Myoclonus epilepsy with ragged-red fibers
Nov. 06, 2023
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The presence of white matter abnormalities in the brain of both symptomatic and asymptomatic individuals has been a source of interest for over a century. CT and MRI detection of these lesions has become more sensitive than even autopsy. Clinical studies have associated these lesions with cognitive decline, gait impairment, and increased cerebrovascular disease and death risk. The etiology of white matter abnormalities varies from cerebrovascular disease to metabolic and demyelinating disorders. This article primarily focuses on cerebrovascular disease.
• White matter abnormalities are present in at least 10% of individuals older than 65 years of age.
• These lesions correlate with an increased risk of cognitive impairment, stroke, and death.
• The causes of white matter abnormalities are many and not fully understood.
In 1894, Binswanger described a male with syphilis who suffered from leg weakness, arm tremors, progressive cognitive decline, including speech and memory, depression, and personality change (12; 13). Although autopsy demonstrated white matter atrophy, Binswanger did not realize the significance of this finding (145). In 1902, Alzheimer described a similar case and attributed the white matter changes to arteriosclerosis of the long, penetrating vessels (02; 146). It was not until 1962 that Binswanger's case was diagnosed as syphilis, and the term “subcortical arteriosclerotic encephalopathy” was proposed to describe cerebral arteriosclerosis affecting vessels of the white matter and subcortical grey matter (124).
CT brain scan, followed by MRI, revealed cerebral white matter changes in both asymptomatic and cognitively impaired individuals (140; 185; 20; 59). These changes appear as hypodensities on CT and are described as white matter lucencies, leukoencephalopathy, or leukoaraiosis. On T2-weighted MRI, these lesions appear hyperintense and are called white matter abnormalities, white matter hyperintensities, cerebral white matter changes, or unidentified bright objects. MRI is more sensitive to these changes (58). Therefore, these white matter changes will be referred to herein as white matter abnormalities.
• The burden of white matter abnormalities increases with age.
• White matter abnormalities may occur in apparently asymptomatic subjects with subtle neurologic deficits.
• The severity of white matter abnormalities is associated with dementia, depression, risk of falls, cerebrovascular disease, and premature death.
As the quality and availability of MRI increased, so did the number of lesions detected in apparently healthy subjects. Most lesions are lacunar infarcts resulting from hypertensive small vessel disease. Although asymptomatic, the patients may have subtle, often unrecognized, deficits in neurologic function. Moreover, these silent infarcts double the risk of stroke and dementia (166). Abnormal three-step motor sequencing and horizontal extraocular tracking tests can predict the presence of periventricular white matter abnormalities (08).
Cognitive dysfunction. In healthy older adults, white matter abnormalities have been associated with decreased processing speed, memory deficit, and executive and even global cognition dysfunction (37; 68). White matter abnormalities in the temporal and occipital areas were associated with greater age, hypertension, late-onset depression, and cognitive impairment (03).
More severe periventricular white matter abnormalities are associated with Alzheimer disease but cannot be used for diagnosis of dementia (75). Subcortical dementia was seen in patients with severe periventricular white matter abnormalities (70). Frontotemporal dementia also correlates with white matter abnormalities (90). However, similar cognitive decline profiles can be caused by different conditions (164).
Different cognitive patterns were noted in patients with various pathogeneses but similar dementia severity. For example, periventricular white matter abnormalities have been associated with worse comprehension and attention, but white matter abnormalities outside the periventricular area have been associated with worse memory and conceptualization performance (88). The severity of white matter abnormalities correlates with the decline in Wechsler Performance IQ scores, Block Design, Object Assembly, and Digit Symbol tests (56).
Not all cognitive decline is explained by white matter abnormalities. Between the ages of 11 and 78 years, the severity of white matter abnormalities was associated with overall cognition, independent of childhood cognitive ability. However, it was suggested that hypertension accounted for at least a portion of the effects of white matter abnormalities in this study (42).
Balance impairment and risk of falls. Sequential MRI scans performed 20 months apart in elderly subjects have demonstrated a five-fold acceleration of the accumulative volume of white matter abnormalities in individuals with decreased mobility (177). In high-functioning elderly patients, over a period of 4 years, self-reported physical impairment was 22% greater in those with moderate compared to those with minimal white matter abnormality burden (139).
Similarly, patients with Alzheimer disease and white matter abnormalities had a four-fold deterioration of gait compared to normal subjects (57; 102). Additionally, white matter abnormalities were associated with decreased limb power and plantar response as well as rooting and palmomental reflexes (152).
