Norrie Disease: Cochlear Enhancement and Cerebellar Signal Abnormalities

Kevin Ferenchak; Julie B. Guerin; Asra Nayab; Gesina F. Keating; Madeline Q. Lopour; Lauren A. Dalvin; Lisa A. Schimmenti; Brittni A. Scruggs; V. Michelle Silvera

doi:10.3174/ajnr.A8707

Compose eLetter

Title *

Author Information

Contributors
First Name and Middle Initial * First or given name, e.g. 'Peter'. Last Name * Your last, or family, name, e.g. 'MacMoody'. Email Address * Your email address, e.g. higgs-boson@gmail.com Occupation * Your role and/or occupation, e.g. 'Orthopedic Surgeon'. Affiliation * Your organization or institution (if applicable), e.g. 'Royal Free Hospital'.

Statement of Competing Interests

Competing interests? *

Yes

Please describe the competing interests

Vertical Tabs

Jump to comment:

RE: Response to e-Letter: Low ADC in the Cerebellum of Infants: A Normal Developmental Phenomenon RE: Norrie Disease: Cochlear Enhancement and Cerebellar Signal Abnormalities.
Julie B. Guerin, V. Michelle Silvera, Kevin Ferenchak, Asra Nayab, Gesina F. Keating, Madeline Q. Lopour, Lauren A. Dalvin, Lisa A. Schimmenti and Brittni A. Scruggs

Published on: 18 June 2025
Low ADC in the Cerebellum of Infants: A Normal Developmental Phenomenon
Thibault Agripnidis and Jean-François Hak

Published on: 20 April 2025

Published on: (18 June 2025)
Page navigation anchor for RE: Response to e-Letter: Low ADC in the Cerebellum of Infants: A Normal Developmental Phenomenon RE: Norrie Disease: Cochlear Enhancement and Cerebellar Signal Abnormalities.
RE: Response to e-Letter: Low ADC in the Cerebellum of Infants: A Normal Developmental Phenomenon RE: Norrie Disease: Cochlear Enhancement and Cerebellar Signal Abnormalities.
Julie B. Guerin, Pediatric Neuroradiologist, Mayo Clinic, Rochester, MN
Other Contributors:
V. Michelle Silvera, Pediatric Neuroradiologist

Kevin Ferenchak, Pediatric Neuroradiologist

Asra Nayab, Pediatric Neuroradiologist

Gesina F. Keating, Pediatric Neuroradiologist

Madeline Q. Lopour, Pediatric Neuroradiologist

Lauren A. Dalvin, Pediatric Neuroradiologist

Lisa A. Schimmenti, Pediatric Neuroradiologist

Brittni A. Scruggs, Pediatric Neuroradiologist
We thank Drs. Agripnidis and Hak for their thoughtful critique of our recent publication and for highlighting the importance of age-specific interpretation of diffusion-weighted imaging (DWI) of the cerebellum in infants.

Their observations raise important points regarding normal cerebellar maturation, which we agree must inform interpretation of diagnostic brain MRIs in early infancy. However, we believe that the cerebellar abnormalities presented in our Norrie Disease (ND) cases reflect a pathologic process beyond expected developmental change.

Importantly, we would like to provide additional clinical and imaging information that was not included in our original manuscript for reasons of brevity. In both patients, cerebellar signal abnormality on T2-weighted images was present at presentation (Figs 1, 4, and 5), along with reduced ADC values, and cerebellar enhancement. In Case 1 (the 5-week-old), a follow-up MRI at 3 years and 6 months demonstrated chronic evolved cerebellar injury (Fig 2 and 3).

Additionally, the cerebellar ADC abnormalities in both infants were first detected through subjective visual inspection and subsequently confirmed by quantitative analysis. This diagnostic approach reflects standard clinical practice and emphasizes the contribution of visually recognizing apparent, regionally specific signal abnormalities, particularly in genetically confirmed neurovascular conditions.

Quantitative ADC measurements from the initi...
Show More

We thank Drs. Agripnidis and Hak for their thoughtful critique of our recent publication and for highlighting the importance of age-specific interpretation of diffusion-weighted imaging (DWI) of the cerebellum in infants.

Their observations raise important points regarding normal cerebellar maturation, which we agree must inform interpretation of diagnostic brain MRIs in early infancy. However, we believe that the cerebellar abnormalities presented in our Norrie Disease (ND) cases reflect a pathologic process beyond expected developmental change.

