Amyotrophic lateral sclerosis established as a multistep process across phenotypes.

BACKGROUND AND PURPOSE: Given the accepted multistep process of disease causation in amyotrophic lateral sclerosis (ALS), the present study was undertaken to determine the number of steps required for disease onset across each of the ALS phenotypes. METHODS: Clinical and demographic data were prospectively accumulated using the Australian Motor Neurone Disease Registry (2005-2016), and age-specific incidence rates were calculated. Poisson regression was utilized to assess the relationship between log age-specific incidence and log age of onset, with McFadden's R2 used to assess the goodness of fit of the model. RESULTS: In total, 2647 ALS patients were included, with mean disease-onset age being 62.2 ± 12.1 years. A linear relationship between log incidence and log age was established across ALS phenotypes, with variable slope estimates: bulbar 5.1 (95% confidence interval [CI] 4.6-5.6); cervical 2.7 (95% CI 2.3-3.0); lumbar 3.5 (95% CI 3.2-3.9); flail arm 4.7 (95% CI 3.9-5.5); flail leg 3.6 (95% CI 2.6-4.5); primary lateral sclerosis 2.7 (95% CI 1.8-3.7). Slope estimates were significantly higher in the bulbar compared to the cervical, lumbar and primary lateral sclerosis phenotypes. McFadden's R2 values were >0.4 for all phenotypes indicating excellent model fit. DISCUSSION: A multistep process has been established across all ALS phenotypes with variable slope estimates, suggesting that the number of steps to develop disease is different across clinical presentations. Identification of mechanisms underlying slope estimate variability could exert pathophysiological significance.

Possible Influence of Ethnicity on CT Perfusion Parameter Thresholds in Acute Ischemic Stroke.

Introduction Tissue at risk, as estimated by CT perfusion utilizing Tmax+6, correlates with final infarct volume (FIV) in acute ischemic stroke (AIS) without reperfusion. Tmax thresholds are derived from Western ethnic populations but not from ethnic Asian populations. We aimed to investigate the influence of ethnicity on Tmax thresholds. Methods From a clinical-imaging registry of Australian and Indonesian stroke patients, we selected a participant subgroup with the following inclusion criteria: AIS under 24 hours and absence of reperfusion therapy. Clinical data included demographics, time metrics, stroke severity, premorbid, and 3-month Modified Rankin Score. Baseline CTP and MRI <72 hours were performed. Volumes of Tmax utilizing different thresholds and final infarct volumes (FIV) were calculated. Spearman correlation was used to evaluate relationship involving ordinal variables and calculate the optimal Tmax threshold against FIV in both populations. Results Two hundred patients were included in the study sample 100 in Jakarta and 100 in Geelong. The median National Institutes Health Stroke Scale (IQR) were 6(3-11) and 3(1-5), respectively. The median Tmax+6(IQR) was 0 (0-46.5) in Jakarta group and 0(0-7.5) in Geelong group. The median FIV(IQR) was 0 (0-30.5) and 0 (0-5.5). Tmax +8s in Jakarta population against FIV showed Spearman's coefficient =0.72, representing the optimal Tmax threshold. Tmax+6s showed Spearman's coefficient =0.51 against FIV in the Geelong population. Conclusions Tmax thresholds approximating FIV were possibly different in the Asian when compared with the non-Asian populations. Future studies are required to extend and confirm the validity of our findings.

Magnetic Resonance Iron Imaging in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) results in progressive impairment of upper and lower motor neurons. Increasing evidence from both in vivo and ex vivo studies suggest that iron accumulation in the motor cortex is a neuropathological hallmark in ALS. An in vivo neuroimaging marker of iron dysregulation in ALS would be useful in disease diagnosis and prognosis. Magnetic resonance imaging (MRI), with its unique capability to generate a variety of soft tissue contrasts, provides opportunities to image iron distribution in the human brain with millimeter to sub-millimeter anatomical resolution. Conventionally, MRI T1-weighted, T2-weighted, and T2*-weighted images have been used to investigate iron dysregulation in the brain in vivo. Susceptibility weighted imaging has enhanced contrast for para-magnetic materials that provides superior sensitivity to iron in vivo. Recently, the development of quantitative susceptibility mapping (QSM) has realized the possibility of using quantitative assessments of magnetic susceptibility measures in brain tissues as a surrogate measurement of in vivo brain iron. In this review, we provide an overview of MRI techniques that have been used to investigate iron dysregulation in ALS in vivo. The potential uses, strengths, and limitations of these techniques in clinical trials, disease diagnosis, and prognosis are presented and discussed. We recommend further longitudinal studies with appropriate cohort characterization to validate the efficacy of these techniques. We conclude that quantitative iron assessment using recent advances in MRI including QSM holds great potential to be a sensitive diagnostic and prognostic marker in ALS. The use of multimodal neuroimaging markers in combination with iron imaging may also offer improved sensitivity in ALS diagnosis and prognosis that could make a major contribution to clinical care and treatment trials. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 3.

