Neuroradiology (2004) 46: 296–300

DOI 10.1007/s00234-003-1096-8 DIAGNOSTIC NEURORADIOLOGY

Yuan-Heng Mo
Ya-Fang Chen
Adrenomyeloneuropathy, a dynamic
Hon-Man Liu progressive disorder: brain magnetic
resonance imaging of two cases

Received: 14 July 2003

Abstract Adrenomyeloneuropathy Review of the literature shows that
Accepted: 29 July 2003 (AMN) is a phenotype variant of the brain magnetic resonance find-
Published online: 4 March 2004 X-linked adrenoleukodystrophy. We ings of adrenomyeloneuropathy may
Ó Springer-Verlag 2004 present two patients with adult- include normal brain, tract demye-
onset AMN who were initially lination, white matter demyelina-
suspected to have demyelinating tion, or brain atrophy. Disease
disorders radiologically and finally progression was demonstrated by
Y.-H. Mo Æ Y.-F. Chen (&) Æ H.-M. Liu diagnosed on the basis of laboratory follow-up imaging.
Department of Medical Imaging, data. The brain magnetic resonance
National Taiwan University Hospital, images showed abnormal signal Keywords Adrenomyeloneuropathy Æ
7 Chung-Shan South Road, intensity at pyramidal tracts and Adrenoleukodystrophy Æ Magnetic
100 Taipei, Taiwan
E-mail: [email protected]
cerebellar hemisphere bilaterally resonance imaging Æ Demyelination
Tel.: +886-2-23122570 with abnormal enhancement after
Fax: +886-2-23224552 contrast medium administration.

Introduction of these two patients were evaluated, and the charac-

teristic findings of AMN reported in the literature were
Adrenomyeloneuropathy (AMN) is the second most reviewed. Disease progression was demonstrated by
common phenotype of X-linked adrenoleukodystrophy follow-up MRI in both cases.
(ALD). It contrasts with the more common and severe
cerebral form of ALD, involves mainly the spinal cord
and the peripheral nerves, begins in adulthood, and is Case report
slowly progressive over a period of decades [1]. Typically
AMN has a slow progression and symptoms of spastic Case 1
paraparesis and sphincter disturbances with survival into
the eighth decade [2]. Magnetic resonance imaging A 35-year-old man had suffered spastic paraplegia for 18 years.
However, the symptoms had been progressing in recent years into
(MRI) of the spinal cord in AMN with neurological dysarthria, dysphagia, drooling, and choking. In addition to, he
involvement confined to the spinal cord and peripheral had deterioration in muscle power and had finally become wheel-
nerves usually reveals diffuse atrophy with severe loss of chair bound. His elder brother had similar symptoms. Under the
cord tissue and no focal signal change reflecting a more suspicion of progressive spastic paraplegia, such as hereditary
spastic paraplegia or primary lateral sclerosis, he was admitted to
indolent degenerative process with a less intense reaction our hospital. Physical examination showed spasticity and decreased
of demyelination. MRI of the brain in AMN may be muscle tone in bilateral lower extremity with increased deep tendon
normal. However, in some patients with AMN the MRI reflex and incontinence of anal sphincter. There was no sensory
findings may be similar to those in ALD, and the clinical deficit. Brain MRI showed hypointense lesions with hyperintense
rim on T1-weighted images, abnormal hyperintensity on
progression may be as rapid [2]. T2-weighted images, and fluid-attenuated inversion-recovery
We collected two cases of AMN finally diagnosed on (FLAIR) images with equivocal mass effect in posterior limbs of
the basis of abnormal laboratory data. The brain MRI bilateral internal capsule and along the corticospinal tracts down to
 297

