Adrenoleukodystrophy

Case #001
Date: 06/17/10


History


9-year-old male with a long history of behavioral problems, carrying the diagnosis of attention deficit disorder, presents to a community primary care physician with 3 days of foot drop. The patient is referred for CT; following the CT an MRI was ordered.



IMAGES

CT
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Selected axial non-contrast CT slices demonstrate bilaterally symmetrical confluent areas of hypointensity in the subcortical white matter posteriorly. Notice in the involvement of the splenium in the image on the left.





MR

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Selected axial FLAIR images through the level of the splenium (left) and centrum semiovale (right), demonstrate confluent regions of symmetrical hyperintensity, corresponding regions of demyelination. The region of signal abnormality is centered about the trigone of the lateral ventricles, but extends anteriorly, superiorly, and posteriorly. There is also involvement of the splenium of the corpus callosum (left). There is sparing of the the subcortical U fibers.





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A selected T2-weighted images corresponds to the region of FLAIR abnormality noted in the previous set of images. A T1 post-contrast image demonstrates corresponding regions of low signal, but demonstrate an enhancing rim at the periphery of the lesions. This imaging finding is termed a "leading edge", and suggests active inflammation at this region, resulting in contrast enhancement.



Diagnosis: Adrenoleukodystrophy




Imaging Features


Progression of Disease

The demyelination associated with classic ALD begins at the splenium, progressive to the peritrigonal white matter. Subsequent to that, the cortical spinal tracts, visual and auditory pathways, and commissural fibers become involved. The pattern of distribution is usually bilaterally symmetric, confluent, and predominates posteriorly.

Features by Modality

CT
Noncontrast CT: Confluent bilateral decreased density of the peritrigonal and posterior subcortical white matter.
Contrast enhanced CT: Linear enhancement of the intermediate zone is noted, reflecting active inflammation.

MR
T1: Regional hypointensity of the peritrigonal and posterior white matter in a bilaterally symmetrical and confluent pattern.
Postcontrast T1: Very useful in narrowing the diagnosis, the imaging findings demonstrate a leading edge of enhancement, that represents inflammation in the pathologic intermediate zone. This is indicative of active and progressive disease.
T2/FLAIR: Region of increased signal intensity corresponding to the T1 region of hypointensity.
DWI: Imaging is hampered by significant T2 shine through. Increased diffusion in the region of T1 and T2 abnormality may be noted, as well as increased diffusion in regions of otherwise presymptomatic white matter. These findings may be subtle.
MR spectroscopy: A decreased NAA peak noted in presymptomatic white matter, suggests the neuronal this function is present in white matter that is otherwise normal by imaging criteria.


Discussion


Introduction
Adrenoleukodystrophy (ALD) is a set of neurodegenerative of disorders classified as a subgroup of the dysmyelinating diseases that occurs in approximately one per 17,000 births in North American. Adrenoleukodystrophy most commonly presents as an X-linked disorder, presenting in males between 5 to 10 years of age, and therefore called the childhood cerebral, or classic ALD. However, it may also be inherited as an autosomal recessive disorder, presenting in an atypical fashion. Variant conditions include adolescent-onset ALD, adult-onset ALD, adrenomyeloneuropathy (AMN) or mild adult form, and an Addison-only variant. While the above conditions all exist in males, however up to half of female carriers are mildly symptomatic. The classic form and AMN constitute the majority of diagnosed cases.

Presentation
The classic presentation of ALD includes behavioral, learning, date, hearing, envision difficulties, beginning at age 3-10. In some cases, the adrenal symptoms such a skin bronzing, fatigue, and nausea and vomiting precede the neurologic manifestations.
AMN occurs in a broader age group, from the early teens through adulthood, and usually presents with limb weakness. This pattern of disease targets the corticospinal tracts, predominately in the spine, with the brain peripheral nerves less involved.
Adolescent-onset ALD occurs in the 10 to 20 year age group, and demonstrates very rapid progression. Like childhood cerebral ALD, it may be misdiagnosed initially as a psychiatric condition.

Pathology
Adrenoleukodystrophy is fundamentally due to an inability to digest very long chain fatty acids, due to a deficiency in peroxisome metabolism which impairs beta-oxidation of very long chain fatty acids. As a result, there is accumulation of the lung chain fatty acids, most prominently within the white matter of the brain, and within the cortical layer of the adrenal glands, causing dysfunction of these organs. Peroxisomes are organelles involved in catabolic pathways, and in the brain have specific rolls to form and stablize myelin. The accumulation of very long chain fatty acids in the white matter results in brittle myelin. Pathologic examination of brain tissue of advanced disease demonstrates complete myelin loss of the subcortical white matter with gliosis, with preservation of the subcortical U-fibers. There are 3 distinct zones of pathology are noted near the leading edge of the lesions. The innermost necrotic some consists completely of necrosis and gliosis. The intermediate zone demonstrates both active demyelination and inflammation. The peripheral zone demonstrates the myelination only, without inflammation.

Disease Course
The disease is generally incurable, ultimately progressive to a state of spastic quadriparesis, blindness, deafness, and coma. Early bone marrow transplantation has shown some success at halting disease progression, and is thought to stabilize demyelination. Cholesterol-lowering drugs, dietary restrictions, plasmapheresis, interferon, glycerol trioleate/trierucate administration have shown mixed results.




Differential Diagnosis


Metachromatic leukodystrophy
A demyelinating disorder, metachromatic leukodystrophy is a diffuse disorders that affects the bilateral white matter globally and symmetrically, resulting in a "butterfly" pattern, rather than the splenium and peritrigonal white matter seen in classic ALD. While the disease most commonly presents in the infantile period, patients can present as late as adulthood. Mnemonic: Metachromatic = Mostly everywhere.

Alexander disease
A demyelinating disorder, Alexander disease preferentially demonstrates white matter abnormality in a bilateral symmetrical frontal distribution, or at a minimum in the setting of advanced disease where both frontal and occipital white matter is involved, there is a frontal predominance. Macrocephaly is often present. Onset most commonly in the early infantile period, but milder variants can present into adulthood. Mnemonic: Alexander = Anterior.

Canavan disease
A dysmyelinating disorder that demonstrates early and specific involvement of the subcortical U-fibers bilaterally. Also demonstrates involvement of the bilateral basal ganglia and thalamus. Neither findind is present in ALD. Macrocephaly is the common. Different variants begin between the first and fifth years of life. Mnemonic: Canavan = Central (brain stem) and sub-Cortical (sub-cortical U fibers).

Megaloencephalic leukoencephalopathy (MLC)
A dysmyelinating disorder demonstrating diffusely edematous subcortical white matter that involves the subcortical U fibers. Subcortical cysts are common, and most prominent in the temporal and frontoparietal lobes, can progress to several centimeters in size. Macrocephaly is present. Neurodevelopmental degeneration begins at age 2.


Resources

Eichler, FS, Barker, PB, Cox, C, et al. Proton MR spectrosopic imaging predicts lesion progression on MRI in X-linked adrenoleukodystrophy. Neurology 2002; 58:901.
Grossman RI, Yousem DM. Neuroradiology, The Requisites. Elsevier Inc. 2003.
Kumar AJ, Rosenbaum AE, Naidu S, et al. Adrenoleukodystrophy: correlating MR imaging with CT. Radiology 1987;165:497-504
Moser, HW, Raymond GV, Dubey P. Adrenoleukodystrophy: new approaches to a neurodegenerative disease. JAMA 2005; 294:3131.