Radiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Barkhof, F.
Right arrow Articles by Valk, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Barkhof, F.
Right arrow Articles by Valk, J.
(Radiology. 2000;217:869-876.)
© RSNA, 2000

Neuroradiology

Cerebrotendinous Xanthomatosis: The Spectrum of Imaging Findings and the Correlation with Neuropathologic Findings1

Frederik Barkhof, MD, Aad Verrips, MD, Pieter Wesseling, MD, Marjo S. van der Knaap, MD, Baziel G. M. van Engelen, MD, Fons J. M. Gabreëls, MD, Antoine Keyser, MD, Ron A. Wevers, MD and Jaap Valk, MD

1 From the Depts of Radiology (F.B., J.V.) and Pediatric Neurology (M.S.v.d.K.), Academic Hospital "Vrije Universiteit," De Boelelaan 1118, 1081 HV Amsterdam, the Netherlands; and the Depts of Pediatric Neurology (A.V., F.J.M.G.), Pathology (P.W.), and Neurology (P.W., B.G.M.v.E., A.K.) and the Laboratory of Pediatrics and Neurology (R.A.W.), Univ Hosp Nijmegen, the Netherlands. Received Sep 15, 1999; revision requested Nov 5; final revision received Mar 31, 2000; accepted May 1. Address correspondence to F.B. (e-mail: f.barkhof@azvu.nl).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To describe imaging findings and their neuropathologic correlate in patients with cerebrotendinous xanthomatosis (CTX).

MATERIALS AND METHODS: Computed tomographic (CT) and magnetic resonance (MR) images in 24 patients with symptoms (mean age at time of imaging, 37 years; mean disease duration, 18 years) were reviewed for site and frequency of brain, spinal cord, and Achilles tendon involvement. Two patients died, and imaging findings were compared with postmortem neuropathologic findings.

RESULTS: Apart from nonspecific supratentorial atrophy and deep white matter changes, more typical hyperintense lesions were seen on T2-weighted images in the dentate nucleus (in 79% of patients), globus pallidus, substantia nigra, and inferior olive and extended into adjacent white matter as disease progressed. In these locations, lipid crystal clefts and perivascular macrophages, neuronal loss, demyelination, fibrosis, and reactive astrocytosis were found at microscopic examination. Hypointensity was sometimes found on T2-weighted images in the dentate nucleus and was related to deposition of hemosiderin and calcifications. CT depicted fewer lesions; all had low attenuation, except for the calcifications. Spinal cord MR imaging revealed increased signal intensity in the lateral and dorsal columns on T2-weighted images. Achilles tendon xanthomas displayed intermediate signal intensity on T1- and T2-weighted images.

CONCLUSION: The typical pattern of MR imaging findings reflects the classic histopathologic findings and should prompt the diagnosis of CTX.

Index terms: Brain, abnormalities, 13.839, 13.87, 15.839, 15.87 • Brain, atrophy, 13.839, 13.87, 15.839, 15.87 • Brain, diseases, 13.839, 13.87, 15.839, 15.87 • Brain, MR, 10.121411 • Cerebrotendinous xanthomatosis, 10.839, 10.318 • Spinal cord, 31.3189, 32.3189 • Tendons, 469.3189 • Xanthoma, 469.3189


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Cerebrotendinous xanthomatosis (CTX) is an autosomal-recessive lipid storage disease described by Bogaert et al in 1937 (1). In patients with CTX, bile acid synthesis is abnormal because of a defect in the activity of the hepatic mitochondrial enzyme sterol 27-hydroxylase (2). Therefore, synthesis of cholic acid is reduced, and almost no chenodeoxycholic acid (CDCA) is produced. The negative feedback of CDCA on the rate-limiting enzyme in bile acid biosynthesis, 7 {alpha}-hydroxylase, decreases, and by way of a side pathway, an excessive amount of cholestanol that accumulates in many tissues is produced. By way of the 24- and 25-hydroxylase pathways, bile alcohols are produced in patients with CTX (3). Biochemical diagnosis is made by determining the excessive urinary excretion of bile alcohols and the serum cholestanol level (4,5).

The onset of symptoms and signs in patients with CTX usually occurs in childhood, with a combination of bilateral cataracts and diarrhea (6) followed by the development of neurologic abnormalities and tendon xanthomas (3,7). Neurologic symptoms and signs include cerebellar and pyramidal dysfunction, dementia, epilepsy, and polyneuropathy (3). Additional symptoms are premature atherosclerosis (3) and osteoporosis (8). The main disease process in patients with CTX is found in select areas within the central nervous system (1,9–16). At macroscopic examination, atrophy is often found, especially in the cerebellum. At light microscopy, the most severe lesions are found in the dentate nucleus and adjacent white matter. In addition, there are often lesions in the basal ganglia, internal capsule, brain stem, and spinal cord.

Involvement of the central nervous system in patients with CTX has been demonstrated by using computed tomography (CT) and, more frequently, magnetic resonance (MR) imaging. To our knowledge, until now radiologic findings in only small series of patients with CTX have been reported (17–19). In this article, we present the imaging findings in a series of 24 patients who received a biochemical and genetic diagnosis of CTX, including images in the spinal cord and Achilles tendons. The purpose of this study was to better characterize the imaging findings in patients with CTX, which is frequently misdiagnosed. In addition, we related imaging findings to postmortem neuropathologic findings in two patients.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Patients
We retrospectively reviewed MR images in a series of 24 patients with CTX from 16 Dutch families. These patients were identified between 1990 and 1995 and form part of a larger database of 55 patients that was compiled over time at the University Hospital Nijmegen, the Netherlands; the remaining 31 patients did not undergo imaging. The group included nine male patients and 15 female patients who were 7–55 years of age, with a mean age at diagnosis of 33 years ± 12 (SD) and a mean age at the time of imaging of 37 years. The mean age at the onset of neurologic complaints was 19 years ± 11, so that, by the time imaging was performed, the disease duration was, on average, 18 years.

Nine cases were sporadic; in some families, two or even three members were examined. In only one family were the parents consanguineous. The serum cholestanol level was abnormal in all cases, at 33.0–299.0 µmol/L (normal values, 3.3–12.5 µmol/L). In all but three cases, CTX was not initially diagnosed. Typical misdiagnoses included unclassified diarrhea (n = 4), Friedreich ataxia (n = 4), multiple sclerosis (n = 3), hereditary spastic paraparesis (n = 2), and Alzheimer disease (n = 1). In six cases, the disease had remained unclassified for many years, and in one case, only tendon xanthomas were diagnosed. In only one sporadic case was a direct diagnosis of CTX made; two other cases were detected during family screening. In all cases, the diagnosis of CTX was genetically confirmed in accordance with previously described methods (20); mutations in the sterol 27-hydroxylase gene were present in both alleles.