the pontomedullary junction. There was also abnormal signal of these patients were misdiagnosed as having multiple
intensity in bilateral central cerebellum (Fig. 1A–D). The ACTH sclerosis due to similar manifestation such as progressive
stimulation test suggested primary adrenal insufficiency. The profile
of very long chain fatty acid of serum showed marked elevation in weakness of extremity.
the C24/C22 ratio at 1.46 (>0.892) and the C26/C22 ratio at 0.089 The main symptom in our cases is progressive spastic
(>0.0235). This patient was diagnosed as ALD (AMN) on the paraplegia of both lower limbs. Spasticity is the hall-
basis of the laboratory results and was followed up at the outpa- mark of upper motor neuron disease. In clinical practice
tient department under corticosteroid replacement and dietary
therapy. Unfortunately, he had a seizure attack and was returned
the differential diagnoses of long tract lesion may
to our hospital again about 1 year later. Emergent brain MRI include: (a) primary lateral sclerosis, which is a disease
revealed progression in the extent of abnormal signal intensity and of diagnosis by exclusion and should be differentiated
abnormal enhancement (Fig. 1E–H). with cervical spondylotic myelopathy and multiple
sclerosis; (b) hereditary spastic paraplegia, which is
usually autosomal dominant with a family history; and
Case 2 (c) AMN. However, the frequency of positive MRI
A 34-year-old man had had rhythmic jerky movement of both lower abnormalities in cases of pure upper motor neuron
legs and progressive spastic weakness of both legs for 4 years. syndrome is only about 40% (true positives) [7], and this
Recently he became wheelchair bound, with difficulty of stool pas- makes the correct diagnosis a more challenging task.
sage and occasional incontinence. His family found that he had
mildly slurred speech and intermittent choking while drinking. He
The manifestation on brain MRI in our cases was
also felt clumsy in writing. Tracing his family history, his younger bilateral pyramidal tract involvement with signal
brother had similar symptoms. Under the suspicion of progressive change, mild mass effect, and contrast enhancement.
type multiple sclerosis he was admitted to our hospital. MRI showed The presence of mass effect and enhancement is
abnormal signal intensity at the corticospinal tract and subtle suggestive of demyelinating process and makes initial
abnormal enhancement after Gd-DTPA injection at the posterior
limb of the internal capsule, posterior frontal region, and cerebral image diagnosis diverse. However, these lesions are quite
peduncle bilaterally (Fig. 2A–C). The ACTH stimulation test sug- symmetrical, differently than in usual demyelinating
gested adequate adrenal gland function. The profile of very long disorders. Pyramidal tract involvement is also unusual in
chain fatty acid of serum was markedly elevated with C24/C22 at 1.23 demyelinating disorders. Involvement of the pontome-
(>0.892) and C26/C22 at 0.04 (>0.0235). The laboratory results
confirmed the diagnosis of ALD (AMN). Brain MRI performed dullary corticospinal tracts is reported to be a useful
7 months later showed enlargement of the lesions at bilateral cere- finding in the diagnosis of X-linked ALD [8]. There is a
bellum (Fig. 2D–F). Magnetic resonance spectroscopy (MRS) very strong association between contrast enhancement
showed a decreased average N-acetyl-aspartate (NAA)/creatine ratio on T1-weighted images and disease progression revealed
(1.022 and 1.096) and increased average choline/creatine ratio (1.081
and 1.310) at right and left cerebellar hemispheres.
by clinical evaluation and MRI. Contrast enhancement
is attributed to breakdown of the blood-brain barrier
resulting from an autoimmune or cytokine-mediated
inflammatory process. The severity of the inflammatory
Discussion process, in other words, the active demyelinating pro-
cess, is correlated with the rapidity of disease progres-
ALD is the most common of the peroxisomal disorders, sion [9]. As in our case number 1, the progression of
a group of diseases with single enzyme defect preventing disease is accompanied by enlargement of lesions and
the oxidation of very long chain fatty acids (particularly abnormal contrast enhancement.
C24–C26) and resulting in the accumulation of these The phenotypes of ALD include (a) childhood- and
fatty acids within the cells. The prevalence is currently adolescent-onset cerebral ALD, (b) adult-onset cerebral
estimated at 1 in 20,000–50,000. The genetic defect ALD, (c) AMN with symptoms restricted to the spinal
causing X-linked ALD is located in the Xq28 region [3]. cord, (4) AMN with symptoms of spinal cord and cerebral
It usually presents in childhood as a rapidly dementing involvement, (e) AMN with symptoms of spinal cord
illness leading to a vegetative state or death within although cerebral involvement cannot be excluded or
3 years in most patients [1], with a characteristic pattern uncertain, (f) Addison’s disease only—adrenocortical
of demyelination demonstrable by MRI [4]. MRI can insufficiency without neurological involvement, and (g)
detect lesions of cerebral white matter before children asymptomatic—mutant X-linked ALD without neuro-
with the cerebral form of ALD become symptomatic logical or endocrinological deficits [10]. The phenotypic
neurologically [5]. This could allow therapeutic trials to variability of ALD is high, with AMN and childhood-
be started several months before brain lesions extend in onset cerebral ALD accounting for approximately 80% of
an irreversible course. cases [11]. The central nervous system, adrenal cortex, and
AMN is a variant of ALD affecting mainly the spinal testis are most severely affected [2, 11]. Recently it was
cord and clinically characterized by progressive spastic recognized that AMN may be the most frequent pheno-
paraparesis and sphincter disturbance. The lesions of the type [12]. Spinal cord degeneration and neuropathy
spinal cord are usually more common and severe in prevail in AMN, probably as a result of axonal degener-
thoracic region than cervical region [6]. In the past most ation and secondary demyelination [2]. AMN has been
298