Motor neurone disease: progress and challenges.

Major progress has been made over the past decade in the understanding of motor neurone disease (MND), changing the landscape of this complex disease. Through identifying positive prognostic factors, new evidence-based standards of care have been established that improve patient survival, reduce burden of disease for patients and their carers, and enhance quality of life. These factors include early management of respiratory dysfunction with non-invasive ventilation, maintenance of weight and nutritional status, as well as instigation of a multidisciplinary team including neurologists, general practitioners and allied health professionals. Advances in technology have enhanced our understanding of the genetic architecture of MND considerably, with implications for patients, their families and clinicians. Recognition of extra-motor involvement, particularly cognitive dysfunction, has identified a spectrum of disease from MND through to frontotemporal dementia. Although riluzole remains the only disease-modifying medication available in clinical practice in Australia, several new therapies are undergoing clinical trials nationally and globally, representing a shift in treatment paradigms. Successful translation of this clinical research through growth in community funding, awareness and national MND research organisations has laid the foundation for closing the research-practice gap on this debilitating disease. In this review, we highlight these recent developments, which have transformed treatment, augmented novel therapeutic platforms, and established a nexus between research and the MND community. This era of change is of significant relevance to both specialists and general practitioners who remain integral to the care of patients with MND.

Identifying who will benefit from non-invasive ventilation in amyotrophic lateral sclerosis/motor neurone disease in a clinical cohort.

BACKGROUND: Respiratory failure is associated with significant morbidity and is the predominant cause of death in motor neurone disease/amyotrophic lateral sclerosis (MND/ALS). This study aimed to determine the effect of non-invasive ventilatory (NIV) support on survival and pulmonary function decline across MND/ALS phenotypes. METHODS: Cohort recruited via a specialist, multidisciplinary clinic. Patients were categorised into four clinical phenotypes (ALS, flail arm, flail leg and primary lateral sclerosis) according to site of presenting symptom and the pattern of upper versus lower motor neurone involvement. NIV was initiated according to current consensus practice guidelines. RESULTS: Between 1991 and 2011, 1198 patients diagnosed with ALS/MND were registered. 929 patients (77.5%) fulfilled the selection criteria and their data were analysed. Median tracheostomy free survival from symptom onset was 28 months in NIV-treated patients compared to 15 months in untreated (Univariate Cox regression HR=0.61 (0.51 to 0.73), p<0.001). The positive survival effect of NIV persisted when the model was adjusted for age, gender, riluzole and percutaneous endoscopic gastrostomy use (HR=0.72 (0.60 to 0.88, p=0.001). In contrast with the only randomised controlled trial, NIV statistically significantly increased survival by 19 months in those with ALS-bulbar onset (Univariate HR=0.50 (0.36 to 0.70), multivariate HR=0.59 (0.41 to 0.83)). These data confirm that NIV improves survival in MND/ALS. The overall magnitude of benefit is 13 months and was largest in those with ALS-bulbar disease. Future research should explore the optimal timing of NIV initiation within phenotypes in order to optimise respiratory function, quality of life and survival.

Network diffusion model predicts neurodegeneration in limb-onset Amyotrophic Lateral Sclerosis.

OBJECTIVE: Emerging evidences suggest that the trans-neural propagation of phosphorylated 43-kDa transactive response DNA-binding protein (pTDP-43) contributes to neurodegeneration in Amyotrophic Lateral Sclerosis (ALS). We investigated whether Network Diffusion Model (NDM), a biophysical model of spread of pathology via the brain connectome, could capture the severity and progression of neurodegeneration (atrophy) in ALS. METHODS: We measured degeneration in limb-onset ALS patients (n = 14 at baseline, 12 at 6-months, and 9 at 12 months) and controls (n = 12 at baseline) using FreeSurfer analysis on the structural T1-weighted Magnetic Resonance Imaging (MRI) data. The NDM was simulated on the canonical structural connectome from the IIT Human Brain Atlas. To determine whether NDM could predict the atrophy pattern in ALS, the accumulation of pathology modelled by NDM was correlated against atrophy measured using MRI. In order to investigate whether network spread on the brain connectome derived from healthy individuals were significant findings, we compared our findings against network spread simulated on random networks. RESULTS: The cross-sectional analyses revealed that the network diffusion seeded from the inferior frontal gyrus (pars triangularis and pars orbitalis) significantly predicts the atrophy pattern in ALS compared to controls. Whereas, atrophy over time with-in the ALS group was best predicted by seeding the network diffusion process from the inferior temporal gyrus at 6-month and caudal middle frontal gyrus at 12-month. Network spread simulated on the random networks showed that the findings using healthy brain connectomes are significantly different from null models. INTERPRETATION: Our findings suggest the involvement of extra-motor regions in seeding the spread of pathology in ALS. Importantly, NDM was able to recapitulate the dynamics of pathological progression in ALS. Understanding the spatial shifts in the seeds of degeneration over time can potentially inform further research in the design of disease modifying therapeutic interventions in ALS.

