorder and axonal degeneration, and the accompanying CSVD may aggravate this process, especially in watershed area (72). Not only the lesions related to MS and arteries and veins need further study (72), but also the characterization and quantification of CSVD, including the score of arterial wall changes, microbleeding and microinfarction, which is conducive to further exploring the relationship between CSVD and MS. Moreover, Geraldes et al. based on post-mortem study reported that an excess burden of cerebral small vessel disease in multiple sclerosis may explain the link between vascular comorbidity and accelerated irreversibility disability (98).

In conclusion, this review compares and summarizes the clinical, pathological and imaging features of MS and CSVD and the effect of vascular diseases on MS, which is conducive to deepening our understanding of these two diseases, making correct differential diagnosis and giving patients correct treatment strategies in time.

BW, HaoL, and XL contributed to the conceptualization of the manuscript. BW, HaoL, XL, XH, LG, RF, KangC, and WW contributed to the writing of the manuscript. XH, HaiL, KangnC, ZZ, and LX contributed to the editing and revising of the manuscript. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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