The consequence of impaired balance due to white matter abnormalities is a four-fold increase in the risk of falls compared to controls (86). Conversely, twice as many white matter abnormalities were found in mobility-impaired elderly patients compared to normal controls (71). The presence of ApoE ε4, in addition to white matter abnormalities, has a synergistic effect on standing imbalance (31).
White matter disease in children. White matter abnormalities are also found in children’s brain MRIs. Children younger than 5 years of age with white matter abnormalities and decreased tone had significantly less signal abnormality than the control group or a group of patients with normal tone and presence of white matter abnormalities. The children with increased tone had more white matter abnormalities and hyperreflexia. This suggests that increased signal intensity is more likely associated with spasticity, as compared to those children with normal or low-signal intensity white matter abnormalities in whom normal tone or hypotonia is more likely (95).
Dementia. In nondisabled elderly subjects, severe white matter abnormalities are associated with medial temporal lobe atrophy and a four-fold increase in mild cognitive deficits (159). White matter abnormality severity was associated with reduced global cognition (28).
The burden of white matter abnormalities in early patients with Alzheimer disease cannot be distinguished from that in normal subjects (47). However, severe periventricular white matter abnormalities predict poor neuropsychological performance in patients with Alzheimer disease (75). Moreover, severe white matter abnormalities are associated with faster progression of dementia and mortality; this association is supported by more severe loss of myelinated fibers at autopsy (81).
Progression from mild cognitive impairment to Alzheimer disease can be predicted by white matter abnormalities (175). The risk of dementia increased by 67% for each standard deviation increase in severity of periventricular white matter abnormalities, independent of other brain changes (131).
Silent brain infarcts on baseline MRI were associated with a 126% increased risk of dementia, and psychomotor speed was reduced in those with white matter infarcts. Moreover, cognitive function declined only in those who accrued additional white matter lesions (165).
Depression. Elderly depressed patients had more cerebral atrophy and more severe white matter abnormalities than controls (09). Temporal lobe white matter abnormalities independently predicted the Geriatric Depression Scale, whereas neither a history of stroke nor the number of lacunar infarcts did (122).
Retinopathy and stroke. White matter abnormalities in patients with prior stroke predict an increased risk of subsequent stroke (114; 162). White matter abnormalities are associated with retinal microvascular abnormalities. White matter abnormalities associated with retinopathy predict a significantly higher risk of clinical stroke (20% vs. 1.4%) (178).
Imbalance, impaired gait, and falls. High-functioning elderly patients without stroke or dementia have slower gait and a shorter stride and require longer support time (138). Starkstein and colleagues reported that patients with Alzheimer disease and white matter abnormalities had extrapyramidal signs (151)
Premature death. The risk of death is predicted by advanced white matter abnormalities, even after adjustment for hypertension, high cholesterol, diabetes, and coronary artery disease (87).
A 72-year-old male presented with impaired gait. Three years earlier, he was diagnosed with diabetes controlled with oral metformin 500 mg twice daily. For 1 year, his gait had been unstable, as if he was inebriated. He would occasionally catch his toes and fall. Over time, he needed to use the walls for guidance when walking down a hall, and he began to use a cane for mobility assistance. Walking across a dark room was particularly difficult. In addition to gait difficulties, he had become forgetful with daily tasks and sometimes could not recall the names of familiar people.
Past medical, family, and social history were unremarkable. He took no medications. On review of systems, he experienced tingling in both feet, which had become persistent about a year earlier, and he had difficulty sensing temperature if he placed his feet in bathwater.
Examination revealed mild difficulties with verbal memory and moderate to long-term recall of visually identified objects. Language, praxis, and tests of frontal lobe executive functioning were normal. Mini-mental status examination score was 25/30. He had a mild bilateral palmomental reflex. Fundoscopy revealed arteriovenous nicking. Blood pressure was 150/95 mmHg. Visual fields were full. Visual acuity, corrected, was 20/20-2 bilaterally. Pupils and extraocular movements were normal. Strength was normal throughout. Tone was slightly spastic to the left arm and right leg. Reflexes were normal except for bilateral absent ankle jerks. Sensory examination revealed a stocking pattern of pinprick and temperature sensation loss in both feet to the level of the ankle. Vibration and proprioception thresholds were slightly above expected for age at the great toes bilaterally. No dysmetria was present. Gait was narrow-based but slightly staggering; there was no magnetic gait. Tandem gait could not be performed without assistance. Romberg test was slightly positive. No other frontal lobe release signs could be elicited.
