Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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This article includes discussion of white matter abnormalities in the brain, leukoaraiosis, and unidentified bright objects (UBOs). The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
The occurrence of white matter abnormalities in the brains of both symptomatic and asymptomatic subjects has been a controversial entity for over a century. The development of magnetic resonance imaging has led to more sensitive detection of these lesions, perhaps even more sensitive than autopsy inspection. Clinical studies have determined associations with cognitive decline and gait impairment, and perhaps increased relative risk for cerebrovascular disease. An animal model of white matter disease and brain atrophy related to diabetes has been established and may assist in the understanding of the pathophysiology of white matter abnormalities. Further clinical and scientific studies will help us understand the importance of white matter abnormalities in the human brain.
The introduction of CT in the 1970s followed by the subsequent introduction of MRI for imaging of the brain led to the discovery of largely unexpected changes within the cerebral white matter for both asymptomatic and cognitively impaired individuals. Since that time, the pathogenesis, clinical significance, and pathological correlate of these white matter abnormalities has not been well understood. These changes have been described using numerous terms including white matter abnormalities, cerebral white matter changes, unidentified bright objects (UBOs), or leukoaraiosis—used to refer to all white matter changes visible on neuroimaging studies.
In 1894, Binswanger described the case of a male with syphilis who suffered from a progressive decline in mental functioning, including speech and memory disorders, depression, and personality changes, along with lower extremity weakness and upper extremity tremor (Binswanger 1894; 14). Although autopsy demonstrated white matter atrophy, Binswanger did not seem to place much significance on this finding (168). Then, in 1902, Alzheimer described an analogous case in which he attributed the white matter changes to be due to arteriosclerosis of the long penetrating vessels (02; 169). It was not until 1962 that Olszewski diagnosed Binswanger's earlier case as syphilis, and he proposed the term “subcortical arteriosclerotic encephalopathy” to describe cerebral arteriosclerosis with predominant pathology affecting vessels of the white matter and subcortical grey matter (147).
Although the introduction of modern imaging led to pre-mortem diagnosis of Binswanger disease, it later became obvious that such imaging-detected alterations could occur in both symptomatic and asymptomatic subjects (21; 68). Today it not yet clear that those asymptomatic patients with imaging-identified white matter abnormalities are at risk for later cognitive changes. However, recognition of these imaging abnormalities may be important in particular patient groups.
Although earlier papers did not find an association between white matter abnormalities and cognitive decline (104; 116; 82; 172), more recent studies have shown a clearer association between white matter abnormalities and cognitive impairment (77; 170; 107; 111; 199). In the healthy elderly, the presence of white matter abnormalities has been associated with slowing of processing speed, memory deficit, and problems with executive functioning (76). In the Rotterdam Scan Study, presence of white matter abnormalities and periventricular leukoaraiosis were also associated with slower psychomotor functioning, memory impairment, and global functioning of cognition (38).
The presence of white matter abnormalities and periventricular leukomalacia have been associated with a decline in Wechsler Performance IQ scores, Block Design, Object Assembly, and Digit Symbol tests between the ages of 50 and 80 years, with greater decline related to higher numbers of lesions identified on neuroimaging (65). This unique study took data from patients examined at ages 50, 60, and 70 years of age followed by further testing at age 80 years and MRI assessment of the brain, permitting sequential assessments. Although cognitive decline did possess a clear relationship to the presence of white matter abnormalities, this did not explain all cognitive decline seen in all individuals within the study. Further investigations by Deary and colleagues examined cognitive change over the age span of 11 to 78 years (45). This study was unique in that white matter abnormalities and periventricular leukomalacia were evaluated separately, and a wider range of mental functions were assessed. It was determined that the degree of white matter abnormalities present were associated with overall cognition, independent of childhood cognitive ability. Hypertension was suggested as accounting for at least a portion of the effects of white matter abnormalities in this study.
Although also controversial, a positive correlation between presence of white matter abnormalities and cognitive impairment has been inconsistently reported in patients with Alzheimer disease (56; 82; 135; 204) and in nonspecific dementia (97; 19; 104). The severity of leukoaraiosis identified on MRI may correlate with the severity of dementia (178; 61). In normal subjects, the presence of leukoaraiosis identified on either CT or MRI does not affect the performance on cognitive testing (84; 89; 127; 155; 135; 62). However, age is an obvious confounding factor in any study of leukoaraiosis and cognitive function. When multivariate analysis is performed by controlling for age, sex, educational level, and presence of stroke on imaging, leukoaraiosis identified by CT was found to correlate with lower neuropsychological scores in normal subjects (173). Although leukoaraiosis is not associated with a diagnosis of dementia among patients with cognitive impairment (91), patients with leukoaraiosis demonstrate lower cognitive impairments than those without (173). When the more sensitive MRI is used to identify leukoaraiosis abnormalities, their presence does not appear to relate to cognition in normal subjects (89; 184; 166). This may be a threshold effect, as more severe leukoaraiosis abnormalities in normal volunteer subjects have been related to a significant impairment in cognitive and neurobehavioral functions when compared to those subjects without leukoaraiosis (128; 25). It may be that a threshold exists for the volume of abnormal white matter before subtle but significant changes in cognition may be detected; in 1 MRI study, leukoaraiosis greater than 10 cm2 had impairment of attention, processing speed, and frontal lobe functioning (20).