Clinical features are summarized in Table 1. Cataract was present in all but one (96%) of the 24 patients and tendon xanthomas were present in only nine (38%) of the patients. Neurologic abnormalities were present in 23 (96%) patients and most frequently consisted of pyramidal tract involvement, followed by subaverage intelligence (IQ < 70), cerebellar signs, and peripheral neuropathy. One of the earliest cerebellar manifestations was increased speech rate (tachylalia), followed by dysarthric speech later in the disease course. Normal speech was found in patients aged less than 20 years; tachylalia was found in patients aged 20–40 years, and predominantly cerebellar dysarthria was found in patients aged greater than 40 years. This last group of patients was clinically the most severely affected (21). Seven patients had a slowly progressive spinal cord syndrome that remained the main clinical expression of CTX for many years. MR imaging demonstrated white matter abnormalities in the lateral and dorsal columns of the spinal cord. This so-called spinal xanthomatosis is a clinical and radiologic variant of CTX that may easily be misdiagnosed (22). In only two of these seven patients did the classic CTX symptoms manifest 5 and 8 years after the onset of myelopathy.


View this table:
[in this window]
[in a new window]

  		TABLE 1. Symptoms and Signs in 24 Patients with CTX
 
MR Imaging
Brain MR imaging was performed by using various machines and typically included T1-weighted spin-echo imaging in a sagittal or transverse plane and double-echo spin-echo T2-weighted imaging in a transverse plane. Nine patients underwent imaging with the same 1.5-T system (SP63; Siemens, Erlangen, Germany); in these patients, sagittal T1- and T2-weighted spin-echo imaging in the Achilles tendons also was performed. Spinal MR images were available in five patients (and were also included in a recent study [22]). The images were reviewed by two readers (F.B., M.S.v.d.K.) in conference. The images were scored for the presence of atrophy (supra- and infratentorially) or other abnormalities in the periventricular white matter, basal ganglia, brain stem, and cerebellum by using a four-point scale (a score of 0 meant that no abnormalities were present; 1, minor abnormalities were present; 2, moderate abnormalities were present; or 3, severe abnormalities were present). In four patients, CT scans also were available, and the same areas were scored for the presence of abnormalities.

Histopathologic Examination
Autopsy was performed in two patients. Patient A was a 54-year-old woman with a progressive pyramidal and cerebellar syndrome, decline of cognitive function, bilateral cataracts, and xanthomas in the triceps and Achilles tendons who had received a diagnosis of CTX at the age of 39 years. Since that time, she had been treated with 750 mg of CDCA daily. At age 53, cerebral MR imaging was performed (Fig 1a–1c). One year later, she died of bronchopneumonia. Another MR imaging examination was performed before sectioning the formalin-fixed brain (Fig 1d). Patient B was a woman with juvenile bilateral cataracts who developed a progressive spastic paraparesis at the age of 30 years. From the age of 40 years, progressive cerebellar symptoms and dementia manifested. No tendon xanthomas were present, and CTX was not diagnosed until 2 weeks before she died of bronchopneumonia at the age of 45 years. One year before diagnosis, cerebral CT had been performed (Fig 2a); no MR imaging had been performed.



View larger version (172K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1a. Images in patient A, a 54-year-old woman. (a-c) Transverse T2-weighted MR images (repetition time msec/echo time msec, 2,200/90) show symmetric high-signal-intensity lesions in (a) the globus pallidus and adjacent part of internal capsule (arrows), (b) the substantia nigra, extending into the deep part of the cerebral peduncles (arrows), and (c) the cerebellar white matter (large straight arrows) and inferior olive (small straight arrows); note the central hypointensity of the dentate nucleus (curved arrows). (d) Postmortem coronal T2-weighted MR image (3,000/90) shows low signal intensity in the dentate nucleus (arrows), which corresponded to deposits of hemosiderin and calcification at histopathologic examination. (e) Macroscopic section shows a yellow and gray discoloration, with a glassy appearance of the dentate nucleus and surrounding cerebellar white matter (arrows). (f) Macroscopic section obtained at the level of the mesencephalon shows similar changes in the paramedian part of the cerebral peduncle that extends into the substantia nigra (arrows). (g) At microscopic examination, the area of the dentate nucleus shows extensive fibrosis, with multiple dispersed lipid crystal clefts, foamy macrophages, and some lamellae of myelinlike material. (Luxol fast-blue and hematoxylin-eosin stains; original magnification, x200.)

 


View larger version (175K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1b. Images in patient A, a 54-year-old woman. (a-c) Transverse T2-weighted MR images (repetition time msec/echo time msec, 2,200/90) show symmetric high-signal-intensity lesions in (a) the globus pallidus and adjacent part of internal capsule (arrows), (b) the substantia nigra, extending into the deep part of the cerebral peduncles (arrows), and (c) the cerebellar white matter (large straight arrows) and inferior olive (small straight arrows); note the central hypointensity of the dentate nucleus (curved arrows). (d) Postmortem coronal T2-weighted MR image (3,000/90) shows low signal intensity in the dentate nucleus (arrows), which corresponded to deposits of hemosiderin and calcification at histopathologic examination. (e) Macroscopic section shows a yellow and gray discoloration, with a glassy appearance of the dentate nucleus and surrounding cerebellar white matter (arrows). (f) Macroscopic section obtained at the level of the mesencephalon shows similar changes in the paramedian part of the cerebral peduncle that extends into the substantia nigra (arrows). (g) At microscopic examination, the area of the dentate nucleus shows extensive fibrosis, with multiple dispersed lipid crystal clefts, foamy macrophages, and some lamellae of myelinlike material. (Luxol fast-blue and hematoxylin-eosin stains; original magnification, x200.)

