Subthalamic Nucleus Activity during Cognitive Load and Gait Dysfunction in Parkinson's Disease.

BACKGROUND: Gait freezing is a common, disabling symptom of Parkinson's disease characterized by sudden motor arrest during walking. Adaptive deep brain stimulation devices that detect freezing and deliver real-time, symptom-specific stimulation are a potential treatment strategy. Real-time alterations in subthalamic nucleus firing patterns have been demonstrated with lower limb freezing, however, whether similar abnormal signatures occur with freezing provoked by cognitive load, is unknown. METHODS: We obtained subthalamic nucleus microelectrode recordings from eight Parkinson's disease patients performing a validated virtual reality gait task, requiring responses to on-screen cognitive cues while maintaining motor output. RESULTS: Signal analysis during 15 trials containing freezing or significant motor output slowing precipitated by dual-tasking demonstrated reduced θ frequency (3-8 Hz) firing compared to 18 unaffected trials. CONCLUSIONS: These preliminary results reveal a potential neurobiological basis for the interplay between cognitive factors and gait disturbances including freezing in Parkinson's disease, informing development of adaptive deep brain stimulation protocols. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Single Center Experience in Cerebrospinal Fluid Dynamics Testing.

Normal pressure hydrocephalus is more complex than a simple disturbance of the cerebrospinal fluid (CSF) circulation. Nevertheless, an assessment of CSF dynamics is key to making decisions about shunt insertion, shunt malfunction, and for further management if a patient fails to improve. We summarize our 25 years of single center experience in CSF dynamics assessment using pressure measurement and analysis. 4473 computerized infusion tests have been performed. We have shown that CSF infusion studies are safe, with incidence of infection at less than 1%. Raised resistance to CSF outflow positively correlates (p < 0.014) with improvement after shunting and is associated with disturbance of cerebral blood flow and its autoregulation (p < 0.02). CSF infusion studies are valuable in assessing possible shunt malfunction in vivo and for avoiding unnecessary revisions. Infusion tests are safe and provide useful information for clinical decision-making for the management of patients suffering from hydrocephalus.

Hitting the brakes: pathological subthalamic nucleus activity in Parkinson's disease gait freezing.

Gait freezing is a complex and devastating paroxysmal motor arrest commonly suffered in Parkinson's disease that causes significant impairment to mobility, commonly resulting in falls and subsequent injury. The neurobiological basis of gait freezing in Parkinson's disease is poorly understood and thus, currently available therapies are partially effective at best. We used a validated virtual reality gait paradigm to elicit freezing behaviour intraoperatively in eight patients undergoing subthalamic nucleus deep brain stimulation surgery while microelectrode recordings were obtained. This allowed us to directly test the hypothesis that increases in pathological multi-unit activity in the subthalamic nucleus are associated with freezing onset in real time, manifest as dysfunctional firing of lower limb muscles typical of freezing that were detected by EMG. We present evidence that freezing is related to transient increases in pathological subthalamic nucleus activity. We performed time-frequency analysis to characterize the oscillatory dynamics of subthalamic nucleus activity coincident with freezing onset, demonstrating an increase in pathological beta and theta rhythms that are followed by a temporal chain of activity culminating in characteristically abnormal lower limb muscle firing detected by EMG. Finally, we interrogate the potential clinical utility of our findings by contrasting the subthalamic nucleus activity signature during pathological freezing against purposeful stopping. These results advance our understanding of the neurobiological basis of gait freezing in Parkinson's disease, highlighting the role of the subthalamic nucleus and emergent synchronous activity in basal ganglia circuits in driving non-purposeful motor arrests in individuals with Parkinson's disease. Pathological subthalamic nucleus activity identified in association with freezing is discernible from that of volitional stopping, paving the way towards more effective therapeutics such as adaptive closed-loop deep brain stimulation protocols.

Documenting the process of developing the Victorian voluntary assisted dying legislation.

