In vivo assessment of the ocular biomechanical properties in patients with idiopathic normal pressure hydrocephalus.

PURPOSE: Idiopathic normal pressure hydrocephalus (iNPH) is associated with an increased prevalence of open-angle glaucoma, attributed to variations of the pressure gradient between intraocular and intracranial compartments at the level of the lamina cribrosa (LC). As ocular biomechanics influence the behavior of the LC, and a lower corneal hysteresis (CH) has been associated to a higher risk of glaucomatous optic nerve damage, in this study we compared ocular biomechanics of iNPH patients with healthy subjects. METHODS:  Twenty-four eyes of 24 non-shunted iNPH patients were prospectively recruited. Ocular biomechanical properties were investigated using the ocular response analyzer (Reichert Instruments) for the calculation of the CH, corneal resistance factor (CRF), Goldmann-correlated intraocular pressure (IOPg), and corneal-compensated intraocular pressure (IOPcc). Results were compared with those of 25 eyes of 25 healthy subjects. RESULTS:  In iNPH eyes, the median CH value and interquartile range (IQR) were 9.7 mmHg (7.8-10) and 10.6 mmHg (9.3-11.3) in healthy controls (p = 0.015). No significant differences were found in IOPcc [18.1 mmHg (14.72-19.92) vs. 16.4 mmHg (13.05-19.6)], IOPg [15.4 mmHg (12.82-19.7) vs. 15.3 mmHg (12.55-17.35)], and CRF [9.65 mmHg (8.07-11.65) vs. 10.3 mmHg (9.3-11.5)] between iNPH patients and controls. CONCLUSIONS:  In iNPH patients, the CH was significantly lower compared to healthy subjects. This result suggests that ocular biomechanical properties may potentially contribute to the risk of development of glaucomatous optic nerve damage in iNPH patients.

Choroidal morphology and microvascular structure in eyes of patients with idiopathic normal pressure hydrocephalus before and after ventriculo-peritoneal shunt surgery.

The present study aims to investigate the choroidal morphology and microvascular structure in eyes of patients with idiopathic normal pressure hydrocephalus (iNPH) compared with the eyes of healthy age-matched individuals, and to assess the choroidal structure in eyes of iNPH patients before and after shunt surgery using Optical Coherence Tomography (OCT). The primary objective was to assess the choroidal morphology in eyes of iNPH patients before and after ventriculo-peritoneal (VP) surgery compared to age and sex-matched healthy individuals. The secondary objective was to compare the choroidal morphology of iNPH patients before and after a mean of 56 days from shunt surgery. Eighteen consecutive patients diagnosed with iNPH and 18 healthy controls were prospectively recruited between November 2021 and October 2022. Spectral-domain optical coherence tomography (SD-OCT) with enhanced depth imaging (EDI) was conducted before and within 4 months after shunt surgery. Images were binarized using the ImageJ software, and the choroidal vascular index (CVI) was calculated. Sub-foveal choroidal thickness (SFCT), total choroidal area (TCA), luminal choroidal area (LCA), and stromal choroidal area (SCA) were significantly increased in iNPH patients before surgery compared to the control group (p < 0.05). SFCT, TCA, and SCA were significantly increased in iNPH patients after surgery compared to the control group (p < 0.05). There were no differences in the CVI between iNPH patients and controls. No statistical differences in the choroidal structure were observed before and after VP shunt surgery (p > 0.05). In conclusion, the choroid was thicker in iNPH patients before and after VP shunt compared to age-matched healthy individuals. However, there were no difference in the choroidal microstructure in the eyes of iNPH patients before and after a mean of 3 months from VP shunt surgery.

Gait Apraxia and Hakim's Disease: A Historical Review.

In 1965, Prof. Salomón Hakim described, for the first time, a condition characterized by normal pressure hydrocephalus and gait alterations. During the following decades, definitions such as "Frontal Gait", "Bruns' Ataxia" and "Gait Apraxia" have been frequently used in pertinent literature in the attempt to best define this peculiar motor disturbance. More recently, gait analysis has further shed light on the typical spatiotemporal gait alterations that characterize this neurological condition, but a clear and shared definition of this motor condition is still lacking. In this historical review, we described the origins of the terms "Gait Apraxia", "Frontal Gait" and "Bruns' Ataxia", starting with the first works of Carl Maria Finkelburg, Fritsch and Hitzig and Steinthal during the second half of the 19th century and ending with Hakim's studies and his formal definition of idiopathic normal pressure hydrocephalus (iNPH). In the second part of the review, we analyze how and why these definitions of gait have been associated with Hakim's disease in the literature from 1965 to the present day. The definition of "Gait and Postural Transition Apraxia" is then proposed, but fundamental questions about the nature and mechanisms underlying this condition remain unanswered.