In addition to cognitive changes, the presence of white matter abnormalities may relate to abnormalities in gait and balance. Gait disturbance and susceptibility to falling has been associated with the presence of leukoaraiosis, likely secondary to disruption of subcortical brain pathways (66; 121; 173; 84; 127; 30). In elderly males, greater than median volumes for white matter abnormalities demonstrated poor performance with standing balance tests. The presence of ApoE4 in addition to white matter abnormalities led to a greater than additive effect for each individual measure when related to impairment in standing balance tests (32). Impairment of gait and balance in the elderly was associated with white matter disease in another study. An abnormal age-related decrease in white matter volume and age-independent increases in white matter abnormalities were demonstrated in a mobility-impaired elderly group when compared with an age-controlled control group (78). Frequency of white matter abnormalities, as well as presence of diffuse or frontal lobe atrophy, has been associated with abnormalities in gait and balance as well as the occurrence of falls in the elderly population (102).
Children are not immune to the potential clinical effects of white matter abnormalities and deficits in white matter volume. Children aged 5 years of age or younger who underwent MRI with demonstration of white matter changes were investigated for abnormalities in muscle tone and muscle stretch reflexes. A control group with normal MRI scans and normal tone was used for comparison. Presence of 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 on MRI. Those pediatric patients with increased tone had more signal abnormalities as well as increased tendon reflexes. This suggests that presence of increased signal intensity is more likely to be associated with presence of spasticity, as compared to those pediatric patients with normal or low-signal intensity white matter abnormalities in whom normal tone or hypotonia is more likely (113).
Besides abnormalities in cognition, physical examination signs that relate most commonly to the presence of white matter abnormalities include an extensor plantar reflex (173; Steingart et al 1987b; 30) and the presence of primitive reflexes (Steingart et al 1987b; 30). The presence of these examination abnormalities probably relates to an abnormality within the subcortical brain region.
Clinical signs such as abnormal 3-step motor sequencing and horizontal extraocular tracking tests can be predictive of the presence of periventricular white matter abnormalities on MRI (07).
The presence of leukoaraiosis in patients with a history of stroke may be suggestive of an increased risk of subsequent stroke (136; 189). Although their presence may be suggestive of impaired cognition, leukoaraiosis do not seem to influence the rate of progression of cognitive impairment in Alzheimer disease patients (140; 141; 82). However, more severe presence of leukoaraiosis seems to be associated with faster progression of cognitive impairment and mortality in Alzheimer disease patients, with evidence of more severe loss of myelinated fibers during autopsy (95). In patients with or without a history of stroke, the presence of white matter abnormalities on MRI are associated with increased risk of death. After an initial clinical evaluation and follow-up for a median of 12 years, higher grades of white matter disease were independently associated with shorter latency to death from any cause, even after statistical adjustment for hypertension, high cholesterol, diabetes, and coronary artery disease (103).
White matter lesions are associated with retinal microvascular abnormalities. Persons with both white matter lesions and retinopathy have a much higher risk of clinical stroke (20% versus 1.4%) (202).
A 72-year-old male presented for assessment of gait difficulties. He had been diagnosed with diabetes 3 years prior to presentation and was controlled using oral metformin 500 mg twice daily. One year ago, he began to note difficulty with walking, leading people to believe that he was inebriated. He would occasionally catch his toes, which would lead to a 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, it was noted that he had become somewhat forgetful with daily tasks and could not recall names of frequently seen persons at all times.
Past medical history was otherwise unremarkable. He was on no other medications. Family and social history were unremarkable. On review of systems, he experienced tingling of both feet that 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 moderate to long term recall of visually identified objects as well as for verbal memory. 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. Funduscopy revealed some occasional arteriovenous-nicking. Blood pressure was found to be 150/95. Visual fields were full to monocular testing bilaterally. 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 to 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 a 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 provided, along with a secondary diagnosis of mild diabetic peripheral neuropathy. Diabetic education was provided, and physical therapy was recommended to assist with ongoing gait difficulties. Physiatrist consultation led to the initiation of a walker for assistance with mobility.
One year later, despite mobility aids, this patient continued to have worsening mobility that led to a fall which caused an epidural hematoma and death.
Until recently, little information on the genetics of stroke and small vessel disease was available. Through genome-wide association studies, the rs12204590 stroke risk allele (on chromosome 6p25, near FOXF2) was associated with increased MRI-defined burden of white matter hyperintensity--a marker of cerebral small vessel disease--in stroke-free adults. Young patients (aged 2 to 32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity (144).
Normal subjects. A matched co-twin analysis of elderly monozygotic twins examined the relationship between midlife cardiovascular risk factors and MRI-based measures of brain atrophy (34). Data regarding cardiovascular risk factors were recorded over 25 years of adult life. Differences within pairs in midlife glucose levels, high-density lipoprotein cholesterol, and systolic blood pressure were significantly associated with differences in white matter hyperintensities. In addition, within-pair differences in volumes of white matter abnormalities were significantly associated with differences in performance on cognitive and physical function tests. Furthermore, the co-occurrence of cerebrovascular disease and the ApoE4 subtype was associated with significantly greater brain atrophy and white matter abnormalities than either ApoE4 or cerebrovascular disease alone (46).