 


View larger version (164K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1c. Images in patient A, a 54-year-old woman. (a-c) Transverse T2-weighted MR images (repetition time msec/echo time msec, 2,200/90) show symmetric high-signal-intensity lesions in (a) the globus pallidus and adjacent part of internal capsule (arrows), (b) the substantia nigra, extending into the deep part of the cerebral peduncles (arrows), and (c) the cerebellar white matter (large straight arrows) and inferior olive (small straight arrows); note the central hypointensity of the dentate nucleus (curved arrows). (d) Postmortem coronal T2-weighted MR image (3,000/90) shows low signal intensity in the dentate nucleus (arrows), which corresponded to deposits of hemosiderin and calcification at histopathologic examination. (e) Macroscopic section shows a yellow and gray discoloration, with a glassy appearance of the dentate nucleus and surrounding cerebellar white matter (arrows). (f) Macroscopic section obtained at the level of the mesencephalon shows similar changes in the paramedian part of the cerebral peduncle that extends into the substantia nigra (arrows). (g) At microscopic examination, the area of the dentate nucleus shows extensive fibrosis, with multiple dispersed lipid crystal clefts, foamy macrophages, and some lamellae of myelinlike material. (Luxol fast-blue and hematoxylin-eosin stains; original magnification, x200.)

 


View larger version (146K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1d. Images in patient A, a 54-year-old woman. (a-c) Transverse T2-weighted MR images (repetition time msec/echo time msec, 2,200/90) show symmetric high-signal-intensity lesions in (a) the globus pallidus and adjacent part of internal capsule (arrows), (b) the substantia nigra, extending into the deep part of the cerebral peduncles (arrows), and (c) the cerebellar white matter (large straight arrows) and inferior olive (small straight arrows); note the central hypointensity of the dentate nucleus (curved arrows). (d) Postmortem coronal T2-weighted MR image (3,000/90) shows low signal intensity in the dentate nucleus (arrows), which corresponded to deposits of hemosiderin and calcification at histopathologic examination. (e) Macroscopic section shows a yellow and gray discoloration, with a glassy appearance of the dentate nucleus and surrounding cerebellar white matter (arrows). (f) Macroscopic section obtained at the level of the mesencephalon shows similar changes in the paramedian part of the cerebral peduncle that extends into the substantia nigra (arrows). (g) At microscopic examination, the area of the dentate nucleus shows extensive fibrosis, with multiple dispersed lipid crystal clefts, foamy macrophages, and some lamellae of myelinlike material. (Luxol fast-blue and hematoxylin-eosin stains; original magnification, x200.)

 


View larger version (146K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1e. Images in patient A, a 54-year-old woman. (a-c) Transverse T2-weighted MR images (repetition time msec/echo time msec, 2,200/90) show symmetric high-signal-intensity lesions in (a) the globus pallidus and adjacent part of internal capsule (arrows), (b) the substantia nigra, extending into the deep part of the cerebral peduncles (arrows), and (c) the cerebellar white matter (large straight arrows) and inferior olive (small straight arrows); note the central hypointensity of the dentate nucleus (curved arrows). (d) Postmortem coronal T2-weighted MR image (3,000/90) shows low signal intensity in the dentate nucleus (arrows), which corresponded to deposits of hemosiderin and calcification at histopathologic examination. (e) Macroscopic section shows a yellow and gray discoloration, with a glassy appearance of the dentate nucleus and surrounding cerebellar white matter (arrows). (f) Macroscopic section obtained at the level of the mesencephalon shows similar changes in the paramedian part of the cerebral peduncle that extends into the substantia nigra (arrows). (g) At microscopic examination, the area of the dentate nucleus shows extensive fibrosis, with multiple dispersed lipid crystal clefts, foamy macrophages, and some lamellae of myelinlike material. (Luxol fast-blue and hematoxylin-eosin stains; original magnification, x200.)

 


View larger version (128K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1f. Images in patient A, a 54-year-old woman. (a-c) Transverse T2-weighted MR images (repetition time msec/echo time msec, 2,200/90) show symmetric high-signal-intensity lesions in (a) the globus pallidus and adjacent part of internal capsule (arrows), (b) the substantia nigra, extending into the deep part of the cerebral peduncles (arrows), and (c) the cerebellar white matter (large straight arrows) and inferior olive (small straight arrows); note the central hypointensity of the dentate nucleus (curved arrows). (d) Postmortem coronal T2-weighted MR image (3,000/90) shows low signal intensity in the dentate nucleus (arrows), which corresponded to deposits of hemosiderin and calcification at histopathologic examination. (e) Macroscopic section shows a yellow and gray discoloration, with a glassy appearance of the dentate nucleus and surrounding cerebellar white matter (arrows). (f) Macroscopic section obtained at the level of the mesencephalon shows similar changes in the paramedian part of the cerebral peduncle that extends into the substantia nigra (arrows). (g) At microscopic examination, the area of the dentate nucleus shows extensive fibrosis, with multiple dispersed lipid crystal clefts, foamy macrophages, and some lamellae of myelinlike material. (Luxol fast-blue and hematoxylin-eosin stains; original magnification, x200.)

 


View larger version (140K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1g. Images in patient A, a 54-year-old woman. (a-c) Transverse T2-weighted MR images (repetition time msec/echo time msec, 2,200/90) show symmetric high-signal-intensity lesions in (a) the globus pallidus and adjacent part of internal capsule (arrows), (b) the substantia nigra, extending into the deep part of the cerebral peduncles (arrows), and (c) the cerebellar white matter (large straight arrows) and inferior olive (small straight arrows); note the central hypointensity of the dentate nucleus (curved arrows). (d) Postmortem coronal T2-weighted MR image (3,000/90) shows low signal intensity in the dentate nucleus (arrows), which corresponded to deposits of hemosiderin and calcification at histopathologic examination. (e) Macroscopic section shows a yellow and gray discoloration, with a glassy appearance of the dentate nucleus and surrounding cerebellar white matter (arrows). (f) Macroscopic section obtained at the level of the mesencephalon shows similar changes in the paramedian part of the cerebral peduncle that extends into the substantia nigra (arrows). (g) At microscopic examination, the area of the dentate nucleus shows extensive fibrosis, with multiple dispersed lipid crystal clefts, foamy macrophages, and some lamellae of myelinlike material. (Luxol fast-blue and hematoxylin-eosin stains; original magnification, x200.)

 


View larger version (156K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2a. CT and neuropathologic findings in patient B, a 45-year-old woman. (a, b) Transverse nonenhanced CT images obtained 1 year before death show (a) symmetric areas of low attenuation in the globus pallidus and adjacent part of internal capsule (arrows) and (b) low attenuation of the dentate nucleus and surrounding cerebellar white matter (long arrows), with a central focal area of high attenuation on the left side (short arrow). (c) Macroscopic section of the left cerebellar hemisphere obtained at the sectioned surface shows a gray, glassy dentate nucleus and white matter, with focal brown discoloration (arrows) caused by past bleeding; there was microscopic evidence of iron pigment deposition and calcification.

