The white matter (WM) constitutes the network of nerve fibers that serves to allow the exchange of information and communication between different areas of the gray matter (GM). It lies beneath the GM in the brain and superficial to GM in the spinal cord. It has evolved more than GM and occupies almost half of the brain.[1] From the comparison of several cross-sections of the spinal cord performed in different regions, it is evident that the size of the area occupied by the WM varies from region to region, depending on the extent of the central GM. In particular, the GM/WM ratio grows from the cervical region to the lumbar region as the WM is decreasing as it proceeds towards the terminal portion of the spinal cord.

The WM contains neural networks formed by bundles of axons to mediate essential connectivity between different key motor and cognitive cortical regions. It comprises of myelinated and unmyelinated axons along with glial cells, including myelin-producing oligodendrocytes, microglia, astrocytes, and oligodendrocyte progenitor cells.

Myelin acts as electrical insulation for axons and is responsible for rapid saltatory impulse propagation and protects the nerve fibers from injury.[2] It has a water content of about 40%. The remaining dry mass (60%) is mainly composed of proteins (15% to 30%) and lipids (70% to 85%), with phospholipids, cholesterol, galactolipids, and plasmalogens in a molar ratio of 2:2:1:1.[3]

The chapter of WM lesions (WMLs) or leukoaraiosis encompasses small vessel vascular brain diseases and non-vascular conditions. Any process leading to change in chemical composition, damage, or ischemia of myelinated fibers can present as WMLs on magnetic resonance imaging (MRI) that represents the gold standard for WMLs investigation. The term WM hyperintensity (WMH) is quite a descriptive expression used on MRI. These lesions are best seen as hyperintensities on T2 weighted and FLAIR (fluid-attenuated inversion recovery) sequences of MRI. FLAIR sequences have a particular role in assessing WMLs close to the ventricular margin by nullifying the cerebrospinal fluid (CSF) signal.

While the WMHs are well-described on MRI, the lesions were firstly illustrated based on brain computed tomography (CT). In 1985, Hachinski in 1985 described "leukoaraiosis" as "diminished density of white matter which is seen on brain computed tomography."[4]

Concerning small vessel vascular brain processes, WMLs are commonly present in MRI of asymptomatic elderly individuals typically located in periventricular (PV-WMH) and deep subcortical regions (DS-WMH). For instance, WMLs are frequently detected in people with untreated chronic hypertension. The volume of WMLs tends to increase with age from small punctate lesions to large confluent lesions. Nevertheless, although the occurrence of WMLs was initially considered a normal, age-related finding, recent investigations proved that large areas of disease in the WM of the brain must be considered as neuroimaging markers of brain frailty. Of note, various longitudinal studies described WMLs as a predictor for future risk of stroke, cognitive decline, depression, disability, and mortality in the general population.[5][6] The clinical significance of the lesions is confirmed by the results of a meta-analysis that demonstrated three times increased risk of dementia and stroke, and a doubled risk of death in people with WMLs.[7] For instance, the ischemic microvascular disease, vascular cause of WML, may cause about 45% of dementia cases and 20% of strokes. Again, WMLs are associated with poor post-stroke outcomes and increased risk of parenchymal hematoma following mechanical thrombectomy.[8][9]

Apart from WMLs secondary to small vessel disease, however, these lesions are also common features of demyelinating inflammatory disorders, leukodystrophies, and degenerative disorders. Clinical aspects, prognosis, management varies according to the distribution and spread of the WM damage.

This group of lesions and diseases, therefore, includes very different clinical conditions in terms of etiology, pathogenesis, pathological features, clinical presentations, imaging, and therapy. This article is aimed at discussing the clinical features and treatment of patients with several types of WMLs. The role of the interprofessional team in evaluating and treating patients is also highlighted.

The etiology of white matter lesions (WMLs) is heterogeneous. Based on etiology, WMLs can be divided into vascular and non-vascular causes.

Vascular causes of WMLs include:

• Microvascular ischemic disease or small vessel disease (SVD)
• Atherosclerosis
• Migraine
• Amyloid angiopathy
• Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) 
• Vasculitis
• Susac syndrome

Non-vascular causes for WMLs include:

• Inflammatory: Multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), neuromyelitis optica spectrum disorders (NMOSD)
• Infectious: HIV encephalopathy, progressive multifocal leukoencephalopathy (PMLE), neuroborreliosis, HSV and CMV encephalitis, neurosyphilis, CNS cryptococcal infection, Whipple disease, Lyme encephalopathy, subacute sclerosing panencephalitis (SSPE). 
• Toxic: Chronic alcohol abuse, carbon monoxide (CO) intoxication, inhalation of toluene, heroin, and cocaine, methotrexate-related leukoencephalopathy.
• Metabolic: Vitamin B12 deficiency, copper deficiency, acute intermittent porphyria, hepatic encephalopathy, Hashimoto encephalopathy.
• Neoplastic: Glial tumors, CNS Lymphoma
• Traumatic: Radiotherapy, post-concussion (traumatic axonal injury, TAI)
• Genetic: 
  • Lysosomal Storage Diseases: Metachromatic leukodystrophy (MLD), Krabbe disease, Fabry disease, gangliosidosis, mucopolysaccharidosis
  • Peroxisomal Disorders: X linked adrenoleukodystrophy, Zellweger syndrome, Refsum disease
  • Mitochondrial Disorders: MERF (myoclonic epilepsy with ragged red fibers), MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes), Leigh disease, Kearns-Sayre disease.
  • Aminoacidopathies and Organic Acidopathies: Canavan disease, glutaric aciduria, urea cycle disorders
  • Unknown Etiology: Alexander disease, Vander Knapp encephalopathy
  • Others: Vanishing white matter disease, myotonic dystrophy

Another nosographic approach distinguishes primary WMLs, derived from an unknown etiology, from secondary ones; these latter due to a great variety of known etiologies.

