White Matter Lesions

Etiology

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

Vascular Causes of White Matter Lesions

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

Non-Vascular Causes for White Matter Lesions

• Inflammatory: Multiple sclerosis, acute disseminated encephalomyelitis, and neuromyelitis optica spectrum disorders 
• Infectious: Human immunodeficiency virus encephalopathy, progressive multifocal leukoencephalopathy, neuroborreliosis, herpes simplex virus, cytomegalovirus encephalitis, neurosyphilis, central nervous system cryptococcal infection, Whipple disease, Lyme encephalopathy, subacute sclerosing panencephalitis. 
• Toxic: Chronic alcohol abuse, carbon monoxide 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, central nervous system, lymphoma
• Traumatic: Radiotherapy, post-concussion (traumatic axonal injury)
• Genetic: 
• Lysosomal storage diseases: Metachromatic leukodystrophy, Krabbe disease, Fabry disease, gangliosidosis, mucopolysaccharidosis
• Peroxisomal disorders: X-linked adrenoleukodystrophy, Zellweger syndrome, Refsum disease
• Mitochondrial disorders: Myoclonic epilepsy with ragged red fibers, 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 white matter lesions, derived from an unknown etiology, from secondary ones; these latter are due to a great variety of known etiologies.

Epidemiology

The prevalence of age-related vascular white matter lesions in the general population is approximately 10% to 20% at 60 years and approaches 100% in those older than 90 years.[10] Studies have reported that white matter lesions are common in Japanese, Chinese, Caucasian, African-American, and Caribbean Black populations.[11] Multiple sclerosis (MS) represents the most common inflammatory neurological condition in young adults. Again, it has been estimated that MS disease affects approximately 2,500,000 people worldwide. In the 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 neuromyelitis optica spectrum disorder (NMOSD) is approximately 1 in 100,000 in the White population and up to 10 per 100,000 in Black populations. In East Asians, the prevalence of NMOSD is about 3.5 per 100,000 population.[13]

Progressive multifocal leukoencephalopathy (PML) is present in 1% to 4% of patients with acquired immunodeficiency syndrome. PML is also a rare yet severe complication of immunosuppression, such as in organ transplant patients. Furthermore, gliomas account for up to 35% of CNS tumors in adolescents and young adults.[14] The incidence of white matter lesions secondary to heritable WM disorder or leukodystrophy is approximately 1 per 8000 live births.[15] However, for acquired WM disorders in children, it is estimated to be 1.66 per 100,000 children.[16]

Pathophysiology

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

Pathophysiology for developing vascular white matter lesions in older 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 and entry of pro-inflammatory proteins into the brain parenchyma and vessel wall. This breakdown will lead to demyelination, axonal loss, vacuolation, and reduced glial density. Results from some studies also suggest the role of venous collagen deposition in the pathogenesis of ischemic white matter lesions.[19] 

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

In white matter lesions 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 and 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 CNS featuring severe immune-mediated demyelination and axonal damage, mainly involving optic nerves and the spinal cord. Although these disorders were studied as a variant of MS, they have distinct pathophysiology. The autoimmune pathogenesis for NMOSD involves immunoglobulin G autoantibody against the aquaporin-4 water channel [23] or the myelin oligodendrocyte glycoprotein. No antibodies are pertinent in a subset of NMOSD (double-seronegative disease).

The exact mechanism of the pathophysiology of acute disseminated encephalomyelitis is still unknown. However, it has been related to inflammation initiated by infection or vaccination in genetically susceptible individuals, causing demyelination. Progressive multifocal leukoencephalopathy is a central demyelinating disease caused by reactivation (usually occurs at CD4 count less than 200/cm) of latent JC polyomavirus (or John Cunningham virus or human polyomavirus 2) in oligodendrocytes in patients with human immunodeficiency virus. Leukodystrophy causes white matter lesions secondary to substrate accumulation due to enzymatic defects causing demyelination.

Traumatic axonal injury refers to 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 damage through undulations, breaks, and direct membrane mechanoporation with calcium influx. This mechanism leads to the activation of several injurious pathways, including caspase-mediated proteolysis and cytokine-mediated microglia recruitment with impairment of axonal transport and the aggregation of transported proteins in varicose swellings.[24]

History and Physical

Clinical presentation can vary from asymptomatic to patients with disabling disease as per the white matter lesions etiology. Older patients with small punctate cerebral vascular white matter lesions are usually asymptomatic, but they progress to large confluent lesions and can present with subtle functional decline, cognitive impairment, dementia, urinary incontinence, gait and balance impairment, and neuropsychiatric disorders. Within the group of vascular WM diseases, the distribution of lesions varies greatly, and consequently, the clinical aspects. For instance, in small vessel disease, the WMHs are mainly found in basal ganglia and frontotemporal and periventricular WM; these may induce cognitive impairment, loss of balance or coordination, vision loss, and dizziness. Severe headaches can be present in different types of white matter lesions.

Patients with non-vascular etiology of white matter lesions like MS can have heterogeneous presentations, including fatigue, unilateral visual blurring, sensory changes, motor abnormality, urinary incontinence, speech and swallowing difficulties, pain, anxiety, depression, numbness and tingling, and cognitive dysfunction. Nevertheless, the clinical scenario and evolution of the disease vary from patient to patient. Some patients deteriorate rapidly, while in others, an alternation between relapses and remissions is observed.