When both dizygotic and monozygotic male twins were subjected to MRI and neuropsychological testing, genetic influences appeared to play a role in the development of white matter abnormalities and impaired performance in cognitive function (33). Genetic influences appeared to explain about two thirds of the variability in cognitive functioning; neurologic co-variation in presence of white matter abnormalities and cognition could be explained by genetic effect in more than 70% of cases.
Advanced-age subjects. Aging has a large effect on both the frequency and the severity of CT- and MRI-identifiable leukoaraiosis (67; 66; 128; 204; 25). Although other risk factors play a role in the development of white matter abnormalities, aging is certainly an independent risk factor on its own (62; 119; 133; 193; 85; 174). Additional risk factors identified in various multivariate analytical studies have included a history of stroke (04; 91; 175; 30; 25; 174), male sex (91), hypertension (04; 30; 25; 52), diabetes mellitus (164; 52), and heart disease (52; 119). Prospective studies in non-disabled elderly subjects have determined that severe white matter hyperintensities identified with MRI, when occurring in the presence of medial temporal lobe atrophy, have a 4-fold associated increase in mild cognitive deficits (186).
When the presence of white matter abnormalities is examined in normal elderly people, 3 distinct patterns of spatial localization within the brain can be observed. Presence of white matter abnormalities in temporal and occipital areas was associated with greater age, hypertension, late onset depressive disorder, and perhaps poor global cognitive function (03). Even in high-functioning older adults without evidence of stroke or dementia, abnormalities in gait such as slower speed, shorter stride, and greater support time have a positive association with presence of white matter hyperintensities on MRI (160). Sequential MRI scans 20 months apart in elderly subjects with or without mobility impairment have demonstrated a 5-fold acceleration in the accumulative volume of white matter lesions in mobility impaired subjects (201). In addition to the presence of white matter lesions, longitudinal analysis in elderly subjects without dementia has determined that other brain MRI abnormalities such as ventricular enlargement, and subclinical and basal ganglia small brain infarcts contribute to poor motor performance and faster gait speed decline over time (161).
Alzheimer disease. Between 19% and 78% of patients, have identifiable white matter abnormalities using CT studies (53; 108; 15; 49; 123; 154) and 7.5% to 100% using MRI studies (53; 19; 198; 130). It has been speculated that the presence of white matter abnormalities in patients with Alzheimer disease may be associated with presence of cerebral congophilic angiopathy (71; 95).
More elderly patients diagnosed with Alzheimer disease have greater levels of periventricular, lobar white matter and basal ganglia white matter hyperintensities on MRI when compared to a control group. Younger onset Alzheimer disease patients did not have similar white matter abnormalities demonstrable. Despite this difference in the presence of white matter abnormalities, cortical atrophy did not differ significantly between presenile onset and senile onset Alzheimer disease patients. This may suggest that more elderly patients with Alzheimer disease may be subject to greater cerebrovascular risk factors that may play a role in the formation of their dementia (163).
In another imaging-based study, Alzheimer disease patients were found to have significantly more white matter abnormalities than controls, with preferential involvement of the frontal lobes (70%). This study also identified an inverse correlation with grey matter cortical volume. Presence of white matter abnormalities was significantly associated with vascular risk factors and with poorer performances on memory testing (31). In a controlled study, the combination of deep white matter lesion burden and periventricular white matter lesion burden were associated with reduced global cognition in Alzheimer disease patients but not in non-demented elderly patients (29). However, another study examining Alzheimer disease patients with and without white matter abnormalities did not demonstrate an association of white matter abnormality volume with more severe cognitive dysfunction, but did find association with urinary bladder incontinence, presence of grasp reflex, and abnormal motor examinations (86).
In patients with Alzheimer disease and presence of white matter abnormalities, psychiatric evaluation may identify greater apathy, and neurologic examination may demonstrate greater extrapyramidal signs than in Alzheimer disease patients without white matter abnormalities (172). SPECT scans in patients with Alzheimer disease and MRI-identified white matter abnormalities may indicate significant deficits in perfusion over basal ganglia, thalamic, and frontal regions (172).
Elevated homocysteine levels in Alzheimer disease patients have been positively associated with the presence of leukoaraiosis on CT scanning (88). Leukoaraiosis was more noticeable over deep white matter regions than within periventricular regions in this population (88). Hypertension is an oft-cited association with white matter lesions, or leukoaraiosis, and a controlled study has suggested that elevations in pulse pressure correlate with presence of leukoaraiosis in Alzheimer disease patients (114).
An Irish family with familial Alzheimer disease due to an E280G mutation in exon 8 of presenilin-1 has been demonstrated to have spastic changes along with white matter abnormalities identifiable on MRI (148).
White matter abnormalities do not appear to be unique to dementia patients diagnosed with Alzheimer disease, as patients with Lewy body disease also have higher than normal numbers of white matter abnormalities (09). Patients with clinical and radiological patterns of vascular dementia, as could be expected, have higher numbers of white matter abnormalities than either Lewy body disease or Alzheimer disease patients (09). The presence of white matter abnormalities in demented patients may contribute to an increased risk for depressive symptoms (09).
