Reply To: Ventriculomegaly in Prodromal Idiopathic Normal Pressure Hydrocephalus?

We thank Onder and colleagues ¹ for their interest and valuable comments on our recent article reporting longitudinal clinicoradiological data of patient with idiopathic normal pressure hydrocephalus (iNPH) for 16 years before diagnosis. ² We fully agree with their perspectives and would like to clarify and further expand on the topics presented.

Precise diagnosis in the early phase of the disease is essential for improving treatment outcomes of iNPH. However, as Onder et al ¹ pointed out, the triad symptoms of iNPH are common among the elderly population, and the diagnosis of iNPH is sometimes difficult in the early phase, especially for non‐neurologist physicians. Our patient ² was aware of frequent urination and decreased walking speed 6 to 7 years before the diagnosis of iNPH. He underwent annual structured health interviews and checkups by general physicians at that time; however, no objective symptoms were noticed (the symptoms may be equivalent to grade 1 on the iNPH grading scale). In fact, subjective symptoms alone do not lead to a diagnosis of iNPH; however, the disproportionally enlarged subarachnoid‐space hydrocephalus (DESH) became prominent 1 year after the development of two subjective symptoms (ie, urinary dysfunction and gait abnormality) in our case. Therefore, it is possible that the combination of subjective symptoms is useful for the early diagnosis or prediction of iNPH.

The concept of “Asymptomatic ventriculomegaly with features of idiopathic normal pressure hydrocephalus (AVIM)” was proposed based on the results of a cohort study to identify individuals at high risk of developing iNPH. By the original definition, “AVIM” corresponds to a preclinical stage of iNPH, in which patients are objectively asymptomatic, but show DESH on magnetic resonance imaging (MRI). ³ Currently, DESH is considered to be the combination of “ventricular enlargement with an Evans index of >0.3” and “a narrowing of the subarachnoid space and cortical sulci at the high convexity of the cerebrum.” ⁴ Findings of DESH have significant diagnostic value for iNPH; however, it may take a long time to fully develop typical radiological features. The current case developed ventricular enlargement and high‐convexity tightness 13 and 3 years before diagnosis, ² respectively. It took 10 years to fully develop radiological features of DESH, and the period of AVIM in our case would be calculated as 3 years. These results suggest that there is a relatively long subjectively symptomatic period before the onset of AVIM, during which only ventriculomegaly is evident and does not meet the definition of DESH.

We believe that multiple subjective iNPH symptoms with ventriculomegaly may be the characteristics of the preclinical phase of iNPH and may herald the development of DESH. Once the clinical trajectory of subjective symptoms to DESH is elucidated, it may lead to the development of disease‐modifying therapies to prevent or delay the onset of iNPH. To verify this hypothesis, prospective studies with longer follow‐up periods focusing on subjective symptoms and DESH‐like imaging features, in addition, development of further reliable biomarkers are needed in future clinical settings.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript: A. Writing of the First Draft, B. Review and Critique.

T.T.: 1A, 1B, 1C, 2A, 2B

T.B.: 1A, 1B, 1C, 2A, 2B

K.N.: 1B, 1C, 2B

A.T.: 1B, 1C, 2B

Disclosures

Ethical Compliance Statement: This study was approved by the institutional review board (Reference number: R2‐6), and informed consent was obtained from the patient for publication of this case report and accompanying images. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: The authors declare that there are no conflicts of interest relevant to this work. This study was funded by Grants‐in Aid from the Research Committee of CNS Degenerative Diseases, Research on Policy Planning and Evaluation for Rare and Intractable Diseases, Health, Labour and Welfare Sciences Research Grants, The Ministry of Health Labour and Welfare, Japan.

Financial Disclosures for the Previous 12 Months: TB receives research grants from AbbVie Co. Ltd. and honoraria for lectures from Ono Pharmaceutical Co. Ltd., AbbVie Inc., Kyowa Kirin Co. Ltd., Sumitomo Pharma, Takeda Pharma, Otsuka Pharma and Eizai Co. Ltd. AT receives scholarship funds from AbbVie Inc., Eisai Co. Ltd., Kyowa Kirin Co. Ltd., Sumitomo Pharma Co. Ltd., consulting fees from AbbVie Inc., Kyowa Kirin Co. Ltd., Ono Pharmaceutical Co. Ltd., Sony Co., honoraria from AbbVie Inc., Eisai Co. Ltd., Ono Pharmaceutical Co. Ltd., Kyowa Kirin Co. Ltd., Sumitomo Pharma Co. Ltd. and Takeda Pharmaceutical Co. Ltd.