INPH and parkinsonism: A positive shunt response with a negative tap test.

Introduction: The aim of this study was to compare clinical and functional performances of idiopathic normal pressure hydrocephalus (INPH) patients with and without parkinsonism at the initial evaluation, 72 h after the cerebrospinal fluid tap test (CSF TT), and 6 months after ventriculoperitoneal shunt (VPS) surgery. Materials and methods: This is an observational prospective study on patients with INPH who underwent VPS. Patients were classified into INPH with parkinsonism (INPH-P+) and without parkinsonism (INPH-P-). We used the time up and go (TUG) test, Tinetti Performance-Oriented Mobility Assessment (POMA) test, INPH grading scale (INHPGS), and modified Rankin scale (mRS) at baseline, 72 h after CSF TT, and 6 months after VPS surgery. Results: A total of 64 patients with probable INPH were included, 12 patients with INPH-P+ and 52 controls with INPH-P-. Patients with INPH showed significant improvement in all clinical and neurological parameters after VPS including TUG, Tinetti POMA, INPHGS, and mRS (p < 0.001) with the exception of mRS where there was no significant change 72 h after CSF TT compared to baseline for patients with INPH (p = 0.182). Patients with INPH-P+ performed significantly worse than patients with INPH-P- on Tinetti POMA and mRS at baseline, at 72 h post-CSF TT, and at 6 months post-VPS with INPHGS being worst at 72 h post-CSF TT. There was no difference between patients with INPH-P+ and patients with INPH-P- for TUG at baseline (p = 0.270), at 72 h post-CSF TT (p = 0.487), and at 6 months post-VPS (p = 0.182). Patients with INPH-P+ did not show any change in any of the parameters at 72 h post-CSF TT compared to baseline; however, there was a trend toward improvement on TUG (p = 0.058), Tinetti gait (p = 0.062), and Tinetti total (p = 0.067). INPH-P+ significantly improved in all parameters 6 months post-VPS compared to baseline except for mRS (p = 0.124). Patients with INPH-P- significantly improved in all parameters at 72 h post-CSF TT and at 6 months post-VPS compared to baseline, respectively, except on mRS 72 h after CSF TT (p = 0.299). Conclusion: Patients with INPH and parkinsonism overall do worse than patients without parkinsonism. An unsatisfying response to the CSF tap test in INPH patients with parkinsonism should not be used as an exclusion criterion from VPS surgery since patients with and without parkinsonism showed significant improvement post-VPS.

In vivo assessment of Lewy body and beta-amyloid copathologies in idiopathic normal pressure hydrocephalus: prevalence and associations with clinical features and surgery outcome.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a clinico-radiological syndrome of elderly individuals likely sustained by different neurodegenerative changes as copathologies. Since iNPH is a potentially reversible condition, assessing neurodegenerative pathologies in vitam through CSF biomarkers and their influence on clinical features and surgical outcome represents crucial steps. METHODS: We measured α-synuclein seeding activity related to Lewy body (LB) pathology by the real-time quaking-induced conversion assay (RT-QuIC) and Alzheimer disease core biomarkers (proteins total-tau, phospho-tau, and amyloid-beta) by immunoassays in the cerebrospinal fluid (CSF) of 293 iNPH patients from two independent cohorts. To compare the prevalence of LB copathology between iNPH participants and a control group representative of the general population, we searched for α-synuclein seeding activity in 89 age-matched individuals who died of Creutzfeldt-Jakob disease (CJD). Finally, in one of the iNPH cohorts, we also measured the CSF levels of neurofilament light chain protein (NfL) and evaluated the association between all CSF biomarkers, baseline clinical features, and surgery outcome at 6 months. RESULTS: Sixty (20.5%) iNPH patients showed α-synuclein seeding activity with no significant difference between cohorts. In contrast, the prevalence observed in CJD was only 6.7% (p = 0.002). Overall, 24.0% of iNPH participants showed an amyloid-positive (A+) status, indicating a brain co-pathology related to Aß deposition. At baseline, in the Italian cohort, α-synuclein RT-QuIC positivity was associated with higher scores on axial and upper limb rigidity (p = 0.003 and p = 0.011, respectively) and lower MMSEc scores (p = 0.003). A+ patients showed lower scores on the MMSEc (p = 0.037) than A- patients. Higher NfL levels were also associated with lower scores on the MMSEc (rho = -0.213; p = 0.021). There were no significant associations between CSF biomarkers and surgical outcome at 6 months (i.e. responders defined by decrease of 1 point on the mRankin scale). CONCLUSIONS: Prevalent LB- and AD-related neurodegenerative pathologies affect a significant proportion of iNPH patients and contribute to cognitive decline (both) and motor impairment (only LB pathology) but do not significantly influence the surgical outcome at 6 months. Their effect on the clinical benefit after surgery over a more extended period remains to be determined.

