Childhood adrenoleukodystrophy - Classic and variant - Review of clinical manifestations and magnetic resonance imaging.

Adrenoleukodystrophy (ALD) is a genetic disease associated with demyelination of the central nervous system, adrenal insufficiency, and accumulation of very long-chain fatty acids in tissue and body fluids. The attempt of this paper is to review the classical and not-so-classical MR imaging manifestations of adrenoleukodystrophy. A review of literature is done to describe the pathophysiology of the disease and the imaging differences between childhood and adult-onset of the disease. The literature is reviewed to explain the link with Addison's disease. In consensus the magnetic resonance imaging (MRI) findings of symmetrical occipital white matter lesions which progress in a rostro-caudal direction is the classical appearance of ALD. Familiarity with the clinico-pathologic manifestations and progressive MR imaging features of childhood cerebral X-linked ALD will be helpful in evaluating the affected patients.

Introduction

Adrenoleukodystrophy (ALD) is a genetically determined metabolic disorder that manifests clinically as dysfunctions of the central nervous system (CNS), adrenal glands, and testicles. These dysfunctions are related to excessive accumulation of very long-chain fatty acid (VLCFA) in tissues and plasma that is caused by the failure of oxidative degradation of VLCFA, which normally takes place in peroxisomes.[12]

ALD being an X-linked disease affects mostly males, although some women who are carriers can have milder forms of the disease, with an incidence of 1 in 20,000 from all races.[3]

The condition results in the build up of VLCFAs in the nervous system, adrenal gland, and testes, which disrupts normal activity. The three major categories of disease are the:

Childhood cerebral form – appearing in mid-childhood (4-8)

Adrenomyelopathy – occurring in men in their 20s or later and

Impaired adrenal gland function (called Addison disease or Addison-like phenotype) – adrenal gland does not produce enough steroid hormones.

Subjects and Methods

Case 1

A 7-year-old male child presented with decreased hearing. Child had normal neurology on examination. Clinical examination revealed bilateral sensorineural deafness. The motor and sensory functions were normal. There were no other positive clinical findings. Motor examination revealed 5/5 power in all 4 limbs; tone was normal but the deep tendon reflexes were exaggerated. Bilateral plantar reflexes were down going. The sensory system and gait was normal and there were no cerebellar signs. The visual evoked potential (VEP) and nerve conduction studies were normal.

Magnetic Resonance Imaging (MRI) performed on a 1.5 Tesla system (MagnetomAvanto, Siemens, Germany) revealed the following findings as displayed in Figure 1. Bilateral symmetrical linear and patchy areas of altered signal intensities were noted in the splenium and bilateral parieto-occipital white matter. Similar signal intensities were seen involving the medial geniculate bodies, extending to involve the region of the lateral lemniscus and along the brainstem. These regions appear significantly hypointense on T1 weighted and hyperintense on T2 weighted and FLAIR (fluid attenuated inversion recovery sequence) images. There were no signal intensities involving the corticospinal tracts or bilateral internal capsules. Post-contrast study showed typical peripheral enhancement in the corresponding areas of the parieto-occipital white matter and rim like restricted diffusion on diffusion weighted imaging (DWI). Such imaging features were consistent with pathognomonic description of ALD.

Figure 1

Bilateral symmetrical areas of altered signal intensities hypointense on T1 (a) and hyperintense on T2 weighted and FLAIR noted in the splenium (b white arrow). Similar areas in the bilateral parieto-occipital white matter in the T1 (c) T2 weighted (d) and FLAIR sequence (f white arrow). Post-contrast study showed typical peripheral enhancement in the corresponding areas (e) Similar intensities (g and h) seen involving the region of the medial geniculate bodies (h white arrow), extending to involve the region of the lateral lemniscus (i white arrow) and along the brainstem

Case 2

A 6-years-old male child, born out of non-consanguineous marriage presented with regression in milestones since one year. He also had 4-5 episodes of non-projectile vomiting in the past 6 months. On clinical examination, hyperpigmentation of skin, nails, lips, and oral cavity were noted, which had appeared 4 months ago [Figure 2]. On neurological examination the child displayed hyperactivity and was showing easy distractibility. Motor examination revealed 5/5 power in all four limbs; tone was normal but the deep tendon reflexes were exaggerated. Bilateral plantar reflexes were down going. The sensory system and gait was normal and there were no cerebellar signs. An awake-sleep electroencephalogram (EEG) showed slow wave discharges. The VEP and nerve conduction velocity (NCV) studies were normal.