portrayed as a relatively mild and slowly progressing occurred in 19% of AMN patients with initial involve-
variant of ALD, unless cerebral involvement occurs [6]. ment clinically restricted to the spinal cord, including six
One study reports that AMN without cerebral symptoms AMN patients with normal brain MRI at diagnosis, with
can no longer be regarded as a relatively benign pheno- a survival similar to that for childhood-onset cerebral
type, even when the brain MRI at diagnosis is normal. ALD. Although cerebral demyelination most frequently
During 10 years of follow-up additional cerebral disease occurs in the fourth and fifth decades, it can occur in
 299

b AMN patients at any age. There is a high risk for AMN

Fig. 1 A 35-year-old man with progressive spastic paraplegia for patient to develop additional devastating cerebral disease
18 years. A Axial T1-weighted images demonstrates hypointense during a decade of follow-up [10], and we believe that our
lesions with hyperintense rim at bilateral corticospinal tracts, more
on the right side. B Coronal T2-weighted images shows long cases are in same situation.
asymmetric bands of high signal along the corticospinal tracts, To what phenotypes of adult ALD (AMN) do our
from the internal capsules to the brainstem. C, D Axial FLAIR cases belong? The pyramidal tract involvement makes us
images through levels of basal ganglia and cerebellum reveal categorize our cases as AMN with abnormality in long
abnormal high signal change at corticospinal tracts and dentate
nuclei. E, F About 1 year later, follow-up axial FLAIR images
tract, but the bilateral cerebellar hemisphere involve-
at the same level as seen in C and D depict increased lesion ment even with contrast enhancement is quite rare [13].
size. G, H Follow-up axial T1-weighted images after intrave- During the follow-up the clinical symptoms and lesions
nous contrast injection shows enhancement at the front of those shown on MRI of our cases seemed to deteriorate.
lesions Reviewing the literatures, brain MRI findings of the
adult ALD include the following forms: (a) AMN with
normal brain (classic AMN); (b) AMN with abnor-
malities limited to long tracts (spinocerebellar tracts, or
Fig. 2 A 34-year-old man with progressive spastic paraplegia for
4 years. A Axial FLAIR image shows asymmetric abnormal high the medial parts of the posterior fasciculi); (c) AMN
signal intensity at bilateral corticospinal tracts from the internal with diffuse lobar cerebral involvement (the most com-
capsule down to the pons. B Axial FLAIR image reveals abnormal mon pattern is a bilateral parieto-occipital involvement
hyperintensity at right dentate nucleus. C Axial T1-weighted images extending across the splenium of the corpus callosum in
after intravenous contrast injection shows enhancement at those
lesions. D–F Seven months later, there is progression in the extent of combination with bilateral pyramidal tract involvement
those lesions, especially the bilateral corticospinal tracts and dentate in the brainstem and internal capsule); and (d) adult
nuclei onset cerebral ALD (a severe and rapidly progressive
300

disorder with widespread involvement of cerebral of our case are 8.04/8.51 in the right side and 8.1/9.68
hemispheres, including white matter lesions and brain in the left, lesser than the normal value. Proton MRS
atrophy in cortex, subcortical regions, brainstem, and is reported to be able to predict of the progression in
even the corpus callosum, in a patient older than X-linked ALD [15].
21 years of age without clinical evidence of preceding
AMN) [6]. Brain MRI of our cases demonstrated
abnormal signal change along the corticospinal tracts Conclusion
down to the pontomedullary junction and at bilateral
central cerebellum. There was progressive enlargement The manifestations and phenotypes of adult ALD
of the lesion in size during follow-up and good corre- (AMN) show high variability, and there is progressive
lation with the deteriorating clinical course. evolution of phenotype. AMN patients indeed could
The decrease in the NAA/choline ratio obtained from deteriorate during follow-up such as our cases. There-
proton MRS may precede the abnormalities on MRI fore controversy continues over precise classification,
[14]. The ‘‘choline’’ signal in proton brain spectra is a especially in cases with atypical overlapping symptoms
composite consisting predominantly of glycerophosph- and progressive change on brain MRI study. More
ocholine, phosphocholine, and free choline itself, com- information using brain MRI in long-term follow-up is
pounds that are precursors and breakdown products of necessary to establish more precise differentiation of
membranes. The high choline signal in X-linked ALD the adult ALD phenotype for prognostic consideration.
lesions is most likely due to a combination of enhanced We believe that knowing the characteristic abnormali-
myelin turnover related to demyelination and the accu- ties of adult ALD (AMN) on brain MRI not only can
mulation of myelin membrane degradation products. help radiologists to differentiate these from other rare
However, NAA is believed to be of neuronal origin in white matter diseases but can also provide clinical
mature brain, and its decrease in X-linked ALD is most physicians more correct suggestion of the direction of
likely due to either axonal loss or dysfunction. The area evaluation and the choice of proper management as
values of NAA/choline of bilateral cerebellar hemispheres soon as possible.

