Imaging Study of the White Matter Lesions in Children With Metachromatic Leucodystrophy

Late Infantile Metachromatic Leukodystrophy Clinical Trial

— HCIT-MLD  

Official title:

Study of the Natural History of Cerebral White Matter Involvement in Metachromatic Leukodystrophy, Using High-field MRI and Diffusion Tensor Imaging

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01325025
• Other study ID #: P071232
• Status: Completed
• Phase: N/A
• First received: March 9, 2011
• Last updated: July 31, 2016
• Start date: November 2010
• Est. completion date: July 2016

Study information

• Verified date: July 2016
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

High-field MRI and diffusion tensor imaging with 3D reconstruction of the myelin tracks, in combination with multivoxel proton spectroscopy, will allow to precise more accurately the evolution of the white matter lesions in patients affected with Metachromatic Leukodystrophy (particularly in the initial phase of the disease). This will increase the knowledge of the disease and provide new indicators for the selection and evaluation of patients eligible for new therapeutic approaches.

Description:

Metachromatic Leukodystrophy (MLD) is a rare autosomal recessive disorder caused by the deficiency of the Arylsulfatase A enzyme (ARSA), resulting in accumulation of galactosyl sulfatide (cerebroside sulfate), a major constituent of the myelin sheath. Accumulation of sulfatides leads to a progressive degeneration of the white matter in the central and peripheral nervous systems (CNS, PNS) and to a neuronal degeneration. The late-infantile form of MLD, which is usually diagnosed in the second year of life, is the most frequent and severe form of the disease. The prognosis is severe, leading to vegetative stage or death within few years after the diagnosis. There is no treatment for patients affected with this early-onset form of the disease.

Conventional MRI (1.5 Tesla) shows extensive involvement of the cerebral white matter (hypo-T1, hyper- T2 and FLAIR signals) indicative of rapidly progressing leukodystrophy. Early cortical atrophy reflects associated neuronal involvement. Proton MR spectroscopy demonstrates abnormalities of choline and N-acetyl-aspartate (demyelination, neuronal loss), which are non-specific but can serve as indicators to monitor the effects of any therapeutic intervention.

In early-onset forms of MLD, conventional MRI becomes abnormal at a relatively advanced stage of the disease and the neuroradiological diagnosis may be difficult before the age of 2 - 2 1/2 years of age. Moreover, topography and extent of detectable lesions are poorly correlated with the disease severity.

In order to improve information provided by neuroimaging, this study aims to investigate prospectively and longitudinally (over a period of 6 months) white and grey matter lesions in 10 MLD children aged 1 to 6 years, using high-field MRI (3 Teslas) and diffusion tensor imaging (DTI) with 3D reconstruction of the myelin tracks. The time interval between diagnosis and inclusion will not exceed 18 months, thus patients will be included at an early stage of their disease. Each time-point (T0 and 6 months) will also include neurological evaluation to correlate the imaging, cognitive and motor functions. Children will be included over a period of 5 years. The total duration of the study will be 5.5 years. Controls will include 25 age-matched children with cryptogenic partial epilepsy who should have a high-field MRI to detect structural abnormalities. Controls will have a MRI and cognitive evaluation at T0 and 12 months if necessary. This study will increase our knowledge of the natural history of MLD and provide new indicators for the selection and evaluation of patients eligible for new therapeutic approaches.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 29
• Est. completion date: July 2016
• Est. primary completion date: March 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 1 Year to 6 Years

Eligibility

Inclusion Criteria (patients):

• Children with proven metachromatic leukodystrophy (MLD) with decreased activity of arylsulfatase A enzyme in leukocytes and abnormal excretion of urinary sulfatides

• Age = 1 year and = 6 years

• Recently diagnosed (within < 18 months)

Inclusion Criteria (control):

• Children with partial cryptogenic epilepsy or with a suspected brain lesion on conventional MRI, who should have high-field MRI to detect structural abnormalities that could benefit from surgical resection

• Age = 1 year and = 6 years

Exclusion Criteria:

• Evolutive heart, pulmonary, renal or gastrointestinal disease

• Contra-indication to sedation

• Contra-indication to MRI (implanted magnetic material)

Study Design

Allocation: Non-Randomized, Intervention Model: Parallel Assignment, Masking: Open Label

Related Conditions & MeSH terms

• Late Infantile Metachromatic Leukodystrophy
• Leukodystrophy, Metachromatic

Intervention

Other:
• High-field MRI (3 Teslas)
anatomical location conventional anatomical sequence T1, T2, FLAIR diffusion tensor sequence (21 directions) high angular resolution diffusion (HARDI) sequence field map reflexology T1, T2 spectroscopic imaging sequence
• High-field MRI (3 Teslas)
anatomical location conventional anatomical sequence T1, T2, FLAIR diffusion tensor sequence (21 directions) high angular resolution diffusion (HARDI) sequence field map reflexology T1, T2 spectroscopic imaging sequence

Locations

Country	Name	City	State
France	Unité de recherche biomédicale, Neurospin, I2BM / DSV / SAC/ CEA,	Gif-sur-yvette
France	Bâtiment Lavoisier - Unité INSERM U 663,Hôpital Necker Enfants Malades	Paris
France	Service de Neurologie Pédiatrique, Hôpital Bicêtre	Paris

Sponsors (2)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris	European Leukodystrophy Association

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Assess the natural history of the white matter and cortex lesions in MLD using diffusion tensor imaging (DTI)and relaxometry/ high field MRI.	The following parameters will be studied: quantitative measurements of mean diffusivity, longitudinal and transverse fractional anisotropy in ROIs (regions of interest), 3D-tractographic reconstruction of the myelin tracks.	At inclusion (T0) and 12 months for control. At T0 then at 6 months for patients	No
Secondary	Assess the natural history of the white matter and cortex lesions in MLD using using multi-voxel spectroscopic imaging.		At inclusion (T0) and 12 months for control. At T0 then at 6 months for patients	No
Secondary	Assess the evolution of cortical atrophy,		At inclusion (T0) and 12 months for control. At T0 then at 6 months for patients	No
Secondary	Correlate the neuroimaging parameters with motor function measure (Gross Motor Function Measure) and cognitive tests (BSID, WPPSI).		At inclusion (T0) and 12 months for control. At T0 then at 6 months for patients	No