Many countries across the world have legislated for their constituents to have control over their death. Commonalities and differences can be found in the regulations surrounding the shape and practices of voluntary assisted dying (VAD) and euthanasia, including an individual's eligibility and access, role of health professions and the reporting. In Australia there have been perennial debates across the country to attempt legislative change in assisting a terminally ill person to control the ending of their life. In 2017, Victoria became the first state to successfully legislate for VAD. In describing the Victorian process that led to the passage of legislation for VAD, this paper examines the social change process. The particular focus of the paper is on the vital role played by a multidisciplinary ministerial advisory panel to develop recommendations for the successful legislation, and is written from their perspective.

Clinical outcomes in the surgical treatment of idiopathic normal pressure hydrocephalus.

Idiopathic normal pressure hydrocephalus (INPH) is a syndrome of gait disturbance, dementia and urinary incontinence. Outcomes after ventriculoperitoneal shunting for INPH are variable due to a lack of reliable, quantitative outcome data and inconsistent methods of selecting shunt candidates. The aim of this retrospective cohort study was to assess objective and quantitative clinical outcomes of ventriculoperitoneal shunting for INPH. From 2008 to 2013, consecutive patients diagnosed with INPH based on clinical and radiological criteria were included in this single-centre study. All patients received programmable-valve ventriculoperitoneal shunts. Outcome measures were assessed at baseline, 3, 6 and 12months post-operatively. Outcomes included gait time and scores on the Unified Parkinson's Disease Rating Scale part III (UPDRS-III), the Addenbrooke's Cognitive Examination Revised (ACE-R) and the Mini-Mental State Examination (MMSE). Thresholds for improvements were set a priori as ⩾20% decrease in gait time, ⩾10point decrease in UPDRS-III score, ⩾5point increase in ACE-R score and ⩾2point increase in MMSE score at last follow-up. The proportion of patients improving varied between measures, being gait time (60%), UPDRS-III (69%), MMSE (63%), and ACE-R (56%). Overall, improvement in at least one outcome measure was observed in 85% of patients and 38% improved in gait time, UPDRS-III score and cognitive scores. Only 15% of patients experienced no improvement on any measure. This study demonstrates that the majority of INPH patients can sustain improvements in multiple symptoms up to 12months after shunting.

A Review of Clinical Outcomes for Gait and Other Variables in the Surgical Treatment of Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Idiopathic normal pressure hydrocephalus (INPH) is a treatable cause of gait disturbance, cognitive impairment, and urinary incontinence. This clinical triad of symptoms occurs in association with ventriculomegaly and normal cerebrospinal fluid (CSF) pressure. Although the treatment outcomes after CSF shunting for INPH have improved significantly since its first description in 1965, shortcomings in our understanding still remain. Not all INPH patients exhibit clinical improvement after shunting, and it is challenging to identify patients who are more likely to benefit from shunting. METHODS: The Cochrane Library, Medline, Embase, and PubMed databases were searched for English-language publications between 1965 and October 2015. Reference lists of publications were also manually searched for additional publications. RESULTS: The findings of this review indicate that, despite efforts to improve patient selection, the degree of clinical improvement after shunting continues to demonstrate significant variability both within and between studies. These discrepancies in treatment outcomes are the result of controversies in 3 distinct but interrelated domains: the underlying pathophysiology of INPH, the diagnosis of INPH, and the identification of likely shunt-responders. CONCLUSIONS: This review focuses on these 3 areas and their relation to surgical treatment outcomes. Despite the limitations of published outcome studies and limitations in our understanding of INPH pathophysiology, shunting is a safe and effective means of achieving meaningful clinical improvement in most patients with INPH.

Mobile pediatric neurosurgery: rapid response neurosurgery for remote or urgent pediatric patients.