 


View larger version (155K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2b. CT and neuropathologic findings in patient B, a 45-year-old woman. (a, b) Transverse nonenhanced CT images obtained 1 year before death show (a) symmetric areas of low attenuation in the globus pallidus and adjacent part of internal capsule (arrows) and (b) low attenuation of the dentate nucleus and surrounding cerebellar white matter (long arrows), with a central focal area of high attenuation on the left side (short arrow). (c) Macroscopic section of the left cerebellar hemisphere obtained at the sectioned surface shows a gray, glassy dentate nucleus and white matter, with focal brown discoloration (arrows) caused by past bleeding; there was microscopic evidence of iron pigment deposition and calcification.

 


View larger version (139K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2c. CT and neuropathologic findings in patient B, a 45-year-old woman. (a, b) Transverse nonenhanced CT images obtained 1 year before death show (a) symmetric areas of low attenuation in the globus pallidus and adjacent part of internal capsule (arrows) and (b) low attenuation of the dentate nucleus and surrounding cerebellar white matter (long arrows), with a central focal area of high attenuation on the left side (short arrow). (c) Macroscopic section of the left cerebellar hemisphere obtained at the sectioned surface shows a gray, glassy dentate nucleus and white matter, with focal brown discoloration (arrows) caused by past bleeding; there was microscopic evidence of iron pigment deposition and calcification.

 
After formalin fixation, sectioning, and macroscopic evaluation of the brains of both patients and of the spinal cord of patient B, histologic sections of paraffin-embedded tissue were prepared and stained with hematoxylin-eosin, a Luxol fast blue and hematoxylin-eosin combination to accentuate the myelinated structures, and Perl Prussian blue stain to detect iron pigment. Histopathologic evaluation was performed by a pathologist (P.W.) in accordance with a standard protocol, with emphasis on areas with gross macroscopic abnormalities. Specific attention was given to the deposition of lipidlike material, demyelination, calcification, and bleeding.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
In Vivo MR Imaging
Imaging findings are summarized in Table 2. In the brain, atrophy was found in roughly half the patients and usually affected the supratentorial and infratentorial regions equally. Parenchymal abnormalities were present in all patients: Ill-defined signal intensity increase in the periventricular region on T2-weighted images was observed in all patients and was sometimes accompanied by nonspecific focal lesions in the deep white matter. In some patients, this widespread diffuse signal intensity increase on T2-weighted images was accompanied by a prominent enlargement of the Virchow-Robin spaces. The presence and extent of periventricular signal intensity changes and the enlargement of the Virchow-Robin spaces was positively correlated with atrophy, especially supratentorially, and consisted of cortical atrophy and ventricular widening.


View this table:
[in this window]
[in a new window]

  		TABLE 2. Brain MR Imaging Findings in 24 Patients with CTX
 
In addition to the nonspecific supratentorial abnormalities, more characteristic lesions were observed in the basal ganglia and infratentorial region. Lesions with increased signal intensity were seen in the medial part of the globus pallidus on T2-weighted images in 15 (63%) of 24 cases and abutted the lateral border of the posterior limb of the internal capsule. Involvement of the corticospinal tracts was frequently evident as a symmetric increase in signal intensity on T2-weighted images that were obtained in the cerebral peduncles (Fig 1). In the early disease stage, involvement was restricted to the paramedian part of the cerebral peduncles and bordered the substantia nigra. In the advanced stage of disease, the entire region of the cerebral peduncles was involved and extended partly into the tegmentum mesencephali; in the most severe cases, increased signal intensity in the periaqueductal gray matter also was seen (Fig 3b).



View larger version (175K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 3a. MR images in a 47-year-old woman. (a) Sagittal T1-weighted MR image (520/15) shows an area of hypointensity (arrow) in the cerebellum. (b) Transverse mildly T2-weighted MR image (2,800/25) shows extensive symmetric lesions, with increased signal intensity in the ventral part of the pons (arrows).

 


View larger version (173K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 3b. MR images in a 47-year-old woman. (a) Sagittal T1-weighted MR image (520/15) shows an area of hypointensity (arrow) in the cerebellum. (b) Transverse mildly T2-weighted MR image (2,800/25) shows extensive symmetric lesions, with increased signal intensity in the ventral part of the pons (arrows).

 
The cerebellum was affected in most patients (84%) but not in the four (17%) youngest. Cerebellar involvement typically started in the dentate nucleus (Fig 4) and, when more severe, extended into the surrounding white matter of the cerebellar hemispheres (Fig 1). These lesions consisted of areas of high signal intensity on T2-weighted MR images and were isointense or, when extensive, hypointense on T1-weighted images (Fig 3a). In two patients with long-standing disease, areas of decreased signal intensity on T2-weighted images were observed in the dentate nucleus (Fig 1c, 1d). In three patients, symmetric high-signal-intensity lesions were seen in the inferior olive (Fig 1c). In four patients with long-standing disease, CT showed low-attenuating lesions in the cerebellum, with central areas of high attenuation in one patient (Fig 2b).



View larger version (123K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 4. T2-weighted MR image (2,268/90) obtained in the absence of cerebellar symptoms in a 40-year-old woman with a short disease duration shows only subtle lesions with increased signal intensity in the dentate nucleus (arrows).

 
Spinal cord images were available in five patients who had mainly a spinal cord syndrome at presentation. In all of them, extensive, poorly delineated bands of increased signal intensity were observed in the spinal cord on T2-weighted images; on transverse images (available in three of five patients), these bands were restricted to the lateral and dorsal columns (Fig 5).



View larger version (106K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 5a. (a, b) MR images in a 41-year-old woman. (a) Sagittal mildly T2-weighted image (3,500/20 [effective]) in the cervical cord shows increased signal intensity (arrows) throughout the entire length. (b) Transverse heavily T2-weighted MR image (4,500/112 [effective]) in the thoracic cord shows increased signal intensity restricted to the dorsal (short arrow) and lateral (long arrows) columns; the areas of low signal intensity (*) dorsal to the cord are caused by cerebrospinal fluid flow voids. Although brain abnormalities also were present in this patient, spinal localization and symptoms may be the only manifestation in patients with so-called spinal xanthomatosis (22).