Figure 2

Hyperpigmentation of skin and nails

MRI performed on a 1.5 Tesla system (MagnetomAvanto, Siemens, Germany) revealed the following findings as displayed in Figure 3. Bilateral symmetrical linear and patchy areas of altered signal intensities noted in the brainstem; in the pontine fibers extending into the mid-brain (colliculus, tegmentum, and crus cerebri) and bilateral internal capsules (involving anterior limb and genu and posterior limb) and sub-thalamic region in the region of the pyramidal tracts. Similar signal intensities were seen in the white matter of bilateral cerebellar hemisphere including inferior and middle cerebellar peduncles. These areas appeared significantly hypointense on T1 weighted and hyperintense on T2 weighted and FLAIR images. The post-contrast study showed significant linear and peripheral enhancement in the above areas.

Figure 3

Bilateral symmetrical linear and patchy areas of altered signal intensities noted in the bilateral internal capsules (a white arrow), seen in the pontine fibers extending into the mid-brain (B white arrow) and middle cerebellar peduncles (c white arrow). The post-contrast study showed significant linear and peripheral enhancement in the above areas (c, d, e white arrows)

There were no areas of restricted diffusion on DWI images. On Magnetic Resonance spectroscopy there was partial N-acetyl aspartate (NAA) loss and partially raised lactate within these hyperintensities.

In view of the clinical features of adrenal insufficiency and the MRI features, the diagnosis of ALD was provided.

Biochemical investigations showed plasma renin to be 4.23 units (high); Plasma aldosterone: 8.7 units (normal). The Adrenocorticotrophic hormone (ACTH) units were more than 1250 units (high). The ACTH stimulation test did not reveal any increase in cortisol levels. The confirmatory test was elevated levels of VLCFAs in plasma. These elevated levels were confirmed in a reputed lab in the USA (United States of America) [Figure 4].

Figure 4

Biochemical reports show elevated levels of very long chain fatty acids in plasma

The diagnosis of ALD was provided on the basis of hyperpigmentation of skin and biochemical findings; this being consistent with adrenal insufficiency and the MR findings.

Discussion

Leukodystrophies comprise a broad group of progressive, inherited disorders affecting mainly myelin. Though the ultimate diagnosis is not found in many patients with leukodystrophies, distinctive features unique to them aid in diagnosis, treatment, and prognostication. The diagnosis of ALD is primarily based on clinical, MR imaging and biochemical studies. Newer modalities like diffusion and spectroscopy have provided new inputs into the disease.

The attempt of this paper is to review the classical and not-so-classical MR imaging manifestations of ALD. A review of literature is done to describe the pathophysiology of the disease, the imaging differences between childhood and adult-onset of the disease. The literature is reviewed to explain the link with Addison's disease.

The MRImaging of Case 1 showed bilateral and symmetric increased signal intensities consistent with demyelination around the atria of the lateral ventricles, the posterior aspect of the cerebrum, posterior part of the posterior corpus callosum, splenium, and pyramidal tracts similar to the findings described by Patel et al.[4] The MR imaging findings of symmetrical occipital white matter lesions which progress in a rostralcaudal direction is the classical appearance of ALD.[5]

The altered signals involving the medial geniculate bodies, extending to the lateral lemniscus and along the brainstem is the pattern of involvement of the auditory pathway [Figure 5].

Figure 5

Schematic diagram of central auditory pathway

Kim et al., in their review of childhood X-linked ALD state that brain magnetic resonance (MR) imaging is an essential tool for initial and follow-up evaluation. It allows early detection and helps to differentiate ALD from other disorders.[6]

Singhal BS in his paper states that commonest leukodystrophy seen in India is Megalencephalic Leukodystrophy with sub-cortical cysts[7]; seen more in the Agarwal community in India.