OBJECT: Time-critical neurosurgical conditions require urgent operative treatment to prevent death or neurological deficits. In New South Wales/Australian Capital Territory patients' distance from neurosurgical care is often great, presenting a challenge in achieving timely care for patients with acute neurosurgical conditions. METHODS: A protocol was developed to facilitate consultant neurosurgery locally. Children with acute, time-critical neurosurgical emergencies underwent operations in hospitals that do not normally offer neurosurgery. The authors describe the developed protocol, the outcome of its use, and the lessons learned in the 9 initial cases where the protocol has been used. Three cases are discussed in detail. RESULTS: Nine children were treated by a neurosurgeon at 5 rural hospitals, and 2 children were treated at a smaller metropolitan hospital. Road ambulance, fixed wing aircraft, and medical helicopters were used to transport the Newborn and Paediatric Emergency Transport Service (NETS) team, neurosurgeon, and patients. In each case, the time to definitive neurosurgical intervention was significantly reduced. The median interval from triage at the initial hospital to surgical start time was 3:55 hours, (interquartile range [IQR] 03:29-05:20 hours). The median distance traveled to reach a patient was 232 km (range 23-637 km). The median interval from the initial NETS call requesting patient retrieval to surgical start time was 3:15 hours (IQR 00:47-03:37 hours). The estimated median "time saved" was approximately 3:00 hours (IQR 1:44-3:15 hours) compared with the travel time to retrieve the child to the tertiary center: 8:31 hours (IQR 6:56-10:08 hours). CONCLUSIONS: Remote urgent neurosurgical interventions can be performed safely and effectively. This practice is relevant to countries where distance limits urgent access for patients to tertiary pediatric care. This practice is lifesaving for some children with head injuries and other acute neurosurgical conditions.

Dramatic improvement of truncal tardive dystonia following globus pallidus pars interna deep brain stimulation.

Truncal predominant tardive dystonia is an uncommon presentation of dystonia, and may be associated with significant disability. We report a patient with near-complete resolution of severe, disabling truncal tardive dystonia following globus pallidus pars interna deep brain stimulation. Her unusual clinical presentation highlights the difficulties in diagnosing unusual forms of dystonia, and the therapeutic gains that can be achieved once the diagnosis is recognised.

Influence of comorbidities in idiopathic normal pressure hydrocephalus - research and clinical care. A report of the ISHCSF task force on comorbidities in INPH.

Idiopathic normal pressure hydrocephalus (INPH) is a syndrome of ventriculomegaly, gait impairment, cognitive decline and incontinence that occurs in an elderly population prone to many types of comorbidities. Identification of the comorbidities is thus an important part of the clinical management of INPH patients. In 2011, a task force was appointed by the International Society for Hydrocephalus and Cerebrospinal Fluid Disorders (ISHCSF) with the objective to compile an evidence-based expert analysis of what we know and what we need to know regarding comorbidities in INPH. This article is the final report of the task force. The expert panel conducted a comprehensive review of the literature. After weighing the evidence, the various proposals were discussed and the final document was approved by all the task force members and represents a consensus of expert opinions. Recommendations regarding the following topics are given: I. Musculoskeletal conditions; II. Urinary problems; III. Vascular disease including risk factors, Binswanger disease, and white matter hyperintensities; IV. Mild cognitive impairment and Alzheimer disease including biopsies; V. Other dementias (frontotemporal dementia, Lewy body, Parkinson); VI. Psychiatric and behavioral disorders; VII. Brain imaging; VIII. How to investigate and quantify. The task force concluded that comorbidity can be an important predictor of prognosis and post-operative outcome in INPH. Reported differences in outcomes among various INPH cohorts may be partly explained by variation in the rate and types of comorbidities at different hydrocephalus centers. Identification of comorbidities should thus be a central part of the clinical management of INPH where a detailed history, physical examination, and targeted investigations are the basis for diagnosis and grading. Future INPH research should focus on the contribution of comorbidity to overall morbidity, mortality and long-term outcomes.

Treating pediatric hydrocephalus in Australia: a 3-year hospital-based cost analysis and comparison with other studies.