Psychiatric disorders. Although any association remains uncertain due to methodological problems, including lack of a suitable control group, psychiatric disorders have been described as having excessive numbers of leukoaraiosis using MRI for detection (24; 37; 176; 47; 129; 06; 85). A small study examined the frequency of MRI hyperintensities in patients with bipolar disorder and a matched control group, with hyperintensities found within the right frontoparietal subcortical white matter in patients only. No periventricular white matter lesions were demonstrated in any group (75). Although substantiation is required, a small study of patients with major depressive disorder has suggested the presence of a greater number of subcortical white matter lesions, particularly in those patients with depressed folate levels or hypertension (93).
The brains of patients with schizophrenia may be subject to abnormalities in white matter without a loss of white matter volume. Relative to control subjects, males with schizophrenia who were subjected to MRI diffusion tensor imaging demonstrate lower anisotropy, without changes in grey matter. The abnormal white matter anisotropy is present throughout—from frontal to occipital white matter (118). Brain anisotropy relates to proton movement, which is a reflection of physically restricted water movement; in white matter, brain anisotropy is related to the presence of myelin. When T2 and proton density maps for gray matter and white matter are examined in schizophrenic males and controls, longer T2 values are found within both white and grey matter within the brains afflicted with schizophrenia. It does not appear that whatever process is producing prolonged T2 values fully accounts for the abnormally low anisotropy observed selectively in white matter in schizophrenia (152).
CADASIL. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy is characterized by multiple subcortical infarcts and leukoencephalopathy with an autosomal dominant pattern of inheritance related to a genetic defect on chromosome 19q12 (182). Patients with CADASIL also experience migraine, mood disturbances, and recurrent strokes, often with progression to subcortical dementia and premature death. White matter abnormalities in CADASIL may be more likely to occur in insular regions and temporal lobes as compared to white matter abnormalities in hypertensive patients. In addition, involvement of the external capsule and corpus callosum may be more specific for CADASIL patient brains (150). 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; 72).
As patients with CADASIL age, MRI signal abnormalities increase (35). 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 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 formation of new blood vessels 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 (81).
Miscellaneous disorders. 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 (153).
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 (64).
Neuroacanthocytosis is an uncommon neurodegenerative disorder associated with a movement disorder, dementia, and acanthocytosis. T2-weighted MRI may identify regions with increased signal within the white matter of the periventricular regions, as well as within the corpus callosum (145).
Dystonia has not been associated with traditional MRI changes, but the new technique of diffusion tensor imaging may be sensitive enough to detect subcortical white matter asymmetry in dystonia patients (16). 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 (16).
Fragile X-associated tremor and ataxia syndrome (FXTAS) 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 characteristic white matter abnormalities, particularly within cerebral and cerebellar locations (73). The neuropathological hallmark of FXTAS is an intranuclear inclusion found in both neurons and astrocytes throughout the CNS (74).
Children with cerebral palsy have frequent abnormalities identified using MRI. 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/subcortical regions are also commonly seen (11). Such changes were reported in 71% of children with diplegia and could also be found in cerebral palsy patients with 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 cerebral palsy patients with basal ganglia or thalamic changes tended to have a dystonic form of cerebral palsy (76%) (11).
Susac syndrome is clinically composed of the triad of encephalopathy, retinopathy, and hearing loss. This disease of recurrent flares is a microvasculopathy secondary to thrombosis for unclear reasons (69; 203).
Although their significance is uncertain in myopathic disorders, both myotonic dystrophy type 1 and type 2 patients have white matter abnormalities demonstrable using MRI (110). Of these disorders, intellectual dysfunction, possibly related to presence of cerebral atrophy and white matter abnormalities, has been demonstrated in patients with myotonic dystrophy type 2.
Prolonged hypoglycemic encephalopathy can lead to chronic encephalopathic changes and prolonged coma. In addition to acute MRI changes similar to that of ischemia, such as hyperintensity in the cerebral white matter and in the boundary zones between vascular territories, as well as superficial laminar necrosis, later assessments can demonstrate white matter changes consistent with pathologically identified severe myelin loss with astrocytosis (138).
Trauma. The occurrence of closed-head injury in patients subjected to trauma may also be associated with presence of white matter changes. Of those patients found with white matter abnormalities (which may be less than 10%), the co-occurrence of SPECT abnormalities with abnormal perfusion to frontal, temporal, or parietal lobes performed 6 months after injury may suggest a poorer outcome 2 years after head injury. Patients with both white matter abnormalities and SPECT scan abnormalities were found to have poor function within rehabilitation programs and with activity of daily living scores (192).
Patients suffering from electrical injury can be subject to both brain atrophy, sometimes progressive, and supratentorial white matter lesions (134). Electrical injury may result in various acute neurologic complications such as coma, amnesia, seizures, and such delayed complications such as choreoathetosis, cerebellar ataxia, and parkinsonism (99). MRI performed in the acute stages after electrocution may demonstrate discrete hyperintense signal changes in the subcortical regions and basal ganglia. Several weeks after electrocution, white matter changes may still be present, or other findings such as cerebellar and cerebral atrophy may be identified (99).