References

1. Aubourg P, Adamsbaum C, Lavallard- 5. Aubourg P, Sellier N, Chaussain JK, 11. Geel BM van, Assie J, Wanders RJA,
Rousseau MC, Lemaitre A, Boureau F, Kalifa G (1989) MRI detects cerebral Barth PG (1997) X-linked adrenoleu-
Mayer M, Kalifa G (1992) Brain MRI involvement in neurologically asymp- kodystrophy: clinical presentation,
and electrophysiologic abnormalities in tomatic patients with adrenoleukodys- diagnosis and therapy. J Neurol
preclinical and clinical adrenomyelo- trophy. Neurology 1511–1532 Neurosurg Psychiatry 63:4–14
neuropathy. Neurology 42:85–91 6. Kumar AJ, Köhler W, Kruse B, Naidu 12. Geel BM van, Assies J, Weverling GJ,
2. Mitsumoto H (2000) Disorders of upper S, Bergin A, Edwin D, Moser HW Barth PG (1994) Predominance of the
and lower motor neurons. In: Bradley (1995) MR findings in adult-onset leukodystrophy in the Netherlands: a
WG, Daroff RB, Fenichel GM, Mars- adrenoleukodystrophy. AJNR Am J survey of 30 kindreds. Neurology
den CD (eds) Neurology in clinical Neuroradiol 16:1227–1237 44:2343–2346
practice. Butterworth-Heinemann, 7. Powers JM, Moser HW (1998) Peroxi- 13. Waragai M, Takaya Y, Hayashi M,
Boston, pp1985–2017 somal disorders: genotype, phenotype, Shibata N, Kobayashi M (1996) MRI of
3. Evans OB, Parker CC, Hass RH, Naidu major neuropathologic lesions, and adrenoleukodystrophy involving pre-
S, Moser HW, Bock HGO (2000) pathogenesis. Brain Pathol 8:101–120 dominantly the cerebellum and brain
Inborn errors of metabolism of the 8. Barkovich AJ, Ferriero DM, Bass N, stem. Neuroradiology 38:788–791
nervous system. In: Bradley WG, Boyer R (1997) Involvement of the 14. Tzkika AA, Ball WS Jr, Vigueron DB,
Daroff RB, Fenichel GM, Marsden CD pontomedullary corticospinal tracts: a Dunn RS, Nelson SJ, Kirks DR (1993)
(eds) Neurology in clinical practice. useful finding in the diagnosis of Childhood adrenoleukodystrophy:
Butterworth-Heinemann, Boston, pp X-linked adrenokeukodystrophy. Assessment with proton MRS.
1640–1641 AJNR Am J Neuroradiol 18:95–100 Radiology 189:467–480
4. Kumar AJ, Rosenbaum AE, Naidu S, 9. Melhem ER, Loes DJ, Georgiades CS, 15. Eichler FS, Barker PB, Cox C, Edwin
Wener L, Citrin CM, Lindenberg R, Raymond GV, Moser HW (2000) D, Ulug AM, Moser HW, Raymond
Kim WS, Zinreich SJ, Molliver ME, X-linked Adrenoleukodystrophy: the GV (2002) Proton MR spectroscopic
Mayberg HS (1987) Adrenoleukodys- role of contrast-enhanced MR imaging imaging predicts lesion progression on
trophy: correlating MR images with in predicting disease progression. AJNR MRI in X-linked adrenoleukodystro-
CT. Radiology 165:497–504 Am J Neuroradiol 21:839–844 phy. Neurology 58:901–907
10. Geel BM van, Bezman L, Loes DJ,
Moser HW, Raymond GV (2001)
Evolution of phenotypes in adult male
patients with X-linked adrenoleuko-
dystrophy. Ann Neurol 49:186–194