 


View larger version (131K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 5b. (a, b) MR images in a 41-year-old woman. (a) Sagittal mildly T2-weighted image (3,500/20 [effective]) in the cervical cord shows increased signal intensity (arrows) throughout the entire length. (b) Transverse heavily T2-weighted MR image (4,500/112 [effective]) in the thoracic cord shows increased signal intensity restricted to the dorsal (short arrow) and lateral (long arrows) columns; the areas of low signal intensity (*) dorsal to the cord are caused by cerebrospinal fluid flow voids. Although brain abnormalities also were present in this patient, spinal localization and symptoms may be the only manifestation in patients with so-called spinal xanthomatosis (22).

 
The Achilles tendons were affected in seven of eight patients studied, with bilateral involvement in six patients. The tendon xanthomas typically showed intermediate signal intensity on T1-weighted images (Fig 6) that was comparable with that of muscle and had a patchy appearance; they showed mixed intermediate and high signal intensity on T2-weighted images.



View larger version (126K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 6. Sagittal T1-weighted (570/15) MR image in the Achilles tendon in a 54-year-old man shows a gross morphologic mass (arrows) with intermediate signal intensity.

 
The MR imaging abnormalities tended to be more severe in older patients with a longer disease duration. In patients younger than 20 years, most abnormalities were found supratentorially and consisted of mild to moderate periventricular white matter hyperintensities. In the older patients, infratentorial atrophy and lesions in the dentate nucleus, cerebellar white matter, and mesencephalon were more frequently found. In seven patients, MR imaging was repeated after CDCA therapy: in one patient after 5 years, in four patients after 4 years, and in two patients after 2 years (23). In all patients, the preexisting MR imaging abnormalities remained unchanged. Although pyramidal tract and cerebellar involvement were clinically present in a majority of patients, no clear correlation with the presence or severity of the lesions seen at MR imaging could be determined. Moreover, no correlations were present between the extent of abnormalities at MR imaging and the serum cholestanol levels or genotype (data not shown).

Postmortem Findings
In patient A, postmortem MR imaging was performed and revealed the same areas of increased signal intensity as those seen on T2-weighted images in vivo: at the border of the globus pallidus and the posterior limb of the internal capsule, and at the mesencephalon, inferior olives, and cerebellum. Apart from the high-signal-intensity areas on T2-weighted images, symmetric, remarkably hypointense signals were found in the area of the dentate nucleus (Fig 1d).

In patient B, only CT scans were available and showed low-attenuating lesions in the internal capsule, cerebral peduncles, dentate nucleus, and cerebellar white matter that were comparable with the MR imaging findings in patient A (Fig 2a, 2b). Only the cerebellar white matter lesions showed a central area of high attenuation (Fig 2b).

Neuropathologic findings were similar in both patients. The cerebrum and brain stem were externally unremarkable at gross inspection, whereas the cerebellum showed mild to moderate atrophy. The cerebellum and brain stem were relatively firm. The brains had a normal weight, 1,255 and 1,220 g. On the sectioned surface specimens, prominent symmetric lesions were seen in the dentate nucleus and the surrounding cerebellar white matter, mesencephalon (Fig 1e, 1f), globus pallidus, and internal capsule.

At microscopic examination, the dentate nucleus and surrounding white matter of both cerebellar hemispheres showed extensive rarefaction, with severe neuronal loss and demyelination, lipid crystal cleft fibrosis, reactive astrocytosis (Fig 1g), scattered (in patient A) to widespread (in patient B) deposition of hemosiderin pigment, and focal calcifications. The lesions contained many macrophages with foamy cytoplasm and occasional lymphocytes, and the macrophages were often accumulated around blood vessels. Furthermore, a dispersed extracellular, sometimes perivascular deposition of homogeneous myelinlike material that was stained strongly blue when Luxol fast-blue was present. The cerebellar cortex showed some loss of Purkinje cells and proliferation of Bergmann glia. Otherwise, the cortex and subcortical white matter were normal.

In the medial part of the cerebral peduncle, severe demyelination, astrocytosis, infiltration of foamy macrophages, and some lipid crystal clefts were present. In the central part of this tract, only some dispersed macrophages and reactive astrocytes were found. The lesions in the cerebral peduncles extended into the substantia nigra. Smaller areas of demyelination, astrocytosis, and macrophage infiltration were found in the optic tract and internal capsule. In the basis pontis, the longitudinal tracts were more severely involved than the transverse tracts. In the globus pallidus, severe neuronal loss was present and accompanied by rarefaction of the tissue, astrocytosis, and some macrophage infiltration. Both inferior olives showed severe neuronal loss and astrocytosis, without accumulation of macrophages. Apart from occasional perivascular macrophages and correlation with the prominent enlargement of the Virchow-Robin spaces on MR images, other regions of the brain, including the periventricular white matter, were normal.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
We report the spectrum of imaging abnormalities in a large series of patients with CTX and its correlation with neuropathologic findings in two patients. In all patients, clinical and biochemical findings were diagnostic of CTX. Even though typical findings (eg, neurologic abnormalities, xanthomas, cataracts, and diarrhea) were present in many patients, almost all cases were initially misdiagnosed, for example, as multiple sclerosis or Friedreich ataxia. Moreover, abnormalities were frequently not recognized at CT and MR imaging; the majority of the images obtained in the cohort presented in our study were initially interpreted as normal. It is important to recognize these abnormalities, because effective therapy is available and consists of the combination of CDCA and simvastatin, with no progression of MR imaging abnormalities that are being treated (23,24).

Diffuse nonspecific periventricular white matter abnormalities were present in all cases, but the most characteristic imaging findings consisted of lesions in the basal ganglia and infratentorial region. In accordance with the pathologic findings, abnormal signal intensity at MR imaging was found in the globus pallidus, abutting the lateral border of the posterior limb of the internal capsula, in the cerebral peduncles extending into the substantia nigra, in and around the dentate nucleus, and, in some cases, in the inferior olives. The symmetric picture, which was also observed in the spinal cord, is highly suggestive of metabolic disease, with a remarkable preference for involvement of several gray matter nuclei, with disease extending into the adjacent white matter structures. It should be noted that, in certain cases, the presentation might be purely spinal, presenting as a chronic myelopathy, with no cerebellar and cerebral signs and no tendon xanthomas (22). Although cataract is present in such cases, MR imaging may be particularly helpful in depicting the symmetric lesions in the lateral and posterior columns and the subclinical lesions in the posterior fossa and globus pallidus, which suggested a diagnosis of CTX (22).