Migraine. MRI evaluations of migraineurs have demonstrated a high incidence of increased signal intensity in the white matter on T2-weighted scans (100; 171; 94). In particular, these white matter abnormalities have been identified in patients under 40 years of age, which is unusual for an entity expected in an elderly population (149). When compared to an age- and sex-controlled population without headache, 14% of migraineurs have demonstrable white matter abnormalities seen usually in the periventricular white matter or near grey-white matter junctional areas, as compared to 4% of control subjects. In migraineurs, these lesions were usually in the parietal regions (159). Another older study reported a 40% incidence of white matter abnormalities in patients with migraine, more commonly found in patients with migraine with aura or complicated migraine (90). No pathological studies of white matter abnormalities in migraineurs exist, but it may be possible that white matter abnormalities in this patient group may represent an immune-mediated demyelination, which may explain the peculiar distribution of the migraine-associated lesions. Alternatively, ischemia or other forms of demyelination may be responsible (159).
AIDS dementia. Patients with acquired immunodeficiency syndrome dementia complex can have associated deep white matter changes and cerebral atrophy identified on MRI. The presence of white matter abnormalities in deep white matter was associated with a trend to having an increased risk for AIDS dementia complex in patients with defined AIDS. However, higher grades of deep white matter abnormalities were more likely to be associated with AIDS dementia complex, and presence of white matter signal intensities in the splenium was associated with AIDS dementia complex. Conversely, diffuse cerebral atrophy was significantly associated with AIDS dementia complex (p = .001) (27).
Apolipoprotein E epsilon 4 status. Carriers for ApoE4 have a significantly higher subcortical white matter abnormalities volume burden than ApoE33 carriers independent of hypertension. Subjects with the combination of hypertension and at least 1 ApoE4 allele have the highest amounts for both subcortical and periventricular white matter abnormalities (42). Yet in another study controlling for confounding cerebrovascular risk factors, the number of ApoE4 alleles was not associated with presence of white matter abnormalities, which were only found to be associated positively with age and hypertension (87).
Cardiovascular risk factors. Patients with atrial fibrillation detected by electrocardiography (41) are more likely to have severe number and volume of periventricular white matter abnormalities when compared to control subjects (relative risk of 6.3). However, atrial fibrillation did not appear to be a risk factor for subcortical white matter abnormalities.
Diabetes mellitus has been associated with the presence of cerebral atrophy and white matter abnormalities. Even in patients not specifically diagnosed with diabetes mellitus, elevated glycated hemoglobin levels can be found in non-demented elderly patients with MRI-identified white matter lesions (143). There are significantly more deep WMA found in patients with diabetes, with or without hypertension, when compared to control subjects undergoing MRI. One cross-sectional study has suggested that type 2 diabetes is an independent risk factor for deep WML in living elderly patients (188). Not only is type 2 diabetes associated with deep WMAs, but it is also associated with both cortical and subcortical atrophy and impaired cognitive performance (attention and executive function, information-processing speed, and memory) (125). The most common locations for diabetes-associated white matter abnormalities are in the caudate and putaminal nuclei, internal capsule, thalamus, dentate nucleus, supratentorial white matter, and brainstem (167). Diabetic-associated white matter abnormalities, in themselves, are a risk factor for stroke (63), as well as for cognitive deficits such as memory and executive functioning and abnormalities in gait and balance dysfunction (05; 109). In the diabetic brain, periventricular brain regions are predominantly affected with increased T2-weighted MRI signals (180), possibly due to changes in periventricular fluid dynamics with a disrupted subependymal lining (83). Other previously speculated mechanisms in the development of white matter abnormalities in the diabetic brain include vascular border zone hypoperfusion, subclinical ischemia (205), neuronal loss and axonal degeneration (08), and abnormalities in the blood-brain barrier and cerebrospinal fluid dynamics (205). In older patients with long-standing type I diabetes, informational processing speed is compromised when compared to controls, but several other measures are only mildly affected in older type I diabetes patients. In this type I diabetes patient population, there were no definite WMA detected when compared to patients without diabetes, and brains exposed to long-term type I diabetes showed a trend toward brain atrophy only. Among patients with diabetes, age, hypertension, hemoglobin A1C levels, and retrograde hemoglobin A1C levels were related to significant slowing of information processing. The duration of diabetes was also inversely related to memory, attention and executive functioning, with disease onset before age 18 showing greatest relationship. Onset of diabetes prior to age 18 in combination with known atherosclerotic disease were also related to the presence of WMA.
Pathologically, areas of white matter abnormalities in diabetic and other brains relate to presence of regions of myelin pallor with relative loss of axons, myelinated fibers, and oligodendrocytes over affected regions, which may demonstrate spongiosis and extracellular space expansion (22; 164; 59). The most common locations for white matter abnormalities in human brain are in the caudate and putaminal nuclei, internal capsule, thalamus, dentate nucleus, supratentorial white matter, and brainstem (142).
Hypertension is commonly associated with presence of white matter abnormalities, whether in patients with co-existing stroke, transient ischemic attack, or vascular dementia (18; 158; 195; 189) as well as in asymptomatic control subjects (66). In addition, the presence of leukoaraiosis on CT is strongly associated with presence of lacunar infarcts and intracerebral hemorrhage (92; 30), both of which occur in the presence of hypertension.
