Whole body MRI technique in early treated non-neuronopathic patients with enzyme replacement therapy at least eight years

Larissa Moos, Jörg Reinke, Miriam Brixius-Huth, Eugen Mengel and Gundula Staatz

Department of Pediatric Radiology and Villa MetabolicaMainz Germany

Department of Pediatric Radiology / Villa Metabolica

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Introduction

• 3rd EWGGD in Lemnos: – Initiation of high dose ERT followed be

individual adapted maintenance dosage inchildren ( signs of GD in preschool age)

– n=10, age: 6-10 years, ERT follow up: – 6 years

• 10th EWGGD in Paris– Same cohort ( + 5 pts, 1 pts lost to follow up )– 13 years later

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Most of these Patients > 50 yearsWhat about red marrow and yellow marrow in young adults?Can we prevent bone disease ?

MOTIVATION

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AIM OF THE STUDY

To show the outcome of early treated patients with treatment initiation before the age of 10

years after 8 – 20 years of ERT, when they become young adults.

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• Inclusion Criteria:a) Typ 1 GD is confirmed, clinical relevant manifestationb) Treatment initiation before the age of 10! c) Treated since a minimum of 8 years

• ∑ 14 patients• Age of 17- 26 years• Mainzer treatment protocol is used

Patients

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Initial:• Clinical manifestions

before the age of 10 years!

• Advice: 60 IE/kg KG / 14 days

Maintenence:• Permanent therapy to

prevent detoriation and complications

• Advice: 15-60 IE/kg KG/14 days

• Mainzer Protocol: Dosage depends on clinical symptoms and increase of chitotriosidase!Average: 38.5 IE/kg KG/14 days

TRETAMENT PROTOCOL FOR ERT

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Outcome Measures

Bone-marrow Scores – Whole body MRI:

• Düsseldorfer Gaucher Score (DGS)

• Vetebra-Disc-ratio (VDR)

• Bone Marrow Burden Score (BMB)

All-domain- Score:

• Sverity Score Index Type 1 (GD-S3)

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VDR, BMB, & DGS-Scores

Source : vom Dahl S. et al. Cur Med Res Opin 2006;22:1045-1064

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• Includes only lower extremities

• Differentiates between A-&B Pattern

• Bone infiltration always bilateral

• A maximum of 8 points can obtained

DGS-SCORE

Source: Poll et al. (2003)

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Normal:• hyperintense-signal intensity

(T1-sequence)/ fine- structured

Source: Institut für Kinderradiologie, Johannes-Gutenberg-Universität

GRADUATION OF BONE-MARROW INFILTRATION

Low:• mostly hyperintense-signal intensity

with beginng of Gaucher-cell infiltration→hypointense (T1) /regular-structured

Medium:• more hypointense-signal intensity/

regular structured

High:• severe hypointense-signal intensity/ inhomogenous

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Joint destruction

FractureBone pain

Short stature

Osteopenia/Osteoporosis

Bone infarct

Early beginning with ERT could prevent BONE COMPLICATIOS

Bone complications

0/14

0/140/14

0/14

0/14 0/14

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GD-S3 Scoring System

Source: Weinreb N, et al. Gen Med 2010;12:44–51

9-16

VAS

0/141/14

0/14

0/14

0/14

0/14

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Median Q25 Q75 Range

Bone-marrow-Score:

BMB-Sc.: 7 6 8,26 3-11

DGS-Sc.: 4A 4A 4A 3-5 A-B

VDR-Sc.: 1,33 1,05 1,59 1,19-2,01

All- Domain-Score:

GD-S3 1,6 1,6 1,6 0-2,26

Score-classifications:

• BMB-Sc.: 0-4 (mild)/ 5-8 (moderate)/ 9-16 (severe) [Range: 0-16]• DGS-Sc.: 1-6 (low)/ 7-8 (high) compared with type A & B-morphology [Range: 1-8]• VDR-Sc.: 1.9 ±0.30 (normal)/ 1.29 ± 0.31 (untreated pat.)/ 1.7. ± 0.33 (long-treated

pat.)

Results

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Vertebra-Disc-Ratio

Untreated Patient Long-treated Patient

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Social aspects

• 8 pts with high school degree• 1 pts still in high school• 5 pts with jobs in offices or trades• 4 pts had there own family: 7 healthy ERT-

babies• No hospitalisation

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• All Whole- Body-MRIs were well tolerated

• NO BONE COMPLICATIONS

• Typical manifestions of GD are reduced to a minimum!• Only bone marrow infiltration was observed

• BMB-Score

• DGS-Score LOWER LEVEL

• GD-S3 Score

• VDR-Score EXCEPTION: located in the spectrum of non-treated pat.

• Postponed bone marrow conversion ?? Minimum effective dose ??

Consequence: Follow-up studies

Conclusion

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Thanks

• Patients• Larissa Moss• Cooperation: Prof. G. Staatz, Pediatric

Radiology Mainz• Team of the Villa metabolica

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• Maas, M.; van Kuijk, C.; Stoker, J.; Hollak, C. E. M.; Akkerman, E. M.; Aerts, J. F. M. G.; den Heeten, G. J. (2003):Quantification of Bone Involvement in Gaucher Disease: MR Imaging Bone Marrow Burden Score as an Alternative to Dixon Quantitative Chemical Shift MR Imaging--Initial Experience.In: Radiology 229 (2), S. 554–561.

• Poll, Ludger W.; Cox, Marie-Louise; Godehardt, Erhard; Steinhof, Verena; Vom Dahl, Stephan (2011):Whole body MRI in type I Gaucher patients: Evaluation of skeletal involvement.In: Blood Cells, Molecules, and Diseases 46 (1), S. 53–59.

• Weinreb, Neal J.; Cappellini, Maria D.; Cox, Timothy M.; Giannini, Edward H.; Grabowski, Gregory A.; Hwu, Wuh-Liang et al. (2009):A validated disease severity scoring system for adults with type 1 Gaucher disease.In: Genet Med 12 (1), S. 44–51.

• Di Rocco, M.; Giona, F.; Carubbi, F.; Linari, S.; Minichilli, F.; Brady, R. O. et al. (2008):A new severity score index for phenotypic classification and evaluation of responses to treatment in type I Gaucher disease.In: Haematologica 93 (8), S. 1211–1218.

• http://radiopaedia.org/encyclopaedia/quizzes/all/8366• http://www.primary-surgery.org/ps/vol2/html/sect0322.html• http://www.123rf.com/photo_11530363_human-knee-pain-running-man-skeleton-x-ray-visual-bone-health-fitness-exercise-chart-

symbol.html• http://seekingalpha.com/article/175098-growth-report-for-third-quarter-2009-part-i

References

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MAINZER TREATMENT PROTOCOL