The distribution of the lesions at MR imaging was consistent with the clinical presentation with pyramidal and cerebellar signs. The latter was more prominent in patients with advanced disease, in accordance with more severe MR imaging abnormalities later in the disease. However, in individual cases, the correlation between the extent of imaging abnormalities and clinical presentation was not clear (nor with the cholestanol level or type of mutation). Cerebellar lesions at MR imaging, for example, were more frequent than cerebellar symptoms (Fig 4), especially in the later phases of the disease; this illustrates the high sensitivity of MR imaging in the preclinical stage.

Investigators in previous studies (17–19) of CT and MR imaging in patients with CTX have reported cerebral and cerebellar atrophy and focal and diffuse high-signal-intensity lesions in the cerebral and cerebellar white matter at T2-weighted MR imaging as the main findings. No correlation with neurologic symptoms and signs was found, the spinal cord was not investigated, and, during CDCA therapy (18), neither deterioration nor improvement was observed at MR imaging. Slight atrophy of the cervical spinal cord was reported in one study (25). Our imaging findings are in line with these earlier reports. The high frequency of lesions in the spinal cord and infratentorial region that was found in the current study probably reflects the advances of modern imaging, notably, MR imaging. This modality enables visualization of even subtle involvement of, for example, the dentate nucleus. We found lesions in the dentate nucleus in a large percentage of patients (79%); this finding provided a sensitive marker of central nervous system involvement in patients with CTX.

In comparison with the findings of previous studies (17–19), our findings emphasize the frequent involvement of gray matter structures, which were in agreement with the pathologic findings. This spectrum of MR imaging findings, in particular, the symmetric basal ganglia and infratentorial lesions, seems typical for patients with CTX. The findings may be not be completely specific for CTX, since some of these radiologic findings can also be observed in patients with other rare disorders, such as Langerhans cell histiocytosis (26), Erdheim-Chester disease (27,28) (both form part of the Langerhans cell histiocytosis spectrum), adrenomyeloneuropathy (29–31), and Refsum disease (32) (both are peroxisomal membrane disorders).

Although most of the lesions in patients with CTX contained lipid depositions at microscopic examination, none of the central nervous system or tendinous lesions were hyperintense on T1-weighted MR images; this probably reflects the fact that the accumulated material contains sterols rather than fatty acids. All were hyperintense on T2-weighted images, with the exception of the dentate nucleus lesions. The low signal intensity in those two patients on T2-weighted MR images can be explained at histopathologic examination by deposition of hemosiderin, small hemorrhages, and focal calcifications. At CT, hemosiderin and calcifications showed high attenuation in patient B, whereas the other lesions showed low attenuation. Investigators in earlier studies (17,19) reported that cerebral CT scans in patients in the early stages of CTX do not show abnormalities. In most patients in advanced disease stages, however, diffuse cerebral atrophy was seen in addition to cerebellar and brainstem atrophy, with low-attenuating deep cerebellar lesions; sometimes high-attenuating areas were seen within these lesions, as in patient B (17,19,33). These high-attenuating lesions are usually interpreted as calcifications; deposition of hemosiderin pigment and small hemorrhages may also contribute to the high attenuation.

The main disease process in patients with CTX is found in selective areas within the central nervous system. The central nervous system lesions in patients with CTX are characterized at histologic examination by a combination of xanthomatous lesions, spindle-shaped lipid crystal clefts (unique for CTX), fibrosis, and hemosiderin deposition, especially in the area around the dentate nucleus. These are pathognomonic for this disease. The pathogenesis of central nervous system involvement is hypothetic. Several authors (1,9,12–14,34) have suggested demyelination as the primary pathologic lesion, whereas others (10,11) have suggested primary neuroaxonal disease with secondary myelin loss. Our imaging findings suggest a localization-related disease process in patients with CTX that initially afflicts particular gray matter areas within the central nervous system.

Until now, several mechanisms that may lead to central nervous system abnormalities in patients with CTX have been described. Salen et al (35) reported a defect of the blood-brain barrier, with large amounts of apolipoprotein B, a carrier of cholestanol, in the cerebrospinal fluid; this defect was reversible after CDCA therapy. Results obtained from animal studies (36,37) suggest a selective accumulation of sterols within the central nervous system. During CDCA therapy, toxic metabolites responsible for the blood-brain barrier dysfunction may disappear (35), which possibly explains the lack of progression of abnormalities at MR imaging after the start of CDCA therapy (23,24).

Apart from central nervous system involvement, CTX derives its name from the occurrence of tendon xanthomas. These seldom develop before the age of 20 but more typically start to develop in the 4th decade of life, frequently in the Achilles tendons, either symmetrically or asymmetrically (7). Additional xanthomas can be found at the extensor surface of the metacarpophalangeal and interphalangeal joints, olecranon, and knees. The presence of tendon xanthomas is not obligatory for the diagnosis of CTX, and to our knowledge, there is no indication to perform MR imaging to detect them. Other conditions in which tendon xanthomas can be found are familial hypercholesterolemia (38,39) and cholestatic liver diseases (40). However, in patients with these conditions, other types of xanthomas beside tendon xanthomas can occur, such as those in the skin and the palm of the hand (eg, eruptive xanthomas) and periorbital xanthomas (xanthelasmata) (41).

Limitations of this study included its retrospective nature and the fact that only patients with (neurologic) symptoms in whom imaging data were already available were included. By nature of the study, images were acquired by using different machines, and cerebral CT and spinal MR images were not available in all subjects. The observers were not blinded to age and diagnosis, nor was there a control group to address the issue of specificity of the imaging findings. Autopsy data were available in only two patients.

In conclusion, the MR imaging findings in patients with CTX are symmetric, which suggests the inherited metabolic nature of this disease. Typical infratentorial and basal ganglia lesions may be subtle in the early disease stage. In addition, nonspecific supratentorial abnormalities are frequently found. In particular, gray matter nuclei, which include the globus pallidus, substantia nigra, dentate nucleus, and inferior olive are involved; these lesions extend into the adjacent white matter of the internal capsule, cerebral peduncles, and cerebellum during disease progression. Although many of these lesions contained lipid depositions at microscopic examination, none of the lesions in the brain or tendons were hyperintense on T1-weighted MR images, but all lesions were hyperintense on T2-weighted MR images, with the exception of lesions in the dentate nucleus, in which the low signal intensity could be explained by deposition of hemosiderin and calcifications (with high attenuation at CT). The typical pattern of lesions on MR images reflects the classic histopathologic findings and should prompt the diagnosis of CTX, a treatable disorder. Because imaging is performed frequently in these patients before the diagnosis of CTX is made, our detailed description of the imaging findings should contribute to earlier recognition in patients with this disease.