Blood tests revealed a random glucose of 12 mmol/L, and hemoglobin A1C was elevated at 7.4%. Nerve conduction studies identified a mild axonal sensory-dominant peripheral neuropathy. MRI of the brain identified numerous white matter abnormalities throughout subcortical regions, along with mild diffuse cerebral atrophy.
A diagnosis of white matter abnormalities with mild cognitive impairment was made, along with a secondary diagnosis of mild diabetic peripheral neuropathy. Diabetic education was provided. Physical therapy and a walker were recommended for gait difficulties. One year later, worsening mobility led to a fall that caused an epidural hematoma and death.
• There is a genetic influence in the appearance of white matter abnormalities.
• Several mechanisms contribute to the etiology of white matter abnormalities: breakdown of the blood-brain barrier, circulating metabolites, impaired metabolite clearance, and decreased cerebral perfusion.
• Pathology studies reveal loss of axons, myelin, and oligodendrocytes. Thickened blood vessel walls, gliosis, increased interstitial fluid, and edema also occur.
Circulating metabolites. Circulating metabolites of both lipid and nonlipid nature, measured by mass spectrometry and high-performance liquid chromatography, correlate with white matter abnormalities in middle-aged and older adults. Hydroxyphenylpyruvate, the most common of these metabolites, explains up to 6% and 14% of the variance in white matter abnormality volume in the pooled sample and in men as compared to hypertension (1%), type 2 diabetes (1% to 3%), or smoking (less than 0.1%). This metabolite is a potentially useful biomarker for white matter abnormalities. In women, glucuronate was the only significantly associated metabolite with white matter abnormalities (148).
Blood-brain barrier disruption. The integrity of the blood-brain barrier may play a role in the etiology of the white matter abnormalities, lacunar stroke, and dementia. Endothelial dysfunction allows leakage of serum components across the small cerebral arteries into the surrounding tissue, leading to neuronal and glial damage. This dysfunction may be intermittent or chronic, or it may occur during hypertensive crisis (171).
Impaired metabolism waste clearance. Clearing the brain of metabolic waste products, including beta-amyloid, alpha-synuclein, and tau protein, is important for homeostasis. Because of the selectivity of the blood-brain barrier, an important amount of cerebral waste drainage occurs through the cerebral spinal fluid via the perivascular spaces created by the astrocytic vascular endfeet. The function of this glymphatic system is increased during nonrapid eye movement sleep (179). Although several perivascular spaces are normal, their number increases with age, hypertension, small vessel disease, amyloid angiopathy, and genetic small-vessel diseases like CADASIL and in neurodegenerative disorders like Alzheimer disease. Uncontrolled hypertension disrupts the smooth flow and leads to amyloid deposition in the perivascular spaces. Increased visibility of perivascular spaces may also be associated with white matter abnormality formation around them (134).
Impaired cerebral perfusion. Diminished perfusion of subcortical white matter correlates with the severity of white matter abnormalities (91). Autoregulation impairment may be responsible for white matter abnormality development (01). Additionally, chronic white matter abnormalities are associated with poor collateral recruitment during stroke caused by large vessel occlusion (99). Moderate to severe white matter abnormalities may be responsible for the worse outcome in patients who undergo mechanical thrombectomy (113).
Neuropathology. Pathological evaluation of white matter abnormalities reveals areas of spongiosis and extracellular space expansion due to loss of axons, myelinated fibers, and oligodendrocytes. Myelin thinning and gliosis are often accompanied by small-vessel atherosclerosis and lacunar infarctions (small cavities). However, fewer white matter abnormalities are visible at autopsy compared with those seen with in-vivo MRI (51; 63).
There is evidence that smooth periventricular white matter abnormalities are different from patchy deep white matter abnormalities. Periventricular capping and leukoaraiosis result from patchy loss of the ependymal cell layer, fibrosis of small vessels and reactive gliosis, increased extracellular fluid content resulting in periependymal edema, axonal atrophy, and decreased myelin (154; 97). However, the myelin rarefaction is not true demyelination, as the process also involves axonal destruction (06; 104).
In a small study, atherosclerosis was present in all types of white matter abnormality but not in all lesions (35). In another study, although periventricular and deep white matter abnormalities were of vascular origin, including microcystic infarcts, the capping and smooth halo were not (52).
In the punctate deep white matter abnormalities, thickening of small vessels, perivascular gliosis, and dilated perivascular spaces were noted (163; 172). Confluent white matter abnormalities indicate more extensive ischemic damage (53). The etiology of white matter abnormalities may be transient repeated events of local hypoperfusion that induce an incomplete form of infarction (128).