Gait apraxia evaluation in normal pressure hydrocephalus using inertial sensors. Clinical correlates, ventriculoperitoneal shunt outcomes, and tap-test predictive capacity.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a neurological condition with gait apraxia signs from its early manifestation. Ventriculoperitoneal shunt (VPS) is a surgical procedure available for treatment. The Cerebrospinal fluid Tap Test (CSF-TT) is a quick test used as selection criterion for VPS treatment. Its predictive capacity for VPS outcomes is still sub judice. This study is aimed to test the hypothesis that wearable motion sensors provide valid measures to manage iNPH patients with gait apraxia. METHODS: Forty-two participants of the Bologna PRO-Hydro observational cohort study were included in the analyses. The participants performed the Timed Up and Go (TUG) and the 18 m walking test (18mW) with inertial sensors at baseline, three days after the CSF-TT, and six months after VPS. 21 instrumental variables described gait and postural transitions from TUG and 18mW recordings. Furthermore, participants were clinically assessed with scales (clinical variables). We tested the hypothesis by analysing the concurrent validity of instrumental and clinical variables, their individual- and group-level responsiveness to VPS, and their predictive validity for VPS outcomes after CSF-TT. RESULTS: The instrumental variables showed moderate to high correlation with the clinical variables. After VPS, most clinical and instrumental variables showed statistically significant improvements that reflect a reduction of apraxic features of gait. Most instrumental variables, but only one clinical variable (i.e., Tinetti POMA), had predictive value for VPS outcomes (significant adjusted R2 in the range 0.12-0.70). CONCLUSIONS: These results confirm that wearable inertial sensors may represent a valid tool to complement clinical evaluation for iNPH assessment and prognosis.

The Role of Simultaneous Medical Conditions in Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a chronic neurologic syndrome that affects the elderly population in a context of concomitant medical conditions. The aim of this study was to understand the significance of comorbidities using 4 validated and specific clinical scores: Cumulative Illness Rating Scale (CIRS), American Society of Anesthesiologists (ASA) score, Comorbidity Index (CMI), and Charlson Comorbidity Index (CCI). METHODS: From 2015 until 2019, the Bologna PRO-Hydro multidisciplinary team selected 63 patients for shunt surgery. All comorbidity scores were collected during preoperative anesthesia evaluation. Positive shunt response was defined as an improvement in overall disability (assessed with modified Rankin Scale [mRS]), in risk of fall (assessed with Tinetti Permormance Orientated Mobility Assessment, Tinetti) and in INPH specific symptoms (assessed with INPH Grading Scale, INPHGS). RESULTS: Patients with elevated values of CIRS had worse performance in gait and balance at Tinetti scale, both before (P = 0.039) and after surgery (P = 0.005); patients with high values of CMI had inferior values of Tinetti at baseline (P = 0.027) and higher mRS after surgery (P = 0.009); ASA 2 patients had better postoperative Tinetti scores than ASA 3 patients (P = 0.027). A positive or negative shunt response was not significantly correlated with patients' preoperative comorbidity scores. CONCLUSIONS: Patients with multiple comorbidities have a worse preoperative condition compared to patients with less concomitant diseases, and the proposed comorbidity scores, CIRS in particular, are useful clinical tools for the anesthesiologist. Comorbidities, though, do not impact overall postoperative outcome.

Anterior callosal angle correlates with gait impairment and fall risk in iNPH patients.