OBJECT: The aim of this study was to quantify the financial costs of surgical intervention in patients with newly diagnosed hydrocephalus and patients with treatment failure or complications of previously treated hydrocephalus between 2007 and 2009 at the Children's Hospital at Westmead in Sydney, Australia. METHODS: This was a retrospective study of patients who underwent shunt insertion, shunt revision, treatment of an infected shunt, and endoscopic third ventriculostomy (ETV) between 2007 and 2009. Actual hospital costs associated with each inpatient stay were obtained from the accounting office of Children's Hospital at Westmead. Patients with hydrocephalus secondary to trauma, malignancy, or other complex conditions (except myelomeningocele) were excluded. RESULTS: Hydrocephalus-related procedures comprised approximately one-third of neurosurgical procedures performed each year. From 2007 to 2009, there were 192 admissions during which 300 procedures were performed for 162 patients. The total cost was $4.78 million (Australian) with an average cost of $1.59 million per year. The cost per admission for shunt insertion and ETV were similar ($13,905 vs $14,128, respectively). The average cost per admission for shunt revision was $9,753. However, shunt infection was associated with 40% of total costs, averaging $83,649 per admission. Management of patients with myelomeningocele undergoing insertion of shunt procedures in the same admission accounted for an average cost of $50,186. CONCLUSIONS: Hydrocephalus is a chronic condition that imposes a significant and growing economic burden upon the Australian hospital system. Seventy-five percent of hydrocephalus-related hospital expenditure is used to surgically treat patients for complications or failure of previously treated hydrocephalus. Further research into the economic impact of pediatric hydrocephalus on the Australian health care system and concerted research efforts in the area of effective long-term surgical treatment and complication minimization are essential.

Paediatric germ cell tumours of the central nervous system: Results and experience from a tertiary-referral paediatric institution in Australia.

A retrospective analysis was conducted on consecutive patients with intracranial germ cell tumours diagnosed and treated from 1 January 1997 to 31 December 2007 to assess and determine demographic factors and treatment outcomes of children with these tumours treated in a major paediatric referral hospital in Australia. In this study, intracranial germ cell tumours represented 4.8% of paediatric brain tumours seen. Of the 21 patients identified, 15 (71.4%) were diagnosed with pure germinoma and six (28.6%) with non-germinomatous germ cell tumours (NGGCT) or mixed tumours. One patient received chemotherapy alone, two patients were treated with radiation alone and the remaining 18 received a combination of chemotherapy and radiotherapy. A total of 33 neurosurgical operations were performed with 15 biopsies via open, endoscopic or transphenoidal means; nine open resections; and nine procedures for hydrocephalus comprising seven third ventriculostomies and two ventriculoperitoneal shunts. For patients with pure germinomas, the 5-year disease-free rate (DFS) was 93.3%, and overall survival (OS) rate was 100% compared to NGGCT or mixed tumours (DFS 50%; OS 50%) (DFS p=0.019, OS p=0.004). The data presented show that pure germinomas carry a favourable prognosis. The data also support that treatment with induction chemotherapy followed by dose-attenuated radiotherapy is an effective alternative with results comparable to historical controls treated with craniospinal irradiation. Although chemoradiotherapy has become the mainstay of treatment in intracranial germ cell tumours, surgery remains integral to the management of this condition. Surgery remains important in establishing the histological diagnosis, as well as in the treatment of hydrocephalus. Furthermore, debulking procedures may be advocated in NGGCT as they are often resistant to chemotherapy.

The role of venous sinus outflow obstruction in pediatric idiopathic intracranial hypertension.

OBJECT: The authors examined the role of venous sinus obstruction in the etiology of idiopathic intracranial hypertension (IIH) by reviewing more than 200 MR venograms performed in suspected cases of IIH. METHODS: Individual MR venograms performed in cases of suspected IIH at the Children's Hospital at Westmead in Sydney, Australia, were reviewed. The authors excluded cases in which an intervention was performed before the scan or a structural cause for venous obstruction was identified. Cases with confirmed hydrocephalus were also excluded. For each of the 145 remaining scans, the authors completed a detailed review on a slice-by-slice basis of the 2D source images used to compile the rendered 3D MR venogram. The anatomical configuration of the dural venous sinuses and any areas of decreased flow in circulation were then noted. Where possible, they correlated their radiological findings with evidence of raised intracranial pressure based on LP opening pressures. They also reviewed a control group of 50 MR venograms. RESULTS: Seventy-six (52%) of 145 scans showed evidence of venous obstruction in the dominant-side circulation. Substantial nonphysiological collateral circulation was seen in 68% of cases with dominant-sided obstruction, suggesting a process of recanalization. In contrast, in the absence of dominant-sided obstruction, collateral circulation was uncommon. In 27 cases, CSF opening pressure measurements were available. In 20 cases the opening pressures were in excess of 20 cm H(2)O. Of those, 17 demonstrated evidence of dominant-sided venous outflow obstruction. Among those cases, the median opening pressure was 34 cm H(2)O. Dominant-sided venous outflow obstruction was seen in only 2 of 50 MR venograms in the control group. Furthermore, evidence of collateral circulation was also uncommon in the control group. There was a highly statistically significant difference between rates of dominant-sided venous obstruction in the suspected IIH and control groups (p ≤ 0.001). CONCLUSIONS: A majority of patients presenting for investigation of suspected IIH demonstrated evidence of dominant-sided venous obstruction on MR venogram. In addition there was a high correlation between elevated CSF opening pressures and dominant-sided venous sinus obstruction. This correlation was further supported by evidence of collateral recanalization in patients with elevated CSF pressures and dominant-sided venous obstruction. A control group of 50 MR venograms indicated that dominant-sided venous outflow obstruction is an unlikely incidental finding, and a highly statistically significant difference was found between rates of obstruction in the suspected IIH and control groups.

