White Matter Lesions (2023)

Continuing Education Activity

White matter lesions (WMLs) are areas of abnormal myelination in the brain. These lesions are best visualized as hyperintensities on T2 weighted and FLAIR (Fluid-attenuated inversion recovery) sequences of magnetic resonance imaging. They are considered a marker of small vessel disease. However, there are numerous non-vascular causes, as well. An increase in WMLs increases the risk of stroke, cognitive decline, depression, disability, and mortality in the general population. This activity reviews the evaluation and treatment of patients with WMLs and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Identify the etiology of white matter lesions.

• Describe the typical imaging findings associated with various diseases presenting with white matter lesions.

• Outline the management options available for patients with white matter lesions.

• Explain the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients with white matter lesions.

Access free multiple choice questions on this topic.

Introduction

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 inthe brainand 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 thatthe 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 encompassessmall 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 firstlyillustrated based onbrain 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 arefrequently 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 thatlarge areas of disease in the WM of the brainmust 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 thatdemonstrated 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, maycause 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.Thisarticle is aimed at discussing the clinical features and treatment of patients with severaltypes ofWMLs. The role of the interprofessional team in evaluating and treating patients is also highlighted.

Etiology

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

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  • 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.

Epidemiology

In the general population, the prevalence of age-related vascularWMLs 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 neurologicalcondition 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 heritableWM disorder is approximately 1 per 8,000 live births.[15]However, for acquiredWM 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 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, theprimarycharacteristics of DS-WMH are demyelination, gliosis, andaugmentedtissue loss as the lesions become more serious. By summarizing, the pathological characteristicsof WMLsmay 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 involvesPV-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 againstmyelin 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 disorderthat 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 werestudied as avariant of MS, they have distinct pathophysiology.Theautoimmune 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 toa rotational acceleration of the brain. Although its pathophysiology is complicated, the injury damage is firstlydue to amechanical break involving axonal microtubules. This stretchinducesaxonal 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 theagglomeration of transported proteins in varicose swellings.[24]

History and Physical

Clinical presentation can vary from asymptomatic to patients with disabling disease as per the WMLs etiology. Elderly patients with small punctate cerebral vascular white matter lesions (WMLs) are usually asymptomatic, but they progress to large confluent lesions and can present with subtle functional decline, cognitive impairment, dementia, urinary incontinence, or 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 SVD, the WMHs are mainly found in basal ganglia and frontotemporal and periventricular WM. It may induce cognitive impairment, loss of balance or coordination, vision loss, and dizziness. Severe headachescan be present in different types of WMLs.

Patients with non-vascular etiology of WMLs 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, cognitive dysfunction. Nevertheless,the clinical scenario varies from patient to patient as well as the evolution of the disease. In some patients, indeed, there is a progressive and rapid deterioration, while in others, an alternation between relapses and remissions can be 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 include episodes of intractable nausea, vomiting, hiccups, excessive daytime somnolence or narcolepsy, and seizures. There are a commonlyrelapsing course and variable degrees of recoverywithinweeks to months.[25]

Children with WMLs presenting with progressive symptoms of declining developmental milestones, cognitive impairment, and motor abnormalities should be suspected for leukodystrophy. However, patients in their first or second decade with WMLs secondary to ADEM 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 issuesas well as an increased risk of cognitive decline.[26]

Evaluation

Evaluation of patients presenting with white matter lesions (WMLs) depends on the age of the patient, clinical scenario, and pattern of white matter lesions on MRI.

WMLs on MRI 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 complete metabolic panel, lipid profile, and HbA1c. Also, in these patients, it is worthwhile to quantify WMLs to monitor their progress with time. Various grading scales like the Fazekas scale, age-related white matter changes (ARWMC) rating scale, and Van Swieten scale can be used to assess the extent and progression of WMLs.

Patients with non-vascular WMLs require further evaluation to identify the etiology of the lesions. CSF analysis is helpful in cases of suspected MS (oligoclonal bands), ADEM (lymphocytic pleocytosis with raised proteins), and infectious demyelination (antiviral antibodies). MR spectroscopy can help in the etiological diagnosis of WMLs to differentiate lesions based on different metabolites peaks.