Although not demonstrated, the co-occurrence of cerebrovascular risk factors may be associated with an even higher white matter lesion load.
When patients with Alzheimer disease with or without presence of white matter abnormalities on MRI are examined for hypertension, those patients with white matter abnormalities are more likely to have presence of hypertension. However, the degree of atrophy did not depend on the presence or absence of hypertension in this population (39). Although some authors claim that the risk of Alzheimer disease is increased in patients with type 2 diabetes, it is not clear that the cognitive decline in such patients is clearly related to accentuated Alzheimer disease pathology. However, patients with diagnoses of both type 2 diabetes and Alzheimer disease have greater cortical atrophy identified on MRI when compared to patients with Alzheimer Disease without diabetes. Even though infarcts are more common in patients with Alzheimer disease and type 2 diabetes, these did not explain the increased atrophy identified, suggesting that non-vascular mechanisms are contributing to increased cortical atrophy associated with diabetes (12).
The presence of a positive family history of stroke or hypertension in first degree relatives is significantly associated with the presence of white matter abnormalities (156) and may be one of the best predictors for the existence of white matter abnormalities.
Patients with hypertension have more white matter abnormalities than controls or patients in whom blood pressure was controlled with antihypertensives (50).
White matter abnormalities, in themselves, are a risk factor for stroke (23) and cognitive deficits in functions such as memory and executive functioning as well as abnormalities in gait and balance dysfunction (38; 76; 191). White matter abnormalities disrupt prefrontal-subcortical loops involved in frontal lobe executive control (197).
Pediatric diseases. A variety of white matter diseases, particularly pediatric in onset, can be associated with white matter disease identifiable on MRI. Although some of these disorders may have imaging findings that can appear similar to white matter abnormalities; the nature of the white matter changes is generally dissimilar. Some of these disorders also affect the grey matter and peripheral nervous system. The classic forms of leukodystrophies include adrenoleukodystrophy, Krabbe globoid cell, and metachromatic leukodystrophy, as well as less common entities. These are genetic in origin and are caused by a specific inherited biochemical defect important in the metabolism of myelin proteolipids that results in abnormal accumulation of a metabolite in brain tissue.
Adrenoleukodystrophy is a peroxisomal disorder that leads to abnormal accumulation of very long chain fatty acids. Adrenoleukodystrophy is both a demyelinating and dysmyelinating disorder. Initially, it involves predominantly the parietal-occipital lobes but then progresses forward into the frontotemporal regions over time. Both periventricular and subcortical white matter are affected, and in advanced disease the internal capsule, corpus callosum, corticospinal tracts and other white matter fiber tracts in the brainstem can be involved. The white matter disease tends to be contiguous within fiber tracts and confluent within large white matter regions (112). Typical MR findings include large, symmetric, hyperintense lesions on T2-weighted MRI.
Krabbe disease (globoid cell leukodystrophy) is an autosomal recessive disorder that presents shortly after birth and progresses rapidly. This is due to a deficiency of the enzyme galactocerebroside beta-galactosidase, leading to abnormal production and maintenance of myelin. MRI reveals bilateral, confluent changes within cerebral and cerebellar white matter (48).
Metachromatic leukodystrophy is a lysosomal disorder with autosomal recessive inheritance due to deficiency of arylsulfatase A. This is primarily a dysmyelinating disorder. T2 signal shortening may be seen in the thalamus, the posterior limb of the internal capsule, the cerebellum, and the quadrigeminal plate (105).
Other leukodystrophies that may demonstrate evidence of white matter disease include Alexander disease, Canavan disease, Pelizaeus-Merzbacher disease, Cockayne syndrome, Hurler disease, and Lowe syndrome.
Mitochondrial diseases may also present with evidence of white matter changes. Leigh disease (subacute necrotizing encephalomyelopathy) is a familial disorder with autosomal recessive inheritance, usually with onset in infancy or childhood. MRI may reveal symmetric areas of increased T2 signal within the basal ganglia, brainstem, and cerebellum (131).
Kearns-Sayre syndrome in children may have T2 hyperintensities of the basal ganglia and brainstem (185). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes may have infarct-like lesions within subcortical white matter that does not correspond to vascular territories due to metabolic ischemia (185). Children with combined complex I and IV deficiency can have extensive white matter changes (185; 43).
Another pediatric cause for white matter abnormalities is the presence of pyridoxine deficiency and associated epilepsy (96). These infants may have presence of frontal or occipital white matter lesions.
Another cause of pediatric white matter changes is infection. Cytomegalovirus infection can present with white matter changes on MRI (187), including multifocal lesions with deep parietal white matter.
Pathologically, white matter abnormalities correspond to areas of myelin thinning and gliosis and are often accompanied by lacunar (small holes) infarctions and small vessel atherosclerotic disease. White matter abnormalities relate most commonly to vascular disease and vascular risk factors. Although studies are incomplete, pathological correlation of leukoaraiosis and white matter abnormalities identified on neuroimaging would be expected to help determine the pathogenesis of leukoaraiosis and white matter abnormalities. One problem is that fewer white matter abnormalities are visible postmortem when compared with pre-mortem MRI (57).
