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I would like to thank the authors for these new data on Norrie disease. However, we believe an important point deserves further discussion: the quantitative evidence of low ADC in the neonatal cerebellum in infants under 6 months, ADC values in the cerebellum can physiologically fall around 0.6–0.7 × 10⁻³ mm²/s due to normal maturation processes. Data from Özkan et al. (2019)(1) show that the mean ADC in the cerebellar cortex reaches as low as 0.75, with standard deviations allowing lower bounds down to 0.63. Similarly, the middle cerebellar peduncle shows values dropping to 0.78 with normal variability reaching 0.66. These findings confirm that ADC values near 0.6–0.7 are part of normal cerebellar development, not pathological restriction. (Table 1)
These lower values typically occur during the first few weeks to months after birth and reflect rapid maturation processes rather than diffusion restriction due to injury.
There are several mechanisms behind physiological ADC reduction.
First, early myelination: the cerebellar white matter and peduncles myelinate early, often from birth to 3 months of age on T1-weighted imaging(2). Myelination reduces extracellular water, restricts water diffusion, and lowers ADC.
Second, high cellular density: The cerebellum has a persisting external granular layer in the early postnatal period. This temporary, densely packed layer leads to reduced interstitial space and further restricts diffusion physiologically.
Third, microstructural complexity: As highlighted by Hüppi & Dubois (2006)(3), axon packing, oligodendrocyte proliferation, and early organization of white matter tracts all contribute to lowering diffusivity even before overt myelin is seen on conventional MRI.
Fourth, normal maturation pattern: Mukherjee et al. (2001)(4) show that ADC decreases follow a biphasic exponential decline with age. The steepest decline is in the first 6 months, and the cerebellum is no exception, as its maturation is advanced compared to supratentorial regions.
An ADC around 0.7 × 10⁻³ mm²/s in the cerebellum of infants under 6 months is typically symmetrical and homogeneous, consistent with normal development. It should not be misinterpreted as pathological, such as in cases of hypoxic-ischemic injury or cerebellitis. Crucially, such a pattern lacks associated DWI hyperintensity, T2 signal changes, or cortical swelling, which are hallmarks of true diffusion restriction.
We urge clinicians and radiologists to interpret ADC values in the context of age-specific normative data, anatomical symmetry, and clinical presentation. Similarly, when considering contrast enhancement, the absence of spontaneous T1 hyperintensity on non-contrast sequences must be demonstrated — which, in this case, was not shown by the authors for the cerebellum enhancement.
We trust that these observations will support the ongoing refinement of diffusion imaging interpretation in early infancy and underscore the importance of age-specific reference values.
REFERENCES:
1. Özkan M, Taşkent İ, Teke M. Evaluation of changes in myelination in the brain during infancy and childhood using ADC maps. Journal of Surgery and Medicine [Internet]. 4 nov 2019 [cité 19 avr 2025]; Disponible sur: https://ojs.selsistem.com.tr/doi/10.28982/josam.633584
2. Barkovich AJ, Kjos BO, Jackson DE, Norman D. Normal maturation of the neonatal and infant brain: MR imaging at 1.5 T. Radiology. janv 1988;166(1 Pt 1):173‑80.
3. Hüppi PS, Dubois J. Diffusion tensor imaging of brain development. Seminars in Fetal and Neonatal Medicine. 1 déc 2006;11(6):489‑97.
4. Mukherjee P, Miller JH, Shimony JS, Conturo TE, Lee BC, Almli CR, et al. Normal brain maturation during childhood: developmental trends characterized with diffusion-tensor MR imaging. Radiology. nov 2001;221(2):349‑58.
TABLE 1:
Cerebellar ADC Values in Infants <6 Months (Özkan et al., 2019)
Middle Cerebellar Peduncle (White Matter)
Age Group Region Mean ADC (×10⁻³ mm²/s) SD Lower Bound (Mean - 2SD)
0–3 months Right MCP 0.93 0.05 0.83
0–3 months Left MCP 0.91 0.07 0.77
3–6 months Right MCP 0.80 0.05 0.70
3–6 months Left MCP 0.78 0.06 0.66
Cerebellar Cortex (Gray Matter)
Age Group Region Mean ADC (×10⁻³ mm²/s) SD Lower Bound (Mean - 2SD)
0–3 months Right Cortex 0.87 0.12 0.63
0–3 months Left Cortex 0.88 0.14 0.60
3–6 months Right Cortex 0.75 0.07 0.61
3–6 months Left Cortex 0.76 0.09 0.58