   ACKNOWLEDGMENTS
 
We thank Wouter Kamphorst, MD, for his help in neuropathologic evaluation.


   FOOTNOTES
 
Abbreviations: CDCA = chenodeoxycholic acid, CTX = cerebrotendinous xanthomatosis

Author contributions: Guarantor of integrity of entire study, F.J.M.G.; study concepts, F.B., A.V.; study design, F.B., A.V., B.G.M.v.E., F.J.M.G.; definition of intellectual content, F.B., A.V., B.G.M.v.E., F.J.M.G.; literature research, F.B., A.V., M.S.v.d.K.; clinical studies, A.V., B.G.M.v.E., A.K.; data acquisition, A.V., F.B., P.W.; data analysis, F.B., A.V., P.W., M.S.v.d.K., J.V., R.A.W.; manuscript preparation, F.B., A.V., P.W.; manuscript editing, M.S.v.d.K.; manuscript review, J.V., F.J.M.G.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 

  1. Bogaert L, Scherer H, Epstein E. Une forme cérébrale de la cholestérinose généralisée Paris, France: Masson et Cie, 1937.
  2. Oftebro H, Björkhem I, Stormer FC, Pedersen JI. Cerebrotendinous xanthomatosis: defective liver mitochondrial hydroxylation of chenodeoxycholic acid precursors. J Lipid Res 1981; 22:632-640.[Abstract]
  3. Björkhem I, Boberg KM. Inborn errors in bile acid biosynthesis and storage of sterols other than cholesterol. In: Scriver C, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular basis of inherited disease. 7th ed. New York, NY: McGraw-Hill, 1995; 2273-2299.
  4. Wolthers BG, Volmer M, van der Molen J, Koopman BJ, de Jager AE, Waterreus RJ. Diagnosis of cerebrotendinous xanthomatosis (CTX) and effect of chenodeoxycholic acid therapy by analysis of urine using capillary gas chromatography. Clin Chim Acta 1983; 131:53-65.[Medline]
  5. Wolthers BG, Walrecht HT, van der Molen JC, Nagel GT, Van Doormaal JJ, Wijnandts PN. Use of determinations of 7-lathosterol (5 alpha-cholest-7-en-3 beta-ol) and other cholesterol precursors in serum in the study and treatment of disturbances of sterol metabolism, particularly cerebrotendinous xanthomatosis. J Lipid Res 1991; 32:603-612.[Abstract]
  6. Cruysberg JR, Wevers RA, Tolboom JJ. Juvenile cataract associated with chronic diarrhea in pediatric cerebrotendinous xanthomatosis. Am J Ophthalmol 1991; 112:606-607.[Medline]
  7. Cruysberg JR, Wevers RA, Engelen BGM, Pinckers A, Spreeken A, Tolboom JJ. Ocular and systemic manifestations of cerebrotendinous xanthomatosis. Am J Ophthalmol 1995; 120:597-604.[Medline]
  8. Berginer VM, Shany S, Alkalay D, et al. Osteoporosis and increased bone fractures in cerebrotendinous xanthomatosis. Metabolism 1993; 42:69-74.[Medline]
  9. Diedrich U, Ropte S. Cerebrotendinous xanthomatosis: description of 2 cases and differential diagnosis in relation to encephalomyelitis disseminata. Nervenarzt 1989; 60:444-447[German].[Medline]
  10. Soffer D, Benharroch D, Berginer V. The neuropathology of cerebrotendinous xanthomatosis revisited: a case report and review of the literature. Acta Neuropathol 1995; 90:213-220.[Medline]
  11. Pop PH, Joosten E, van Spreeken A, et al. Neuroaxonal pathology of central and peripheral nervous systems in cerebrotendinous xanthomatosis (CTX). Acta Neuropathol (Berl) 1984; 64:259-264.[Medline]
  12. Elleder M, Michalec C, Jirasek A, Khun K, Havlova M, Ranny M. Membranocystic lesion in the brain in cerebrotendinous xanthomatosis: histochemical and ultrastructural study with evidence of its ceroid nature. Virchows Arch 1989; 57:367-374.
  13. Guillain G, Bertrand I, Godet-Guillain M. Etude anatomo-clinique d’un cas de cholestérinose cérébrale. Revue Neurologique 1942; 74:248-263.
  14. Philippart M, Van Bogaert L. Cholestanolosis (cerebrotendinous xanthomatosis): a follow-up study on the original family. Arch Neurol 1969; 21:603-610.[Medline]
  15. Schimschock JR, Alvord ECJ, Swanson PD. Cerebrotendinous xanthomatosis: clinical and pathological studies. Arch Neurol 1968; 18:688-698.[Medline]
  16. Waterreus RJ, Koopman BJ, Wolthers BG, Oosterhuis HJ. Cerebrotendinous xanthomatosis (CTX): a clinical survey of the patient population in the Netherlands. Clin Neurol Neurosurg 1987; 89:169-175.[Medline]
  17. Hokezu Y, Kuriyama M, Kubota R, Naka-gawa M, Fujiyama J, Osame M. Cerebrotendinous xanthomatosis: cranial CT and MRI studies in eight patients. Neuroradiology 1992; 34:308-312.[Medline]
  18. Berginer VM, Berginer J, Korczyn AD, Tadmor R. Magnetic resonance imaging in cerebrotendinous xanthomatosis: a prospective clinical and neuroradiological study. J Neurol Sci 1994; 122:102-108.[Medline]
  19. Dotti MT, Federico A, Signorini E, et al. Cerebrotendinous xanthomatosis (van Bogaert-Scherer-Epstein disease): CT and MR findings. AJNR Am J Neuroradiol 1994; 15:1721-1726.[Abstract]
  20. Verrips A, Steenbergen-Spanjers GCH, Luyten JAFM, et al. Exon skipping in the sterol 27-hydroxylase gene leads to cerebrotendinous xanthomatosis. Hum Genet 1997; 100:284-286.[Medline]
  21. Verrips A, van Engelen BGM, de Swart B, et al. Increased speech rate (tachylalia) in cerebrotendinous xanthomatosis: a new sign. J Med Speech-Lang Pathol 1998; 6:161-164.
  22. Verrips A, Nijeholt GJ, Barkhof F, et al. Spinal xanthomatosis: a variant of cerebrotendinous xanthomatosis. Brain 1999; 122:1589-1595.[Abstract/Free Full Text]
  23. Verrips A, Wevers RA, Van Engelen BG, et al. Effect of simvastatin in addition to chenodeoxycholic acid in patients with cerebrotendinous xanthomatosis. Metabolism 1999; 48:233-238.[Medline]
  24. Berginer VM, Salen G, Shefer S. Long-term treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid. N Engl J Med 1984; 311:1649-1652.[Abstract]
  25. Bencze KS, Vande Polder DR, Prockop LD. Magnetic resonance imaging of the brain and spinal cord in cerebrotendinous xanthomatosis. J Neurol Neurosurg Psychiatry 1990; 53:166-167.[Abstract]
  26. Poe LB, Dubowy RL, Hochhauser L, et al. Demyelinating and gliotic cerebellar lesions in Langerhans cell histiocytosis. AJNR Am J Neuroradiol 1994; 15:1921-1928.[Abstract]
  27. Bohlega S, Alwatban J, Tulbah A, Bakheet SM, Powe J. Cerebral manifestation of Erdheim-Chester disease: clinical and radiologic findings. Neurology 1997; 49:1702-1705.[Abstract/Free Full Text]
  28. Pautas E, Cherin P, Pelletier S, Vidailhet M, Herson S. Cerebral Erdheim-Chester disease: report of two cases with progressive cerebellar syndrome with dentate abnormalities on magnetic resonance imaging. J Neurol Neurosurg Psychiatry 1998; 65:597-599.[Abstract/Free Full Text]
  29. Aubourg P, Adamsbaum C, Lavallard Rousseau MC, et al. Brain MRI and electrophysiologic abnormalities in preclinical and clinical adrenomyeloneuropathy. Neurology 1992; 42:85-91.[Abstract/Free Full Text]
  30. Snyder RD, King JN, Keck GM, Orrison WW. MR imaging of the spinal cord in 23 subjects with ALD-AMN complex. AJNR Am J Neuroradiol 1991; 12:1095-1098.[Abstract]
  31. Uchiyama M, Hata Y, Tada S. MR imaging of adrenoleukodystrophy. Neuroradiology 1991; 33:25-29.[Medline]
  32. Dubois J, Sebag G, Argyropoulou M, Brunelle F. MR findings in infantile Refsum disease: case report of two family members. AJNR Am J Neuroradiol 1991; 12:1159-1160.[Medline]
  33. Berginer VM, Berginer J, Salen G, Shefer S, Zimmerman RD. Computed tomography in cerebrotendinous xanthomatosis. Neurology 1981; 31:1463-1465.[Abstract/Free Full Text]
  34. Schimschock JR, Alvord ECJ, Swanson PD. Cerebrotendinous xanthomatosis. Trans Am Neurol Assoc 1968; 93:64-65.[Medline]
  35. Salen G, Berginer V, Shore V, et al. Increased concentrations of cholestanol and apolipoprotein B in the cerebrospinal fluid of patients with cerebrotendinous xanthomatosis: effect of chenodeoxycholic acid. N Engl J Med 1987; 316:1233-1238.[Abstract]
  36. Byun DS, Kasama T, Shimizu T, Yorifuji H, Seyama Y. Effect of cholestanol feeding on sterol concentrations in the serum, liver, and cerebellum of mice. J Biochem Tokyo 1988; 103:375-379.[Abstract/Free Full Text]
  37. Inoue K, Kubota S, Seyama Y. Cholestanol induces apoptosis of cerebellar neuronal cells. Biochem Biophys Res Comm 1999; 256:198-203.[Medline]
  38. van den Bosch HC, Vos LD. Images in clinical medicine: Achilles’-tendon xanthoma in familial hypercholesterolemia. N Engl J Med 1998; 338:1591.[Free Full Text]
  39. Bhattacharyya AK, Preacher AB, Connor WE. Ectopic xanthomas in familial (type II) hypercholesterolemia. Atherosclerosis 1980; 37:319-323.[Medline]
  40. Buckley DA, Higgins EM, du Vivier AW. Resolution of xanthomas in Alagille syndrome after liver transplantation. Pediatr Dermatol 1998; 15:199-202.[Medline]
  41. Parker F. Xanthomas and hyperlipidemias. J Am Acad Dermatol 1985; 13:1-30.[Medline]