The presence of periventricular region leukoaraiosis has been correlated with decreased myelin content (177; 115; 70; 190; 36; 58; 162; 137), loss of ependymal cell layer and reactive gliosis at the tip of the frontal horns, (177; 98; 36; 58; 162), increased periependymal extracellular fluid content, axonal loss, and presence of atrophic axons (177). Some authors have also found enlarged perivascular spaces at this periventricular location (70). However, small periventricular lesions exist in all age groups (including newborns) (177; 137); therefore, smaller lesions may not represent a true abnormality.
Pathological studies of white matter abnormalities remain scanty. They have suggested a relationship to frontal atrophy, ventriculomegaly, and presence of reactive astrocytes in the frontal periventricular white matter, as well as increased arteriolar wall thickness (196). An autopsy study examined brain tissues from pathologically confirmed Alzheimer disease with tissue processed for ApoE genotyping. The presence of myelin loss in these brains was not related to the ApoE4 genotype, nor was it related to the presence of pathologically confirmed arteriosclerosis. (179).
The histological correlates of deep subcortical white matter abnormalities are even less consistent than for periventricular leukoaraiosis. Punctate abnormalities correspond to enlarged perivascular spaces (36; 162), lacunes (23; 126; 142), demyelinating lesions, brain cysts, and congenital diverticula of the lateral ventricles (23). More diffuse lesions within the centrum semiovale have been compared to myelin rarefaction sparing of the U fibers (157; 36), sometimes accompanied by reactive astrocytes (58), as well as diffuse vacuolization of the white matter (142). The myelin rarefaction that occurs is not a true demyelination, as the process also will involve axonal destruction (04; 124).
Subcortical white matter abnormalities disrupt short corticocortical fibers, whereas periventricular leukoaraiosis may lead to damage within regions containing closely packed long association fibers connecting distant cortical areas (38). Using the hypothesis that white matter abnormalities lead to a disconnection syndrome (132; 200), white matter abnormalities are more likely to disrupt local neuronal networks, whereas periventricular leukoaraiosis is more likely to impair cognitive functions, requiring the coordination of multiple distinct cortical areas.
There is anatomical, histopathological, clinical, and experimental evidence that at least some white matter abnormalities are ischemic in origin (44; 56; 58; 51; 122; 151). Experimental animal studies have reproduced some aspects of human white matter lesions (151). Some studies have implicated leaks in the blood-brain barrier as at least partially pathogenic for the appearance of white matter abnormalities (101). Alterations in cerebrospinal fluid circulation may play a partial role in the development of white matter abnormalities (106).
Regardless of the location of white matter abnormalities, deficits in frontal lobe metabolism detected by PET are found in predemented diabetic patients (197), perhaps related to structural or metabolic damage to subcortical axons. Abnormalities in MRI T2 values over brain regions with white matter abnormalities could suggest changes in water content or a modification of quantity of molecules or proteins that would produce abnormal and T2 signal. Although early diabetes is associated with mild loss of water content in the brain (183), chronic hyperglycemia, as well as diabetic ketoacidosis, is associated with brain water content preservation or increase, possibly due to osmoprotective molecule production (180).
Neuropathologic studies of the brains of nonhypertensive elderly patients have demonstrated prominent frontal atrophy and ventriculomegaly. In addition, markedly reactive astrocytes were found in periventricular white matter of most patients with white matter abnormalities and gait imbalance. An increased arteriolar wall thickness was demonstrated in some patients with white matter abnormalities as well (196).
Although myoinositol concentrations are significantly increased in the frontal white matter of patients with diabetes as compared to healthy controls, its importance and possible relationship to diabetes-associated gait apraxia and cognitive impairment remains uncertain (01).
An animal model for longstanding diabetes has been associated with the presence of cerebral atrophy and WMA (181). Both MRI volumetric assessments and brain weight revealed brain atrophy in long-term diabetic mice as compared to littermate controls. Furthermore, leukoencephalopathy with evidence of MRI hyperintensities over the hippocampus, thalamus, putamen, corpus callosum, and internal capsule were associated with pathologically illustrated myelin loss or pallor. These pathological changes were also associated with time-related development of cognitive changes during behavioral testing. A possible pathological marker for these changes is the increased expression of RAGE (the receptor for advanced glycation end products), which was found to be increased dramatically within sites of white matter damage. RAGE expression was elevated within neurons, oligodendrocytes, astrocytes and microglia. Meanwhile, RAGE null diabetic mice demonstrated significantly less neurodegeneration when compared to wild-type diabetic mice (181). Further studies examining potential signaling pathways of RAGE are underway, as well as studies to examine blockade of the RAGE pathway with the competitive decoy, soluble RAGE (sRAGE).
White matter abnormalities are frequently detected on T2-weighted MRI of the brain, especially in adults older than 60 years of age. They may be alternatively referred to as white matter lesions, hyperintensities, or unidentified bright objects due to their bright white appearance on T2-weighted MRI. Among people in the general population, the amount of these lesions increases with age between ages 60 and 90 (117; 151; 40). Partly due to their ubiquitous nature in the elderly, there remains uncertainty concerning the clinical relevance of these abnormalities. There is some evidence that smooth periventricular leukoaraiosis is different from patchy deep white matter abnormalities.