In a study of 36 formalin-fixed brain specimens, lacunae accounted for most white matter abnormalities in elderly patients (21). Although MRI cannot distinguish noncystic infarction from either gliosis or demyelination, fluid-containing spaces, including cystic infarction and brain cysts, appear as isointense relative to CSF (22). The frontal lobes are more affected by subcortical small vessel ischemia. Regardless of location, white matter abnormalities are associated with hypometabolism of the frontal lobes and executive dysfunction (156).
Enlarged perivascular spaces may appear in the periventricular region and be confused with lacunar infarcts (84; 63). However, small perivascular spaces are found in all age groups, including newborns, suggesting they may not represent a true abnormality (154).
In addition to arterial stenosis, noninflammatory collagenous thickening of periventricular veins resulting in severe stenosis was found in 65% of brain autopsies in elderly patients (115).
Subcortical white matter abnormalities disrupt the short corticocortical fibers, whereas periventricular lesions disrupt the long association fibers connecting distant cortical areas (37). As a result, white matter abnormalities are more likely to disrupt the local neuronal networks, whereas periventricular lesions affect the cognitive functions requiring the coordination of multiple cortical areas (111; 176). Disruption of the prefrontal-subcortical loops leads to memory, executive, gait, and balance dysfunction (37; 68; 173; 167).
Genetics may explain up to half the variation in white matter abnormalities between individuals (04). The genetic influence explains about two thirds of the variability in cognitive functioning; neurologic covariation in the presence of white matter abnormalities and cognition could be explained by genetic effect in more than 70% of cases (32).
A matched co-twin analysis of elderly monozygotic twins revealed that white matter abnormalities correlate with glucose level, high-density lipoprotein cholesterol, and systolic blood pressure. Additionally, white matter abnormalities were associated with impaired cognition and physical function (33).
Co-occurrence of cerebrovascular disease and ApoE ε4 subtype has a synergistic effect on brain atrophy and white matter abnormalities (43). Both dizygotic and monozygotic male twins may have a higher vulnerability of ApoE ε4 carriers to injury or impaired repair (31).
Through genome-wide association studies, the rs12204590 stroke risk allele (on chromosome 6p25, near FOXF2) was associated with an increased MRI-defined burden of white matter abnormalities in stroke-free adults. Young patients (aged 2 to 32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter abnormalities (120).
In the Multi‐Ethnic Study of Atherosclerosis, after adjustment for cardiovascular risk factors and socioeconomic status, white matter abnormalities were not associated with race and ethnicity (05).
Aging is an independent risk factor for the development of white matter abnormalities (06; 58; 57; 105; 182; 24; 47).
Cardiovascular risk factors. Hypertension and cerebral hypoperfusion due to systolic and diastolic hypotension, orthostatic hypotension, and heart failure have been linked to white matter abnormalities (06; 132). History of stroke or myocardial infarction, factor VIIc activity, and fibrinogen level were also associated with white matter abnormalities (25; 47). Patients with atrial fibrillation have more numerous and larger periventricular white matter abnormalities (39). In asymptomatic patients, the risk of discovering a cardioembolic source with transthoracic and transesophageal echocardiography increases with age (100). Diabetic-associated white matter abnormalities are a risk factor for stroke (54).
Hypertension. Hypertension is commonly associated with white matter abnormalities in asymptomatic subjects and in patients with a history of cerebrovascular disease (06; 57; 17; 162). A family history of stroke or hypertension in first-degree relatives is significantly associated with white matter abnormalities (135). Moreover, well-controlled blood pressure prevents the formation of white matter abnormalities (46). In addition to lacunar infarcts, white matter abnormalities are strongly associated with intracerebral hemorrhage, also caused by hypertension (79).
Although not demonstrated, the co-occurrence of cerebrovascular risk factors may be associated with an even higher white matter lesion load.
Diabetes mellitus. Elevated glycated hemoglobin levels and diabetes mellitus have been associated with white matter abnormalities (142; 47; 118).
Migraine. Migraineurs have a high incidence of white matter abnormalities, 46% in one study (149). These abnormalities occur mostly in young patients (126). White matter abnormalities are usually seen in the periventricular white matter or near grey-white matter junctional areas (136). The white matter abnormalities may be reversible, as was the case of a teenager with basilar migraine (106). No microstructural changes were detected on diffusion tensor imaging between episodic and chronic migraine (119).