Additional tests like serology for autoantibodies in case of suspected vasculitis, anti-MOG antibodies in ADEM, and anti AQP4 antibodies in NMOSD. Also, metabolic and toxicology screens can be helpful in suspected cases. Children with WMLs and clinical scenarios for leukodystrophy require genetic testing.

Treatment / Management

White matter lesions (WMLs) detected incidentally or in MRI of elderly patients with a transient ischemic attack (TIA) require management of vascular risk factors by:

• 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 WMLs. The use of B vitamins to lower homocysteine levels is useful in managing patients with SVD.

Management of patients with non-vascular WMLs is individualized as per etiology. WMLs secondary to MS flares are treated with steroids. However, patients need long term maintenance therapy with disease-modifying treatment to halt disease progression. Furthermore, in patients with ADEM, immunosuppression with high-dose intravenous glucocorticoids is used. Acyclovir has also been reported to have benefits in some cases. Leukodystrophies do not have a specific treatment, and treatment is supportive and symptomatic only.

Differential Diagnosis

Pattern recognition of white matter lesions (WMLs) in MRI is crucial as it may make the diagnosis in many conditions.

The differential diagnosis for symmetric WMLs:

• 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 CADASIL

• Frontal Predominance: Alexander Disease, and metachromatic leukodystrophy

• Parietal/Temporal/Occipital Lobes: PRES (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 (CPM)

The differential diagnosis for asymmetric WMLs:

• Patchy Multifocal Confluent Lesion: MS, autoimmune encephalopathies, and CADASIL

• Parieto-Occipital Regions: PMLE

Prognosis

The prognosis of patients with white matter lesions (WMLs) depends on the etiology of the lesions. Patients with age-related WMLs are irreversible and progressive. Large and confluent WMLs have a poor prognosis and lead to cognitive impairment and global functional decline. A study by Hassan et al. confirmed the association of severity of white matter lesions with mortality.[27]

WMLs secondary to MS have interpatient variability in prognosis. Severe disabilities are present in 5% of patients within the first five years of onset, and 10–20% of patients of MS remain unimpaired without therapy even after 20 years.[28] NMO and ADEM have a variable prognosis from complete recovery to the development of permanent physical disability, especially in post measles ADEM.[29]Acute demyelinating disease prognosis depends upon the severity of the initial illness. Patients responding to treatment have a favorable prognosis. However, leukodystrophies have poor prognosis. Reversible causes, including metabolic and toxic encephalopathies, have a good prognosis.

Complications

Severe white matter lesions (WMLs) are associated with cognitive impairment, global functional decline, cerebrovascular accident, mood disorders,gait, and balance dysfunction. WMLs are also associated with grey matter atrophy and accelerate neurodegeneration.[30]Furthermore, severe, extensive involvement of white matter by non-vascular causes like MS, ADEM, and NMO causes disability.

Deterrence and Patient Education

Patients with vascular risk factors should be identified early and counseled on lifestyle changes as well as control of comorbid conditions. Self-monitoring of blood pressure and blood sugar, dietary modifications, weight reduction, and improving physical fitness has proven to decrease the progression of white matter lesions.[31]Involvement in cognitively complex leisure activity to improve cognitive reserve has been associated with a protective effect on cognitive functioning and late-life depression in patients with WMLs.[32]

Enhancing Healthcare Team Outcomes

As described, white matter lesions (WMLs) have varied clinical presentations, differential diagnoses, and complications. Managing these patients requires extensive collaboration and coordination among a team of professionals, which consists of neurologists, radiologists, internists, ophthalmologists, psychiatrists, neurosurgeons, rheumatologists, microbiologists, pain specialists, nurse specialists, mental health nurses, pharmacists, physical therapists, and nutritionist. It is compulsory to identify the right set of professionals depending on the etiology of a case. Clear and effective communication between these professionals while monitoring the progression and complications of WMLs can decrease mortality.

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Disclosure: Roopa Sharma declares no relevant financial relationships with ineligible companies.

Disclosure: Sandeep Sekhon declares no relevant financial relationships with ineligible companies.

Disclosure: Marco Cascella declares no relevant financial relationships with ineligible companies.