Up to 80% of MRI scans performed in persons older than 65 years have demonstrable changes in their cerebral white matter (202). In this population, presence of white matter abnormalities was associated with increased relative risk of stroke and presence of retinal microvascular abnormalities.
Women tend to have more subcortical white matter abnormalities than men, particularly in frontal regions, and also more periventricular white matter abnormalities, although no statistical significant difference has been shown (40).
Prevention of white matter lesion development may involve control of vascular risk factors, such as diabetes, hyperlipidemia, or hypertension, which appear to play a role in development of white matter abnormalities, although no studies have been performed to examine such intervention and measured end points.
Demyelinating lesions such as those in multiple sclerosis and associated disorders such as Sjögren disease (139) form the most common differential diagnosis for white matter abnormalities. Although these disorders are often differentiated clinically, some radiological features may distinguish them.
The classical definition of multiple sclerosis is the presence of 2 or more central nervous system lesions separated in time and space, not caused by other central nervous system disease. White matter lesions in multiple sclerosis 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 (28). 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 lesions due to multiple sclerosis 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 (146).
Due to the ubiquitous nature of white matter abnormalities, they may be present in essentially asymptomatic subjects or symptomatic patients. Because of this large degree of nonspecificity, the differential diagnosis is large.
Due to the uncertainty of the significance of neuroimaging abnormalities and the reluctance to associate them with a specific disease process, Hachinski and colleagues established the term leukoaraiosis (from the Greek leuko [white] and araiosis [rarefaction]) to designate periventricular and subcortical (centrum semiovale) areas of hypodensity on CT or hyperintensity on T2-weighted MRI (79; 80). The term leukoaraiosis can be used to refer to both the CT- and MRI-demonstrable abnormalities. It is possible that MRI can detect leukoaraiosis earlier than with CT (77).
Leukoaraiosis is detected by CT and MRI both in asymptomatic persons older than 60 years and in cognitively impaired individuals, particularly in those patients who have evidence of cerebrovascular disease or stroke risk factors (92). In patients with a diagnosis of vascular dementia, leukoaraiosis is detected with CT in 41% to 100% of cases (53; 108; 154) and with MRI in 64% to 100% of cases (53; 120; 193). In normal control subjects, leukoaraiosis is usually harder to detect than in demented patients (82; 164; 194). However, leukoaraiosis may be detected in up to 21% of asymptomatic subjects evaluated with CT (173; 55) as well as normal subjects evaluated with MRI (20; 184; 166). Population-based studies have detected leukoaraiosis using MRI in 27% to 38% of subjects older than 65 years of age (26; 119). Obviously, many of these studies have identified a wide variance in the frequency of leukoaraiosis, depending on the subjects’ ages, stroke risk factors, and changes in MRI strength as well as different definitions of leukoaraiosis. One classification system that may be of use for classification of leukoaraiosis is a scheme that separates leukoaraiosis into periventricular and deep subcortical regions, with a grade dependent on the severity of visible leukoaraiosis (56). A visual rating scale possibly useful in quantification of white matter hyperintensities in patients with cognitive decline is the Cholinergic Pathways HyperIntensities Scale, which identifies white matter lesions within well identified cholinergic pathways (17).
Diffusion tensor imaging permits the architecture of the axons in parallel bundles, and their myelin sheaths, to be studied based on the facilitation of diffusion of water preferentially along the main direction traveled by myelinated axons (anisotropic diffusion). Diffusion tensor imaging data can be used to permit tractography within white matter, where a fiber can be tracked along its whole length. Already, diffusion tensor imaging has been used to study patients with mild cognitive impairment and Alzheimer disease. Relative to control subjects, diffusion tensor imaging detected increased mean diffusivity in the centrum semiovale, temporal and hippocampal regions. Fractional anisotropy is decreased within temporal and hippocampal regions in Alzheimer disease patients (60). Further studies in larger series of patients and within other conditions may validate the use of diffusion tensor imaging in future assessment of these conditions.
Attention to reducing vascular risk factors, such as diabetes, hyperlipidemia, and hypertension among others may certainly play a role in the prevention of development of white matter abnormalities, although no studies exist to suggest that an intervention would be beneficial. The use of antiplatelet agents is likewise, unstudied, and the decision to use antiplatelets should be made on an individual patient basis. Excessively low blood pressures (eg, less than 100 mmHg systolic) may also contribute to further extension of white matter disease in some patients.
In terms of the gait and imbalance difficulties, physical therapy and the use of assistive devices such as canes or walkers can certainly be useful. Consultation with occupational therapy or physiatry may be useful in this sense.
The use of central anticholinesterase agents within patients with dementia has been well studied. In vascular dementia patients, 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 (54).
No specific precautions are known in women with white matter disease who become pregnant.
Avoidance of excessive fluctuations during surgery would appear prudent because severe hypotension and severe hypertension may contribute to further injury in patients with impaired cerebral microcirculation.
Brian Silver MD
Dr. Silver of the University of Massachusetts Medical School 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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