Neurology India Medknow Publications on behalf of the Neurological Society of India ISSN: 0028-3886 EISSN: 1998-4022 Vol. 51, Num. 3, 2003, pp. 401-403

Neurology India, Vol. 51, No. 3, July, 2003, pp. 401-403

Cerebrotendinous xanthomatosis: Neuroimaging findings in two siblings from an Indian family

Gaikwad SB, Garg A, Mishra NK, Gupta V, Srivastava A, Sarkar C
Departments of Neuroradiology, Neurology and Neuropathology, Neurosciences Center, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110029

Correspondence Address:
Department of Neuroradiology, A.I.I.M.S, New Delhi - 110029
sgaikwad_63@yahoo.com

Code Number: ni03132

ABSTRACT

Cerebrotendinous xanthomatosis (CTX) is exceptionally rare in the Indian population. We present and discuss the clinical, radiological and histopathologic findings in 2 siblings with CTX. Both the patients had juvenile cataract, mental retardation and marked cerebellar ataxia. The Achilles tendon swelling was present in only 1 patient (Case 2). MR imaging showed typical bilateral and symmetrical involvement of the dentate nuclei, inferior olives, brainstem and cerebellar hemispheric white matter. Although the diagnosis of CTX was made in the 3rd decade in both our cases, early diagnosis is possible if neuroimaging is done in the early course of the disease.

INTRODUCTION

Cerebrotendinous xanthomatosis (CTX) is a rare disorder with an autosomal recessive inheritance characterized by the accumulation of cholestanol and cholesterol, predominantly in the brain, spinal cord, peripheral nerves, lungs, liver, kidneys, tendon xanthomas and bile.[1] Juvenile cataract, mental retardation and swelling of tendons with cerebellar ataxia are the most prominent features of the disease. The neurological syndrome is variable and in the absence of tendon xanthomas may be confused with the Marinesco-Sjoegren syndrome.[2] Early diagnosis is extremely important as patients benefit from therapy with chenodeoxycholic acid and the progression of the disease can be prevented.[3] We describe the CT and MRI findings in 2 siblings of Indian origin.

CASE REPORT

Case 1
A 22-year-old male presented with mental regression and difficulty in speaking since the age of 5 years. He also noticed frequent falls starting from 7 years of age followed by gait ataxia from the age of 9. Since the last 2 years he was having tremulousness in hands. On examination, bilateral cataract was present. All his reflexes were found to be absent except ankle jerks and he had marked cerebellar signs. There was no soft tissue swelling along the muscle tendons. A clinical diagnosis of Friedreich's ataxia was made along with the differential diagnosis of CTX.

CT scan of brain showed symmetrical hypodensity in both the cerebellar hemispheres, involving the white matter [Figure-1]. No evidence of calcification was found. There was no evidence of mass effect or perilesional edema.

MR imaging was done on 1.5 T Siemens System. T1-weighted images revealed hypointense lesions in cerebellar white matter extending along the outgoing tracts of the dentate nuclei [Figure-2]. On T2-weighted images the lesions were hyperintense with the peripheral rim of marked hypointensity along the cerebellar lesions [Figure-3]. The pyramidal tracts, dentate nuclei, substantia nigra and inferior olive also showed hyperintensity with extension into the adjacent white matter. The supratentorial compartment revealed hyperintensities in the periventricular white matter. Based on the MR findings a diagnosis of cerebrotendinous xanthomatosis was made.

Case 2
A 23-year-old female, sister of the earlier patient had presented with cataract at the age of 5 years. Mental retardation and stunted growth was marked by 13 years of age. She also complained of gait ataxia and incoordination of movements for the last 10 years. On examination she was found to have cataract in both her eyes and marked cerebellar signs. A single soft tissue swelling was present on the Achilles tendon. CT scan showed hypodensity in bilateral cerebellar white matter and brainstem. A small area of focal calcification was observed on the left side along the posterior margin of the lesion. MR imaging was done on 1.5 T Siemens system. T1 and T2-weighted axial images along with T2-weighted sagittal images were obtained. MRI showed involvement of the dentate nucleus, inferior olives, and brainstem with hypointense lesions on T1­weighted images [Figure-4] and hyperintense lesions on T2-weighted images. The peripheral rim of marked hypointensity was noted around the cerebellar lesions on both sides. Marked blooming was noted on gradient-echo sequences suggesting the presence of paramagnetic substances.

