Chronic Cerebral Ischemia and Its Association with Normal Pressure Hydrocephalus

Academic Background

Normal Pressure Hydrocephalus (NPH) is a potentially reversible dementia characterized by cognitive impairment, gait disturbance, and urinary incontinence. Despite only a mild increase in intracranial pressure (ICP, approximately 15 mmHg), patients with NPH experience impaired cerebral blood flow (CBF) and neurological function. For a long time, scientists believed that cerebral autoregulation (CA) could stabilize CBF in response to elevated ICP. However, this view contradicts the complex pathogenesis of NPH, which includes components of chronic cerebral ischemia due to mild increases in ICP. This phenomenon has not been fully supported by clinical evidence.

This study aims to explore how venous compression leads to chronic cerebral ischemia in NPH patients and to reveal the role of cerebral autoregulation in NPH. By investigating ICP, CBF, and cerebral oxygenation in NPH patients, the research team hopes to fill the missing link between impaired cerebrospinal fluid (CSF) circulation and CBF impairment in the pathogenesis of NPH.

Source of the Paper

This paper was authored by a team including Tomohisa Ohmura and Yoshinaga Kajimoto from Osaka Medical and Pharmaceutical University, Japan, and published in 2025 in the journal Fluids and Barriers of the CNS. The research was partially funded by the Japan Society for the Promotion of Science.

Research Process and Results

1. Study Subjects and Experimental Design

The study included 21 NPH patients (15 males, 6 females, mean age 61.9 years) who underwent ventriculoperitoneal shunt (VPS) surgery. These patients showed symptom improvement after shunt surgery. The research team measured postoperative ICP by puncturing the Ommaya reservoir and monitored cerebral oxygenation data (e.g., regional cerebral oxygen saturation, rSO2) using near-infrared spectroscopy (NIRS).

2. ICP Measurement and Intermittent CSF Infusion Test

The research team measured ICP after shunt surgery to determine the pressure setting of the Codman-Hakim programmable valve. During the measurement, intermittent CSF infusion was performed to assess intracranial compliance and the relationship between CSF volume loading and ICP. A closed-circuit system was used to prevent infection.

3. Data Analysis and Results

Through NIRS monitoring, the research team found that as ICP (referenced to venous pressure, ICPvein) increased, oxygenated hemoglobin (Oxy-Hb) and total hemoglobin (Total-Hb) gradually decreased, while deoxygenated hemoglobin (Deoxy-Hb) began to increase at 2.5 mmHg. This phenomenon indicates that NPH patients enter a subcritical ischemic phase even with a mild increase in ICP.

The study also found that CSF volume loading caused ICP (referenced to the external auditory canal, ICPeac) to increase quadratically when exceeding 12 mL. Surprisingly, an ICPeac of only 10 mmHg was sufficient to shift the system into the subcritical ischemic phase. These results suggest that CBF impairment in NPH patients begins at very low ICP levels, indicating that cerebral autoregulation fails to adequately compensate for reduced venous blood flow in NPH.

4. Comparison of Different Types of NPH

The study further compared data between idiopathic NPH (iNPH) and secondary NPH (sNPH) patients. The results showed that iNPH patients entered the subcritical ischemic phase at a lower ICP (2.2 ± 1.6 mmHg) compared to sNPH patients (4.9 ± 2.5 mmHg). Additionally, iNPH patients exhibited higher intracranial compliance than sNPH patients.

5. Impact of White Matter Hyperintensities (DWMH)

The study also found that the severity of deep and subcortical white matter hyperintensities (DSWMHs) influenced the ICP threshold for entering the subcritical ischemic phase. Patients with severe DSWMHs entered the subcritical ischemic phase at significantly lower ICP levels compared to those with mild DSWMHs.

Conclusions and Significance

This study reveals the mechanism by which venous compression leads to chronic cerebral ischemia in NPH patients and fills the missing link between impaired CSF circulation and CBF impairment in the pathogenesis of NPH. The findings indicate that NPH patients enter a subcritical ischemic phase even with a mild increase in ICP, and shunt surgery can restore patients from this phase to a physiological phase, thereby improving neurological symptoms.

Furthermore, the study suggests that small vessel arteriosclerosis plays a significant role in the development of NPH and proposes a pathophysiological continuum between NPH and Binswanger disease (a dementia characterized by small vessel disease). These findings not only provide a new theoretical basis for the treatment of NPH but also offer important insights into similar conditions such as normal-tension glaucoma and chronic kidney disease.

Research Highlights

1. Key Finding: NPH patients enter a subcritical ischemic phase even with a mild increase in ICP, indicating that cerebral autoregulation fails to adequately compensate for reduced venous blood flow in NPH.
2. Innovative Method: The research team developed a new method for assessing intracranial compliance through intermittent CSF infusion and NIRS monitoring.
3. Clinical Significance: The results provide a new theoretical basis for the early diagnosis and treatment of NPH and offer important references for research on similar diseases.

Additional Valuable Information

The research team also proposed that the pathophysiological mechanisms of NPH may resemble those of normal-tension glaucoma and chronic kidney disease, where a mild increase in local pressure could also lead to chronic ischemia. This hypothesis opens new directions for future research.