In the general population, the prevalence of age-related vascular WMLs is approximately 10% to 20% at 60 years and approaches 100% in those older than 90 years.[10] Studies have reported that WMLs are common in Japanese, Chinese, Caucasian, African-American, and Caribbean Black populations.[11]

MS represents the most common inflammatory neurological condition in young adults. Again, it has been estimated that the disease affects approximately 2,500,000 people worldwide. In the United States (US), the rate is 57 to 78 cases per 100,000 people in the southern states and 100 to 140 cases in the northern states.[12] The prevalence of NMOSD  is approximately 1/100,000 in the White population and up to 10/100,000 in Blacks. In East Asians, the prevalence is about 3.5/100,000 population.[13]

PMLE is present in 1% to 4% of patients with AIDS. Furthermore, gliomas account for up to 35% of the CNS tumors in adolescents and young adults.[14]

The incidence of WMLs secondary to heritable WM disorder is approximately 1 per 8,000 live births.[15] However, for acquired WM disorders in children, it is estimated to be 1.66 per 100,000 children.[16]

Cerebrovascular risk factors such as age, hypertension, diabetes mellitus, hyperlipidemia, hyperhomocysteinemia, and hypersensitive C-reactive protein are well-known risk factors for vascular WMLs.[11] Genetic factors also play an essential role in the development of WMLs as many genetic loci have been identified, and twin studies have suggested 55-80% heritability.[17][18] 

Pathophysiology for the development of vascular WMLs in elderly patients is thought to be secondary to chronically reduced blood flow by arteriosclerosis, lipohyalinosis, or fibrinoid necrosis of small vessels. Incomplete infarction secondary to persistent hypoxia leads to altered cerebral autoregulation promoting the transcription of many inflammatory genes, leading to the breakdown of the blood-brain barrier (BBB) and entry of pro-inflammatory proteins into the brain parenchyma and vessel wall. This will lead to demyelination, axonal loss, vacuolation, and reduced glial density. Some studies also suggest the role of venous collagen deposition in the pathogenesis of ischemic WMLs.[19] 

The different distribution of the lesions could be linked to different pathogenetic mechanisms. PV-WMH is featured by gliosis, loosening of the WM, loss around convoluted venules in perivascular spaces. In contrast, the primary characteristics of DS-WMH are demyelination, gliosis, and augmented tissue loss as the lesions become more serious.  By summarizing, the pathological characteristics of WMLs may encompass myelin rarefaction, reactive gliosis, axonal loss, infarction, venular collagenosis, arteriosclerotic small vessel alterations. Moreover, BBB impairment plays a pivotal role in the genesis of WM damage, and a different pattern involves PV-WMH and DS-WMH.[20]

In WMLs secondary to non-vascular diseases like MS, demyelination is caused by autoimmune inflammation-mediated primarily by T cells against myelin proteins.[21] While the cause of MS is still unknown, it probably presupposes a combination of genetic susceptibility and nongenetic factors such as viral infection, low vitamin D levels. This combination results in an autoimmune disorder that leads to myelin loss, destruction of oligodendrocytes, and reactive astrogliosis. However, the axon is usually undamaged; in some patients, it is aggressively destroyed.[22]

NMOSD is a group of inflammatory disorders of the CSN featuring severe immune-mediated demyelination and axonal damage, involving optic nerves and spinal cord mostly. Although these disorders were studied as a variant of MS, they have distinct pathophysiology. The autoimmune pathogenesis for NMOSD, indeed, involves IgG autoantibody against the aquaporin-4 (AQP4) water channel [23] or the myelin oligodendrocyte glycoprotein. In a subset of NMOSD, no antibodies (double-seronegative disease).

The exact mechanism of the pathophysiology of ADEM is still unknown. However, it has been related to inflammation initiated by infection or vaccination in genetically susceptible individuals causing demyelination. PMLE is a central demyelinating disease caused by reactivation (usually occurs at CD4 count less than 200/cmm) of latent JC polyomavirus (or John Cunningham virus or Human polyomavirus 2) in oligodendrocytes, in HIV patients. Leukodystrophy causes WMLs secondary to substrate accumulation due to enzymatic defects causing demyelination.

The TAI refers to a severe axonal mechanical damage due to a rotational acceleration of the brain. Although its pathophysiology is complicated, the injury damage is firstly due to a mechanical break involving axonal microtubules. This stretch induces axonal damages through undulations and breaks and direct membrane mechanoporation with calcium influx. This mechanism leads to the activation of several injurious pathways, including the caspase-mediated proteolysis and the cytokine-mediated microglia recruitment with impairment of axonal transport and the agglomeration of transported proteins in varicose swellings.[24]