BACKGROUND: In idiopathic normal pressure hydrocephalus (iNPH), gait and balance impairment is the most frequent symptom, and it is often associated with a higher fall risk. In a prior study, the anterior callosal angle (ACA) was validated as a reliable marker to discriminate iNPH from Alzheimer's disease and healthy controls. However, the potential correlation between the ACA with clinical symptoms and functional outcomes has not been assessed. The objective of this study is to determine the utility of the ACA in predicting gait improvement after ventriculoperitoneal (VP) shunting. METHODS: Patients with probable iNPH who underwent shunt placement at a single institution were prospectively enrolled from May 2015 to May 2019. Patients were assessed preoperatively and at 6 months postoperatively following a standard clinical and MRI protocol. Callosal angle (CA) and ACA were calculated from 3 T MRI preoperatively and at 6 months postoperatively. CA and ACA were tested for correlation with clinical scores. RESULTS: Forty-seven patients with probable INPH who completed 6-month postoperative follow-up were enrolled in the study. Baseline ACA was significantly correlated with preoperative fall risk, gait, and balance impairment assessed with Tinetti POMA scale. Additionally, baseline ACA differentiated patients who experienced improvement at Tinetti POMA scale after surgery. CONCLUSIONS: The baseline ACA is a useful neuroradiological marker to differentiate patients by fall risk and has significant correlation with the improvement in gait and balance impairment following surgery. This study demonstrated that the ACA may be a complementary tool to the CA in predicting shunt responsiveness in iNPH.

Anterior Callosal Angle: A New Marker of Idiopathic Normal Pressure Hydrocephalus?

OBJECTIVE: Diagnosing idiopathic normal pressure hydrocephalus (iNPH) still remains a clinical challenge. The callosal angle (CA) is a widely used neuroradiologic marker for iNPH. However, the relationship of the CA to clinical features has not been well investigated. We hypothesize that iNPH symptoms might better correlate with a variant of the CA (anterior callosal angle [ACA]). We aim to establish the validity of the ACA measurement for the diagnosis of iNPH and compare it with current radiologic parameters. METHODS: The multidisciplinary BOLOGNA PRO-HYDRO Study Group performed a retrospective review of consecutive iNPH patients. Magnetic resonance imaging studies for these patients were collected, as well as magnetic resonance imaging studies from Alzheimer disease and healthy control patients. The CA, ACA, and Evans Index were measured by 2 blinded members of the study team based on magnetic resonance images for each of these populations. RESULTS: The ACA shows high accuracy, sensitivity, and specificity in distinguishing iNPH patients from healthy control and Alzheimer disease patients. The optimal pathologic diagnostic cut-off value for the ACA is 119 degrees. The diagnostic accuracy of the ACA is not significantly different from the CA. CONCLUSIONS: The ACA could be a valid radiologic parameter in the diagnostic armamentarium for iNPH.

The effects of cerebrospinal fluid tap-test on idiopathic normal pressure hydrocephalus: an inertial sensors based assessment.

BACKGROUND: Gait disturbances are typical of persons with idiopathic normal pressure hydrocephalus (iNPH) without signs distinctive from other neurodegenerative and vascular conditions. Cerebrospinal fluid tap-test (CSF-TT) is expected to improve the motor performance of iNPH patients and is a prognostic indicator in their surgical management. This observational prospective study aims to determine which spatio-temporal gait parameter(s), measured during instrumented motor tests, and clinical scale(s) may provide a relevant contribution in the evaluation of motor performance pre vs. post CSF-TT on iNPH patients with and without important vascular encephalopathy. METHODS: Seventy-six patients (20 with an associated vascular encephalopathy) were assessed before, and 24 and 72 h after the CSF-TT by a timed up and go test (TUG) and an 18 m walking test (18 mW) instrumented using inertial sensors. Tinetti Gait, Tinetti Balance, Gait Status Scale, and Grading Scale were fulfilled before and 72 h after the CSF-TT. Stride length, cadence and total time were selected as the outcome measures. Statistical models with mixed effects were implemented to determine the relevant contribution to response variables of each quantitative gait parameter and clinical scales. RESULTS AND CONCLUSION: From baseline to 72 h post CSF-TT patients improved significantly by increasing cadence in 18 mW and TUG (on average of 1.7 and 2.4 strides/min respectively) and stride length in 18 mW (on average of 3.1 cm). A significant reduction of gait apraxia was reflected by modifications in double support duration and in coordination index. Tinetti Gait, Tinetti Balance and Gait Status Scale were able to explain part of the variability of response variables not covered by instrumental data, especially in TUG. Grading Scale revealed the highest affinity with TUG total time and cadence when considering clinical scales alone. Patients with iNPH and an associated vascular encephalopathy showed worst performances compared to pure iNPH but without statistical significance. Gait improvement following CSF-TT was comparable in the two groups. Overall these results suggest that, in order to augment CSF-TT accuracy, is key to assess the gait pattern by analyzing the main spatio-temporal parameters and set post evaluation at 72 h. TRIAL REGISTRATION: Approved by ethics committee: CE 14131 23/02/2015.

A prospective evaluation of clinical and instrumental features before and after ventriculo-peritoneal shunt in patients with idiopathic Normal pressure hydrocephalus: The Bologna PRO-Hydro study.