Dementia. Between 19% and 78% of patients with dementia have leukoaraiosis on CT scan (91; 14; 45; 103); and 7.5% to 100% on MRI (48; 18; 174; 108).
In Alzheimer disease, white matter abnormalities have been associated with advanced age, vascular risk factors, cerebral congophilic angiopathy, and homocysteine levels (81; 141; 78; 30). The members of an Irish family with familial Alzheimer disease due to an E280G mutation in exon 8 of presenilin-1 have developed spasticity along with white matter abnormalities (125).
White matter abnormalities may also occur in patients with Lewy body disease (09). Patients with vascular dementia have higher numbers of white matter abnormalities than those with either Lewy body disease or Alzheimer disease (09).
Apolipoprotein E ε4 status. Carriers of ApoE ε4 have significantly more subcortical white matter abnormalities than ApoE ε3 carriers, independent of hypertension. The combination of hypertension and at least one ApoE ε4 allele leads to the highest amounts for both subcortical and periventricular white matter abnormalities (40). Yet in another study controlling for confounding cerebrovascular risk factors, the number of ApoE ε4 alleles was not associated with white matter abnormalities, which were only found to be associated positively with age and hypertension (77).
AIDS dementia. Patients with AIDS dementia complex can have associated cerebral atrophy and white matter abnormalities in the splenium and deep subcortical areas (26).
Psychiatric disorders. Although any association remains uncertain due to methodological problems, psychiatric disorders that have been associated with an excessive burden of white matter abnormalities include depression in the elderly (36; 76), bipolar disease (153; 07), late-onset mania (107), and late-onset schizophrenia (23). A small study found white matter abnormalities in the right frontoparietal subcortical white matter in patients with bipolar disorder but not in the control group (67). A small study of patients with major depressive disorder has suggested the presence of a greater number of subcortical white matter abnormalities, particularly in patients with depressed folate levels or hypertension (80).
CADASIL. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy is characterized by multiple subcortical infarcts and white matter abnormalities with autosomal dominant inheritance related to a genetic defect on chromosome 19q12 (155). Patients with CADASIL also experience migraine, mood disturbances, and recurrent strokes, often with progression to subcortical dementia and premature death. White matter abnormalities are more likely to occur in the insula and temporal lobes in patients with CADASIL than in hypertensive patients. In addition, involvement of the external capsule and corpus callosum may be more specific for CADASIL patient brains (127). Pathologically, CADASIL is characterized by small, deep strokes and leukoencephalopathy. Small vessels in the brain have a concentric thickening of tunica media secondary to granular eosinophilic infiltration (10; 64).
As patients with CADASIL age, MRI signal abnormalities increase (34). Besides the subcortical and periventricular regions, the brainstem can also be subject to T2 signal hyperintensities, most frequently within the pons, in the brains of CADASIL patients.
CARASIL. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), like CADASIL, is associated with multiple subcortical infarctions and due to a mutation in the HTRA1 gene, which prevents effective regulation of TGF-beta signaling and may lead to abnormal blood vessel formation in the brain. Symptoms typically begin in the patient’s thirties or forties and are characterized by leg spasticity and gait ataxia. About half of patients suffer from a stroke before 40 years of age. Dementia and memory loss typically occur within 20 years of onset. Scalp alopecia and attacks of low back pain are characteristic of the disease (74).
Susac syndrome. Susac syndrome is characterized by the triad of encephalopathy, retinopathy, and hearing loss. The recurrent flares result from a thrombotic microvasculopathy of unclear etiology (62; 181).
Trauma. Traumatic brain injury may result in white matter abnormalities associated with abnormal perfusion on SPECT scan 6 months after injury. Patients with abnormal perfusion to the frontal or temporal lobes had significantly worse outcomes 2 years after the event (168).
Electrical injury can result in brain atrophy, sometimes progressive, and supratentorial white matter abnormalities (112). Electrical injury may result in acute neurologic complications like amnesia, seizures, or coma as well as delayed complications such as choreoathetosis, cerebellar ataxia, and parkinsonism. MRI may demonstrate acute subcortical white matter abnormalities and basal ganglia lesions that may persist for several weeks, in addition to cerebellar and cerebral atrophy (85).
Wilson disease. Wilson disease (hepatolenticular degeneration) is an autosomal recessive disorder of copper metabolism. MRI has demonstrated abnormally increased T2 signal within the putamen and caudate, but also in the thalamus, dentate nuclei, midbrain, and subcortical white matter (130).