Importantly, we would like to provide additional clinical and imaging information that was not included in our original manuscript for reasons of brevity. In both patients, cerebellar signal abnormality on T2-weighted images was present at presentation (Figs 1, 4, and 5), along with reduced ADC values, and cerebellar enhancement. In Case 1 (the 5-week-old), a follow-up MRI at 3 years and 6 months demonstrated chronic evolved cerebellar injury (Fig 2 and 3).

Additionally, the cerebellar ADC abnormalities in both infants were first detected through subjective visual inspection and subsequently confirmed by quantitative analysis. This diagnostic approach reflects standard clinical practice and emphasizes the contribution of visually recognizing apparent, regionally specific signal abnormalities, particularly in genetically confirmed neurovascular conditions.

Quantitative ADC measurements from the initial studies were:

Case 1 (5-week-old): Mean ADC = 688.95 ×10⁻⁶ mm²/s, min = 568.00

Case 2 (5 and a half-month-old): Mean ADC = 702.21 ×10⁻⁶ mm²/s, min = 614.00

These values fall near or below the 2 SD lower bounds published by Özkan et al. for cerebellar cortex in infants under 6 months (1). While values in this range may reflect normal variation, the coexistence of cerebellar enhancement and T2 signal abnormalities at presentation—along with chronic changes on follow-up—suggests that the findings reflected true cerebellar pathology.

We note that while ADC values decrease in early infancy (1), the absolute ADC measurement alone does not distinguish normal from abnormal, especially when diffusion changes are accompanied by enhancement and/or T2 signal abnormalities, which were present in both of our cases. Additionally, while early postnatal ADC reductions can reflect physiological maturation, this process is typically symmetric, homogeneous, and not associated with signal abnormalities or long-term structural injury (2) distinguishing our findings (Fig 6) from expected maturation.

The imaging abnormalities we describe align with the known pathophysiology of Norrie Disease. NDP mutations disrupt Wnt/β-catenin signaling, which is essential for cerebrovascular development and blood-brain barrier integrity. Animal models show cerebellar vascular dysgenesis and increased permeability, providing biological support for our findings of cerebellar enhancement, reduced diffusion, and injury (3, 4,5).

In conclusion, while we agree that cerebellar ADC values can be low in normal infancy, in our cases, this finding occurred alongside cerebellar enhancement, T2 signal changes, and structural injury on follow-up MRI, in a disease with a known vascular mechanism. Together, these features strongly support pathological interpretation.

We appreciate the opportunity for this dialogue and to clarify these points and to expand upon our original findings.

Respectfully, Kevin Ferenchak, MD; Julie B. Guerin, MD; Asra Nayab, MBBS; Gesina F. Keating, MD; Madeline Q. Lopour, MS; Lauren A. Dalvin, MD; Lisa A. Schimmenti, MD; Brittni A. Scruggs, MD, PhD; V. Michelle Silvera, MD.

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

References:

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]

Hüppi PS, Dubois J. Diffusion tensor imaging of brain development. Seminars in Fetal and Neonatal Medicine. 1 déc 2006;11(6):489 97

Xu Q, Wang Y, Dabdoub A, Smallwood PM, Williams J, Woods C, Kelley MW, Jiang L, Tasman W, Zhang K, Nathans J. Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. Cell. 2004 Mar 19;116(6):883-95

Wang Y, Cho C, Williams J, Smallwood PM, Zhang C, Junge HJ, Nathans J. Interplay of the Norrin and Wnt7a/Wnt7b signaling systems in blood-brain barrier and blood-retina barrier development and maintenance. Proc Natl Acad Sci U S A. 2018 Dec 11;115(50):E11827-E11836.

Zhou Y, Wang Y, Tischfield M, Williams J, Smallwood PM, Rattner A, Taketo MM, Nathans J. Canonical WNT signaling components in vascular development and barrier formation. J Clin Invest. 2014 Sep;124(9):3825-46.

Show Less
Competing Interests: None declared.
Published on: (20 April 2025)
Page navigation anchor for Low ADC in the Cerebellum of Infants: A Normal Developmental Phenomenon
Low ADC in the Cerebellum of Infants: A Normal Developmental Phenomenon
Thibault Agripnidis, Neuroradiologist, Department of Neuroradiology, Timone Hospital, Marseille, France
Other Contributors:
Jean-François Hak, Neuroradiologist
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....
Show More

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
Show Less

Competing Interests: None declared.