INTRODUCTION: Idiopathic Normal Pressure Hydrocephalus (iNPH) is a complex and often misdiagnosed syndrome, whose major challenge is to identify which patients will benefit from surgery. Previous studies reported a variability in positive surgery response. The role of tap test(TT) in screening patients suitable for shunting is controversial. The primary aim of this study was to describe the clinical/instrumental features and their longitudinal progression after surgery in iNPH patients. Secondarily, we aimed to investigate the response of the three iNPH domains and the best time of outcome assessment after TT. METHODS: Patients compatible with iNPH underwent a 3-T-MRI and an inpatients program with TT including standardized clinical evaluations, neuropsychological assessments and instrumental gait analysis pre- and after-(24-h and 72-h) TT. The multidisciplinary team selected candidates for surgery. Patients were evaluated 6- and 12-months after surgery. RESULTS: A total of 154 consecutive patients were included from 2015 to 2018, 76 with an iNPH diagnosis (43 underwent surgery, 35 were evaluated after 6-months). Clinical and instrumented quantitative gait measures and urinary symptoms improved over time along with some neuropsychological functions. Concerning pre- and post-TT analyses, the three iNPH domains showed a different response after TT, the delayed motor assessment was more appropriate than the early one and the instrumental measures highlighted the motor improvement. CONCLUSION: iNPH patients improved after surgery, when accurately selected. A multidisciplinary team focused on this disease and a standardized protocol helped in achieving a correct diagnosis and management of iNPH. Our results could impact the management of this disease.

Revisiting the Cerebrospinal Fluid Biomarker Profile in Idiopathic Normal Pressure Hydrocephalus: The Bologna Pro-Hydro Study.

Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in idiopathic normal pressure hydrocephalus (iNPH) with the aim of a better differential diagnosis, but the pathophysiological mechanisms underlying CSF biomarker changes and the relationship between biomarker levels and clinical variables are still a matter of debate. We evaluated CSF amyloid-ß (Aß)42 and Aß40, total (t)-tau, phosphorylated (p)-tau, total prion protein (t-PrP), and neurofilament light chain protein (NfL) in healthy controls (n = 50) and subjects with iNPH (n = 71), Alzheimer's disease (AD) (n = 60), and several other subtypes of dementia (n = 145). Patients with iNPH showed significantly lower levels of Aß42, Aß40, t-tau, and p-tau compared to controls. Similarly, t-PrP values showed a trend toward lower levels in iNPH patients than in controls. At variance, NfL levels were increased in iNPH as in all other neurodegenerative dementias, with no significant difference between "pure" iNPH cases and those with vascular or AD comorbidities. The Aß42/Aß40 ratio showed higher diagnostic value than Aß42 alone in the differential diagnosis between iNPH and AD. There were no clinically relevant associations between neuroimaging markers, scores at clinical and cognitive scales/tests, or rates of response at tap test and CSF biomarker results. In summary, the CSF biomarker signature in patients with iNPH is mainly characterized by reduced CSF concentrations of Aß- and tau-related proteins. The assessment of CSF neurodegenerative biomarker profile in iNPH, including the Aß42/Aß40 ratio, contributes to the differential diagnosis with AD and other dementias but shows poor associations with clinical variables.

Usefulness of a Qualitative Ultrasound Evaluation of the Gastrocnemius-Soleus Complex with the Heckmatt Scale for Clinical Practice in Cerebral Palsy.

Ultrasound is increasingly used for the evaluation of spastic muscles in cerebral palsy. Increased echo intensity is considered indicative of a muscle fibrous involution. The aim of this study was to highlight any correlation between increased echo intensity of the gastrocnemius-soleus complex and clinical tests for stiffness evaluation, age and functional level measured with the Gross Motor Function Classification System. We used the qualitative echo intensity grading system of the Heckmatt scale (HS) and tested its inter-rater reliability. The study group comprised 60 patients with cerebral palsy. We found a weak significant correlation between HS scores and clinical stiffness measures and between HS and age for all muscles studied, and between the HS and Gross Motor Function Classification System only for the soleus muscle. The study indicated moderate inter-rater reliability, with κ values between 0.60 and 0.73, for almost all muscles studied. Ultrasound provides a useful complementary survey of stiffness tests in cerebral palsy.

Superficial siderosis associated with peripheral autonomic failure and tetraventricular hydrocephalus: a case report.

We describe the case of a man whose initial clinical presentation included sensorineural hearing loss and orthostatic hypotension. The patient was diagnosed with superficial siderosis associated with peripheral autonomic failure and tetraventricular hydrocephalus.