Hallervorden-Spatz disease. Hallervorden-Spatz disease is a progressive movement disorder with abnormal iron deposition in the globus pallidus, substantia nigra, and red nucleus. MRI may reveal decreased T2 signal in the lentiform nuclei and perilentiform white matter but increased T2 signal within the periventricular white matter (55).
Neuroacanthocytosis. Neuroacanthocytosis is an uncommon neurodegenerative disorder associated with movement disorders, dementia, and acanthocytosis (abnormal, spiculated, or star-shaped red blood cells). T2-weighted MRI may identify regions with increased signal within the white matter of the periventricular regions and within the corpus callosum (121).
Dystonia. Dystonia has not been associated with traditional MRI changes, but diffusion tensor imaging may be sensitive enough to detect subcortical white matter asymmetry in dystonia patients (15). Although the reason for this diffusion tensor imaging association is not clear, it may relate to activity-dependent microstructural changes in abnormally firing neuronal projection fibers, as patients receiving botulinum toxin for dystonia have at least partial and transient reversal of these diffusion tensor imaging changes (15).
Fragile X-associated tremor and ataxia syndrome (FXTAS). This is an adult-onset neurodegenerative disorder mainly seen in carriers, usually males, of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Clinically, FXTAS may present with progressive intention tremor and gait ataxia, and MRI demonstrates white matter abnormalities, particularly within cerebral and cerebellar locations (65). The neuropathological hallmark of FXTAS is an intranuclear inclusion found in neurons and astrocytes throughout the CNS (66).
Cerebral palsy. Children with cerebral palsy have frequent white matter abnormalities. Eighty-eight percent of children have abnormal findings on MRI, including frequent changes of white matter disease of immaturity. Although focal infarcts are identified in 7% of children with cerebral palsy, periventricular leukomalacia is identified in 43%, and lesions within the basal ganglia and cortical or subcortical regions are also commonly seen (11). Such changes were reported in 71% of children with diplegia and could also be found in patients with cerebral palsy, hemiplegia (34%), and quadriplegia (35%). The location of such white matter lesions in diplegic patients was posterior dominant, whereas patients with quadriplegia had evidence of diffuse white matter changes. Those patients with basal ganglia or thalamic changes tended to have a dystonic form of cerebral palsy (11).
Leukodystrophies. Several disorders with onset in childhood present with white matter disease on MRI. Although they resemble white matter abnormalities in adults, their nature is different. Additionally, the grey matter and peripheral nervous system may be affected. These genetic disorders, resulting in accumulation of abnormal metabolites, disrupt the myelin. The main leukodystrophies are adrenoleukodystrophy, Krabbe globoid cell, and metachromatic leukodystrophy.
Adrenoleukodystrophy. Adrenoleukodystrophy is a peroxisomal disorder resulting in the accumulation of very long-chain fatty acids. It is both a demyelinating and dysmyelinating disorder. Over time, the initial lesions of the parietal and occipital lobes progress towards the frontotemporal regions. In advanced disease, the internal capsule, corpus callosum, corticospinal tracts, and other white matter fiber tracts in the brainstem can be involved. The lesions tend to be contiguous within fiber tracts and confluent within the white matter regions. Typically, the white matter abnormalities are large and symmetric (93).
Krabbe disease. Krabbe disease (globoid cell leukodystrophy) is an autosomal recessive disorder that presents shortly after birth and progresses rapidly. The galactocerebroside beta-galactosidase deficiency leads to abnormal production and maintenance of myelin. MRI reveals bilateral, confluent white matter abnormalities within the cerebrum and cerebellum (44).
Metachromatic leukodystrophy. Metachromatic leukodystrophy is an autosomal recessive lysosomal disorder caused by a deficiency of arylsulfatase A. This is primarily a dysmyelinating disorder. The thalamus, posterior limb of the internal capsule, cerebellum, and quadrigeminal plate are most affected (89).
Other leukodystrophies include Alexander disease, Canavan disease, Pelizaeus-Merzbacher disease, Cockayne syndrome, Hurler disease, and Lowe syndrome.
Mitochondrial diseases. These disorders result in energy metabolism of mitochondria and may also present with evidence of white matter abnormalities.
Leigh disease. Leigh disease (subacute necrotizing encephalomyelopathy) is autosomal recessive, usually with onset in infancy or childhood. T2 MRI may reveal symmetric areas of increased signal within the basal ganglia, brainstem, and cerebellum (110).
Kearns-Sayre syndrome. Kearns-Sayre syndrome in children may appear as T2 hyperintensities of the basal ganglia and brainstem (158).
Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS). MELAS causes metabolic ischemia and infarcts within subcortical white matter that do not correspond to vascular territories (158).
Combined complex I and IV deficiency. Combined complex I and IV deficiency in children presents with extensive white matter abnormalities (158; 41).
Pyridoxine deficiency. Pyridoxine deficiency should be suspected in infants with epilepsy and frontal or occipital white matter lesions (82).
Cytomegalovirus. Cytomegalovirus infection can present with white matter abnormalities on MRI, including multifocal lesions within deep parietal white matter (160).
Myotonic dystrophy. Most patients with type 1 or 2 myotonic dystrophy exhibit white matter abnormalities or cerebral atrophy. In type 1, intellectual dysfunction is associated with white matter abnormalities in the anterior temporal lobe (92).
• Up to 80% of elderly individuals have white matter abnormalities.
• The burden of white matter abnormalities increases with age.
• Cerebrovascular risk factors and disease increase the risk of white matter abnormalities.
• African Americans have a lower burden of white matter abnormalities than European Americans.
Population-based studies have detected white matter abnormalities in up to 80% of subjects older than 65 years of age (178). In the general population, the burden of white matter abnormalities increases with age (38). White matter abnormalities are detected in asymptomatic subjects with both CT and MRI (152; 50; 19; 157; 144).
Moreover, white matter abnormalities are detected by both CT and MRI in cognitively impaired individuals, particularly in those with cerebrovascular disease or stroke risk factors (79; 75).
In patients with vascular dementia, white matter abnormalities are detected in up to 100% of cases both by CT and MRI (48; 101; 132).
African Americans had a lower prevalence of white matter abnormalities but a higher proportion of more severe white matter abnormalities than European Americans. White matter abnormalities were significantly associated with smoking, lower education, systolic blood and pulse pressure, and less with diastolic pressure (98).
• Control of the cerebrovascular risk factors seems reasonable to prevent white matter abnormalities.
• Intensive blood pressure control is more effective than standard blood pressure control at delaying an increase in white matter abnormality burden.
• Angiotensin-converting enzyme inhibitors were associated with the best prevention of white matter abnormality progression.
• Statin use may reduce the risk of dementia, but the effect on white matter abnormalities and intracerebral hemorrhage is unclear.
• There is no evidence for using antiplatelet medication for white matter abnormality prevention.
As white matter abnormalities share the risk factors with cerebrovascular disease, it is reasonable to assume that prevention should involve control of vascular risk factors, such as diabetes, hyperlipidemia, or hypertension. However, the benefit of various measures should be weighed against the potential side effects.
Control of hypertension reduces the burden of white matter abnormalities (161). In an observational cohort analysis of the SPRINT-MIND trial (Systolic Blood Pressure Trial Memory and Cognition in Decreased Hypertension), which included 448 individuals, angiotensin-converting enzyme inhibitors were associated with the best prevention of white matter abnormality progression over a 4-year period. This effect was independent of blood pressure control or age (60). On the other hand, intensive blood pressure treatment (systolic blood pressure lower than 120 mm Hg), compared with standard therapy (systolic blood pressure lower than 140 mmHg), was associated with a slower increase of white matter abnormalities (133). The beneficial effects of blood pressure control should be balanced against the increased risk of brain volume loss, syncope, and renal dysfunction (150).
Administration of simvastatin in healthy, middle-aged adults resulted in preserved white matter microstructure and volume at 18 months (169). High-dose atorvastatin decreased the risk of stroke more in patients with internal carotid artery stenosis than in those with small vessel disease (147). Although statins were found to reduce the risk of dementia (83; 184), their use was associated with both prevention and progression of white matter abnormalities (69; 61). Of additional concern is the increased risk of intracerebral hemorrhage with intensive cholesterol reduction (137). However, statin use before intracerebral hemorrhage does not seem to adversely influence the outcome (96).
Antiplatelets are widely used to prevent ischemic stroke. However, there is no convincing evidence that antiplatelets prevent dementia in patients with white matter abnormalities, but there may be an increased risk for hemorrhagic complications (94).
Enlarged perivascular spaces are areas surrounding the blood vessels filled with CSF. Lacunar stroke appears in T2 MRI as white matter hyperintensity surrounding a small cavity. However, in approximately 20% of patients with recent small subcortical strokes, the cavitation is not visible on MRI by 3 months (129).
Because fluid suppression may be affected by multiple factors, the FLAIR sequence may not be able to distinguish white matter abnormalities from lacunes or perivascular spaces as well as T1- and T2-weighted sequences (116). Moreover, approximately 50% of enlarged perivascular spaces are surrounded by FLAIR hyperintensity reflecting perivascular spaces, gliosis, or both (29).