This article has been cited by other articles:


Home page
 NeurologyHome page
B. P. Mehta and R. H. Shmerling
Teaching NeuroImage: Cerebrotendinous xanthomatosis
Neurology, July 8, 2008; 71(2): e4 - e4.
[Full Text] [PDF]

Home page
 Am. J. Neuroradiol.Home page
H. Prosch, N. Grois, M. Wnorowski, M. Steiner, and D. Prayer
Long-Term MR Imaging Course of Neurodegenerative Langerhans Cell Histiocytosis
AJNR Am. J. Neuroradiol., June 1, 2007; 28(6): 1022 - 1028.
[Abstract] [Full Text] [PDF]

Home page
 NeurologyHome page
L. Schols, T. Nagele, R. Schule, and D. Berg
Cerebrotendinous xanthomatosis
Neurology, December 12, 2006; 67(11): E20 - E20.
[Full Text] [PDF]

Home page
 Arch NeurolHome page
M. T. Lorincz, S. Rainier, D. Thomas, and J. K. Fink
Cerebrotendinous Xanthomatosis: Possible Higher Prevalence Than Previously Recognized
Arch Neurol, September 1, 2005; 62(9): 1459 - 1463.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Neuroradiol.Home page
D. Prayer, N. Grois, H. Prosch, H. Gadner, and A. J. Barkovich
MR Imaging Presentation of Intracranial Disease Associated with Langerhans Cell Histiocytosis
AJNR Am. J. Neuroradiol., May 1, 2004; 25(5): 880 - 891.
[Abstract] [Full Text] [PDF]

Home page
 J Child NeurolHome page
A. Federico and M. T. Dotti
Cerebrotendinous Xanthomatosis: Clinical Manifestations, Diagnostic Criteria, Pathogenesis, and Therapy
J Child Neurol, September 1, 2003; 18(9): 633 - 638.
[Abstract] [PDF]

Home page
 Am. J. Neuroradiol.Home page
M. Inglese, N. DeStefano, E. Pagani, M. T. Dotti, G. Comi, A. Federico, and M. Filippi
Quantification of Brain Damage in Cerebrotendinous Xanthomatosis with Magnetization Transfer MR Imaging
AJNR Am. J. Neuroradiol., March 1, 2003; 24(3): 495 - 500.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)