Expression of AQP1 and AQP4 in paediatric brain tumours.

Aquaporins (AQP) are water-channel proteins with roles in tumour cell migration, angiogenesis, cerebral oedema and cell-cell adhesion. We aimed to determine the expression of AQP1 and AQP4 in paediatric brain tumours. Twenty tumour bank specimens were subject to Western blot analysis and quantitative polymerase chain reaction (PCR) to determine the expression of AQP1 and 4. Immunohistochemical staining was used to determine the distribution of AQP1 and 4 expression. Medulloblastomas, primitive neuroectodermal tumour, germinomas and higher grade gliomas did not express AQP1 and 4. Of the ependymomas, those in the posterior fossa all demonstrated markedly increased expression of AQP1 and 4. A supratentorial ependymoma demonstrated a moderate increase in AQP1 but not AQP4. Pilocytic astrocytomas demonstrated high levels of AQP1 and 4 but had a more variable pattern of staining. AQP1 and 4 have relevance to paediatric brain tumours and are worthy of further investigation in developing potential therapeutic strategies.

Altered cellular localization of aquaporin-1 in experimental hydrocephalus in mice and reduced ventriculomegaly in aquaporin-1 deficiency.

Hydrocephalus is a pathological accumulation of cerebrospinal fluid (CSF) in the cerebral ventricles that constitutes a significant cause of neurological morbidity and mortality. Surgical treatment involving shunt placement is associated with a high failure rate and complications due to infection, motivating the development of alternative, non-surgical therapies. Here, we investigated the role in hydrocephalus of water channel aquaporin-1 (AQP1), which is expressed at the apical membrane of choroid plexus epithelium and is believed to facilitate CSF production. AQP1 expression and subcellular localization were studied in a kaolin-induced hydrocephalus model in mice and the effect AQP1 deficiency on the severity of hydrocephalus was determined. While total choroidal AQP1 protein was not significantly altered in hydrocephalus, ~50% of AQP1 protein was redistributed from the apical membrane to intracellular vesicles. We found that the ventricular size in AQP1-deficient mice was smaller than in wild-type mice, both at baseline and following hydrocephalus. The reduced plasma membrane AQP1 localization following kaolin-induced hydrocephalus, which involves endocytosis, may be a compensatory mechanism to reduce CSF secretion. The reduced ventricular size in AQP1-deficient mice following kaolin-induced hydrocephalus suggests AQP1 inhibition or down-regulation as a potential adjunctive treatment for hydrocephalus.

Metachronous multifocal desmoid-type fibromatoses along the neuraxis with adenomatous polyposis syndrome.

Desmoid-type fibromatosis, aggressive fibromatosis, or desmoid tumor is an uncommon benign but locally aggressive fibroblastic lesion. Although intraabdominal desmoid-type fibromatoses are well described in association with adenomatous polyposis syndrome, their occurrence along the neuraxis is extremely rare. The authors report the case of a 14-year-old boy with metachronous intracranial and spinal desmoid-type fibromatoses with preceding medulloblastoma. He was ultimately diagnosed with adenomatous polyposis syndrome. This is the first reported case of spinal desmoid-type fibromatosis in association with adenomatous polyposis syndrome. The identification of an underlying genetic instability allows for screening to detect lesions and institute measures to avoid preventable mortality from nonneurological tumors.