In consensus the MRI findings of symmetrical occipital white matter lesions which progress in a rostro-caudal direction is the classical appearance of ALD.[5]

Nascimento et al., described a similar case as Case 2 who presented with fatigue and hyperpigmentation with onset at 2-years age. Blood tests revealed mineralocorticoid insufficiency. Serum adrenocorticotropic hormone and cortisol concentrations were compatible with adrenal insufficiency. The authors highlight that primary adrenal insufficiency may be the first sign of of X-linked ALD.[8]

The MR imaging was typical of corticospinal tract involvement without the typical occipital white matter involvement. Barkovich AJ et al.,[9] concluded in their review of 10 patients that ponto medullary corticospinal tract involvement is a common finding in ALD and is unusual in other leukodystrophies. Awareness of this not-so-classical finding can facilitate the radiologic diagnosis of ALD and may expedite management of affected patients.

Laureti et al.,[10] on the basis of biochemical analysis of VLCFA in 14 male patients (age ranging from 12 to 45 years) diagnosed ALD in cases who presented with primary idiopathic adrenocortical insufficiency, reiterating the fact that ALD is a frequent cause of idiopathic Addison's disease in children and adults.

MRI has been used to prognosticate the disease. The extent of brain MRI abnormality utilizing the MRI-scoring system devised by Loes et al., was used by Moser HW in 372 patients.[11] There was strong correlation between MR findings and the neurology and neuropsychology scores at baseline and such scores are highly predictive of future clinical course.[11]

Good correlation has established relationship between MR spectroscopy metabolite ratios and a patient's clinical status. Hence, MR spectroscopy[12] appears to be a useful, non-invasive tool to monitor patients with ALD.

Histopathologic features of the affected areas detected by conventional MR imaging, is divided into three distinct zones known as Schaumburg zones, that is,

Outermost zone (zone 1) of active destruction of the myelin sheath

Middle layer zone (zone 2) of perivascular inflammatory cells and active demyelination, and

Central zone (zone 3) of gliosis and scattered astrocytes with absence of oligodendroglia, axons, myelin, and inflammatory cells.[13]

The middle layer corresponds to the typical enhancement pattern seen in classical ALD.

Proton MR spectroscopy and Diffusion tensor imaging provide more clues to the pathogenesis and prognostication of the disease.

Recent papers have asserted that although conventional MRI has significantly contributed to recent progress in the diagnostic work up of these diseases, diffusion-weighted imaging has the potential to further improve our understanding of underlying pathological processes and their dynamics through the assessment of normal and abnormal diffusion properties of cerebral white matter. Patay et al., describe medium grade myelin edema in X-linked adrenoleukodystrophy.[14] We noted that there was medium grade myelin edema in Case 1 which had classical MR imaging manifestations of ALD.

To summarise:

Leukodystrophies can be classified as

Lysosomal Storage Diseases:

Metachromatic Leukodystrophy

Krabbes Disease

Peroxisomal Diseases: ALD, Zellweger syndrome

Mitochondrial Dysfunction: Leigh disease, MELAS

Amino acid and organic acid metabolism disorders – Canavan disease

A mnemonic has been developed, “LACK Proper Myelin”,[15] which can serve as a spring board in developing a differential diagnosis in a child with a dysmyelinating leukodystrophy. Certain distinguishing features of the diseases can be used including laboratory evaluation, head size and sex of the child. The important common ground that all the dysmyelinating leukodystrophies share, they all are inherited disorders that have an enzymatic or biochemical abnormality resulting in the development of abnormal myelin. Conventional MRI has significantly contributed to recent progress in the diagnostic work-up of these diseases.

X-Linked ALD is a genetic disease associated with demyelination of the central nervous system, adrenal insufficiency, and accumulation of VLCFA in tissue and body fluids. The phenotypic expression of X-linked ALD (X-ALD) ranges from the rapidly progressive childhood cerebral form to the milder adrenomyeloneuropathy (AMN) in adults. Familiarity with the clinical-pathologic manifestations and progressive MR imaging features of childhood cerebral X-linked ALD will be helpful in evaluating affected patients.