The biopsy from the Achilles tendon swelling was received in 10% neutral buffered formalin. It was routinely processed and paraffin-embedded. Five micron sections were cut and stained with routine hematoxylin and eosin (H and E) stain. Sections revealed a lesion largely comprising histocytic cells having foamy to vacuolated cytoplasm. Most of the cells were mononuclear with the nucleus located eccentrically. However, the occasional Touton type of giant cells with wreath nuclei were present. These foam cells were admixed with fibrotic areas. Immunohistochemical stains showed the foam cells to be positive for CD 68 (KP 1) and negative for S-100 protein, confirming their macrophage nature. Based on the above findings, a histochemical diagnosis of xanthoma was made [Figure-5].

DISCUSSION

CTX results from a defect of the hepatic mitochondrial steroid 26-hydroxylase.[4] van Bogaert et al are credited with the description of the disease for the first time in 1937.[5] Its unique chemical feature, deposition of cholesterol within the nervous system, was uncovered only in 1968 by Menkes et al.[6] The onset of the disease usually occurs towards the end of the first decade of life, and most individuals live beyond middle age. Progression is generally slow, and in many instances, the illness doesn't interfere with a normal lifespan. Slowly progressive spinocerebellar ataxia, pyramidal signs and mental retardation are seen commonly. The typical MRI findings in CTX have been documented in over 90% of cases. Cataracts are present in 76% cases and are generally seen as early as 5-6 years of age.[1] Seizures are encountered in 40-50% cases, and can be the presenting problem in some cases. A sensory-motor neuropathy has also been documented. Xanthomas usually develop in adult life, most frequently on the Achilles tendon. The major biochemical findings are an increased concentration of cholestanol in the serum and erythrocytes but the cholesterol levels are generally normal.[1]

The chronically progressive neurological deficit can be improved and in some cases is partially reversible by treatment with chemodeoxycholic acid. Therefore, early diagnosis is mandatory and CTX should be considered in every patient with intellectual impairment, spastic-ataxia signs, juvenile cataracts and tendon xanthomas and imaging should be done as soon as possible.

Imaging findings commonly consist of diffuse or focal lesions in the cerebral and cerebellar hemispheres, centrum semiovale, corona radiata, and globus pallidum,[4],[7] while on the other hand atrophy of the cord,[8] brainstem and corpus callosum,[4] including lesions of the spinal lateral and dorsal columns[7],[8] are uncommon. Since CTX is a late onset neurometabolic disorder, high cholestanol levels for a prolonged period may have a toxic effect on the neurons and myelinated axons leading to atrophy and secondary demyelination.[4]

MR abnormalities in the dentate nuclei are the earliest imaging findings and have been consistently present in these patients.[9] Therefore, all efforts should be made to perform MR imaging whenever a clinical diagnosis is suspected. As the disease progresses, there is involvement of the pyramidal tracts, inferior olive and the outgoing fiber tracts of these structures.[7] The demyelinated areas appear hyperintense on T2-weighted images and the peripheral rim of marked hypointensity on T2-weighted images is caused by the xanthomas. At pathology, these lesions are characterized by the accumulation of mononuclear cells with foamy cytoplasm, and multinucleated giant cells with a high concentration of cholestanol, which most likely results in the formation of foreign body granulomas.[1] Both our cases showed this hypointense rim that helped us arrive at the correct diagnosis even though tendon swelling was present in only 1 case (Case 2).

This well-defined disease has a predilection for Jewish patients of Moroccan origin. The Oriental, Chinese and Japanese population can be affected rarely.[10] The occurrence in the Indian population is exceptionally rare. In 1999, Gobinda et al[11] reported CTX in 2 siblings from an Indian family, whose clinical features consisted of bilateral tendon xanthomas, bilateral cataract, poor memory and early cerebellar signs.

If tendon xanthomas are not present, a diagnosis of CTX often will not be made, unless biochemical tests are performed.[2],[12] Clinically, CTX strongly resembles the Marinesco­-Sjoegren syndrome, an autosomal recessive disorder characterized by the triad of cerebellar ataxia, congenital cataract, and mental retardation.[2] A definite distinction between CTX without tendon xanthomas and the Marinesco-Sjoegren syndrome, based on clinical presentation alone may be difficult. Such differentiation is crucial since CTX is a treatable condition.[2]

Besides typical MRI findings in CTX, a close correlation has been documented between the values of N-acetylaspartate resonance and patients' disability on MR spectroscopy and can be used as a measure to assess the disease outcome.

REFERENCES

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