Clinical aspects of NMOSD include acute attacks of bilateral optic neuritis with significant visual loss or transverse myelitis, inducing limb weakness, sensory loss, and bladder dysfunction. Other symptoms can consist of episodes of intractable nausea, vomiting, hiccups, excessive daytime somnolence or narcolepsy, and seizures. Commonly relapsing courses and variable degrees of recovery occur within weeks to months.[25]

Children with white matter lesions presenting with progressive symptoms of declining developmental milestones, cognitive impairment, and motor abnormalities should be suspected of leukodystrophy. However, patients in their first or second decade with white matter lesions secondary to acute disseminated encephalomyelitis present with acute onset and rapidly progressive symptoms of fever, headache, vomiting, confusion, or altered sensorium. Although migraine was associated with structural changes in the brain WM, these lesions are generally not linked to any neurological issues, as well as an increased risk of cognitive decline.[26]

Evaluation

Evaluating patients presenting with white matter lesions depends on the patient's age, clinical scenario, and pattern of white matter lesions on MRI, which are common manifestations of cerebral small vessel disease and are associated with vascular risk factors. These patients should be screened for vascular risk factors by routine laboratory tests, including a complete metabolic panel, lipid profile, and HbA1c. Also, it is worthwhile to quantify white matter lesions to monitor their progress with time in these patients. Various grading scales like the Fazekas scale and age-related white matter changes rating scale can be used to assess the extent and progression of white matter lesions (see Image. Fazekas Grade 3 White Matter Lesions).[27][28][29]

Patients with non-vascular white matter lesions require further evaluation to identify the etiology of the lesions. Cerebral spinal fluid analysis is helpful in cases of suspected MS (oligoclonal bands), Acute disseminated encephalomyelitis (ADEM; lymphocytic pleocytosis with raised proteins), and infectious demyelination (antiviral antibodies). MR spectroscopy can help in the etiological diagnosis of white matter lesions to differentiate lesions based on different metabolite peaks.

Additional tests like serology for autoantibodies in case of suspected vasculitis, anti-myelin oligodendrocyte glycoprotein antibodies in ADEM, and anti-AQP4 antibodies in NMOSD. Also, metabolic and toxicology screens can be helpful in suspected cases. Children with white matter lesions and clinical scenarios for leukodystrophy require genetic testing.[30]

Treatment / Management

White matter lesions in older adults most commonly reflect underlying small vessel ischemic lesions and, more probably, cognitive dysfunction. Proper management may prevent further deterioration by targeting all vascular risk factors.[31] White matter lesions detected incidentally on MRI of older patients require management of vascular risk factors by:(B3)

• Intensively controlling the blood pressure
• Strict diabetes control
• Improving dyslipidemia
• Promoting physical fitness
• Avoiding smoking
• Avoiding alcohol
• Use of antiplatelets 

Prophylaxis of migraine with aura can also help decrease the risk of white matter lesions. Using B vitamins to lower homocysteine levels is useful in managing patients with small vessel disease. Managing non-vascular white matter lesions is individualized as per etiology. White matter lesions secondary to MS flares are treated with steroids. However, patients need long-term maintenance therapy with disease-modifying treatment to halt disease progression.

Furthermore, immunosuppression with high-dose intravenous glucocorticoids is used in patients with ADEM. Acyclovir has also been reported to have benefits in some cases. Leukodystrophies do not have a specific treatment; treatment is only supportive and symptomatic. Other white matter lesions caused by specific diseases, such as progressive multifocal leukoencephalopathy (PML), human immunodeficiency virus (HIV), and gliomas, must be treated for those specific causes.

Differential Diagnosis

Pattern recognition of white matter lesions in MRI is crucial as it may make the diagnosis in many conditions.[32]

The differential diagnosis for symmetric white matter lesions can include:

• Bilateral hemispheres: toxic encephalopathy, HIV encephalopathy, autoimmune encephalopathies, and vitamin B12 deficiency
• Periventricular lesions: small vessel disease, HIV encephalopathy, vitamin B12 deficiency, metachromatic leukodystrophy, X-linked adrenoleukodystrophy, and vanishing white matter disease
• Subcortical including arcuate fibers: Alexander disease, Kearns-Sayre syndrome, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
• Frontal predominance: Alexander disease and metachromatic leukodystrophy
• Parietal/temporal/occipital lobes: posterior reversible encephalopathy, heroin abuse, and Krabbe disease
• Corpus callosum: Marchifava-Bignami disease, metachromatic leukodystrophy, and Krabbe disease
• Cerebellum: toxic encephalopathy and mitochondriopathies
• Central pons: central pontine myelinolysis 

The differential diagnosis for asymmetric white matter lesions:

• Patchy multifocal confluent lesion: MS, autoimmune encephalopathies, and CADASIL
• Parieto-occipital regions: PML

Prognosis

The prognosis of patients with white matter lesions depends on the etiology of the lesions. Patients with age-related white matter lesions are irreversible and progressive. Large and confluent white matter lesions have a poor prognosis and lead to cognitive impairment and global functional decline.[33]

White matter lesions secondary to MS have interpatient variability in prognosis. Severe disabilities are present in 5% of patients within the first 5 years of onset, and 10% to 20% of patients of MS remain unimpaired without therapy after 20 years.[34] NMO and ADEM have a variable prognosis from complete recovery to the development of permanent physical disability, especially in post-measles ADEM.[35] Acute demyelinating disease prognosis depends upon the severity of the initial illness. Patients responding to treatment have a favorable prognosis. However, leukodystrophies have a poor prognosis. Reversible causes, including metabolic and toxic encephalopathies, have a good prognosis.

Complications

Severe white matter lesions are associated with cognitive impairment, global functional decline, cerebrovascular accident, mood disorders, gait, and balance dysfunction. White matter lesions are also associated with grey matter atrophy and accelerated neurodegeneration.[36] Furthermore, severe, extensive involvement of white matter by non-vascular causes like MS, ADEM, and NMO causes disability.