Demyelinating lesions, such as those in multiple sclerosis and associated disorders such as Sjögren disease (117), form the most common differential diagnosis for white matter abnormalities. Although these disorders are often differentiated clinically, and some radiological features may help distinguish them, they cannot be readily differentiated (22).
Multiple sclerosis. The classical definition of multiple sclerosis is the presence of two or more central nervous system lesions separated in time and space, not caused by other central nervous system diseases. White matter abnormalities in MS are traditionally referred to as plaques. Although some acute plaques will enhance with gadolinium, early plaques or inactive plaques can be hyperintense or even isointense on T2-weighted MRI (27). Most early active lesions appear hyperintense on T2-weighted MRI with a hypointense ring, possibly containing activated macrophages. Late active lesions that are hyperintense on T2-weighted images often appear hypointense on T1-weighted images, possibly related to axonal loss and demyelination. Some typical features for white matter abnormalities due to MS include the presence of multiple ovoid-shaped bright lesions on T2-weighted MRI; some infratentorial lesions, particularly in the cerebellar peduncles; lesions having an abrupt loss of T2 signal at the gray matter; lesions in a periventricular location; lesion size greater than 5 mm; and the presence of lesions in the corpus callosum (123).
This is a T1-weighted MRI of the brain with gadolinium provision of a young female patient with clinically definite multiple sclerosis. Several lesions demonstrate gadolinium enhancement, most typical for active demyelinating d...
• Brain CT identifies white matter lesions as hypodensities.
• Brain MRI is more sensitive to the presence of white matter abnormalities than CT.
• MRI can better differentiate white matter abnormalities from lacunes and enlarged perivascular spaces.
Due to the unknown significance of periventricular and subcortical areas of hypodensity on CT or hyperintensity on T2-weighted MRI, the term leukoaraiosis was coined from the Greek leuko [white] and araiosis [rarefaction] (72; 73). MRI can detect leukoaraiosis earlier than CT (70).
White matter abnormalities help differentiate vascular dementia from Alzheimer disease, although both can coexist (48). In patients with vascular dementia, white matter abnormalities are more visible in those with basal ganglia, thalamus, or thromboembolic infarctions and confluent, irregular periventricular white matter abnormalities, whereas in Alzheimer disease, the lesions are more confined to the uncal-hippocampal and insular cortex (142; 170).
A visual rating scale possibly useful in quantifying white matter abnormalities in patients with cognitive decline is the Cholinergic Pathways HyperIntensities Scale, which identifies white matter abnormalities within well-identified cholinergic pathways (16).
• There is no treatment for white matter abnormalities.
• The benefits of controlling the vascular risk factors should be weighed against the potential side effects of any intervention.
Because white matter abnormalities share risk factors, such as diabetes, hyperlipidemia, and hypertension, with cerebrovascular disease, it is reasonable to control them. However, the side effects of any intervention must be considered.
Statin use has not decreased the severity of Alzheimer or vascular dementia (109). However, in an observational study, statins decreased the rate of white matter abnormality and dementia progression (180). A randomized controlled trial showed that telmisartan did not reduce the burden of white matter abnormalities, but low-dose rosuvastatin reduced the risk of new white matter abnormalities and cognitive impairment (183).
In patients with vascular dementia, the presence of cholinergic deficits due to basal forebrain ischemia can be assisted with the use of agents such as donepezil, galantamine, and rivastigmine on an individual patient basis (49).
Physical therapy and using assistive devices, such as canes or walkers, are indicated for gait difficulty and imbalance.
Progression of white matter disease appears to be associated with an increased risk of cognitive and gait decline. Aside from risk factor modification, there is no specific treatment for white matter disease. Because of the heterogenous nature of the disorder, treatment tailored to individual needs might best limit the risks of treatment-related complications, such as excessive reduction in cerebral perfusion in those with poor cerebral perfusion as a mechanism.
No specific precautions are known in women with white matter disease who become pregnant.
Avoidance of excessive fluctuations in blood pressure during surgery would appear prudent because severe hypotension or hypertension may contribute to further injury in patients with impaired cerebral microcirculation.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Adrian Marchidann MD
Dr. Marchidann of Kings County Hospital has no relevant financial relationships to disclose.See Profile
Steven R Levine MD
Dr. Levine of the SUNY Health Science Center at Brooklyn has no relevant financial relationships to disclose.See Profile
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