MiNDAUS partnership: a roadmap for the cure and management of motor Neurone disease.

An innovative approach to patient management, evidence-based policy development, and clinical drug trials is required to provide personalized care and to improve the likelihood of finding an effective treatment for Motor Neurone Disease (MND). The MiNDAus Partnership builds on and extends existing national collaborations in a targeted approach to improve the standard and coordination of care for people living with MND in Australia, and to enhance the prospects of discovering a cure or treatment. Relationships have been developed between leading clinical and research groups as well as patient-centered organizations, care providers, and philanthropy with a shared vision. MiNDAus has established a corporate structure and meets at least biannually to decide on how best to progress research, drug development, and patient management. The key themes are; (i) empowering patients and their family carers to engage in self-management and ensure personalized service provision, treatment, and policy development, (ii) integration of data collection so as to better inform policy development, (iii) unifying patients and carers with advocacy groups, funding bodies, clinicians and academic institutions so as to inform policy development and research, (iv) coordination of research efforts and development of standardized national infrastructure for conducting innovative clinical MND trials that can be harmonized within Australia and with international trials consortia. Such a collaborative approach is required across stakeholders in order to develop innovative management guidelines, underpinned by necessary and evidence-based policy change recommendations, which, will ensure the best patient care until a cure is discovered.

Application of Machine Learning Techniques to Identify Data Reliability and Factors Affecting Outcome After Stroke Using Electronic Administrative Records.

Aim: To use available electronic administrative records to identify data reliability, predict discharge destination, and identify risk factors associated with specific outcomes following hospital admission with stroke, compared to stroke specific clinical factors, using machine learning techniques. Method: The study included 2,531 patients having at least one admission with a confirmed diagnosis of stroke, collected from a regional hospital in Australia within 2009-2013. Using machine learning (penalized regression with Lasso) techniques, patients having their index admission between June 2009 and July 2012 were used to derive predictive models, and patients having their index admission between July 2012 and June 2013 were used for validation. Three different stroke types [intracerebral hemorrhage (ICH), ischemic stroke, transient ischemic attack (TIA)] were considered and five different comparison outcome settings were considered. Our electronic administrative record based predictive model was compared with a predictive model composed of "baseline" clinical features, more specific for stroke, such as age, gender, smoking habits, co-morbidities (high cholesterol, hypertension, atrial fibrillation, and ischemic heart disease), types of imaging done (CT scan, MRI, etc.), and occurrence of in-hospital pneumonia. Risk factors associated with likelihood of negative outcomes were identified. Results: The data was highly reliable at predicting discharge to rehabilitation and all other outcomes vs. death for ICH (AUC 0.85 and 0.825, respectively), all discharge outcomes except home vs. rehabilitation for ischemic stroke, and discharge home vs. others and home vs. rehabilitation for TIA (AUC 0.948 and 0.873, respectively). Electronic health record data appeared to provide improved prediction of outcomes over stroke specific clinical factors from the machine learning models. Common risk factors associated with a negative impact on expected outcomes appeared clinically intuitive, and included older age groups, prior ventilatory support, urinary incontinence, need for imaging, and need for allied health input. Conclusion: Electronic administrative records from this cohort produced reliable outcome prediction and identified clinically appropriate factors negatively impacting most outcome variables following hospital admission with stroke. This presents a means of future identification of modifiable factors associated with patient discharge destination. This may potentially aid in patient selection for certain interventions and aid in better patient and clinician education regarding expected discharge outcomes.

Improving clinical trial outcomes in amyotrophic lateral sclerosis.

Individuals who are diagnosed with amyotrophic lateral sclerosis (ALS) today face the same historically intransigent problem that has existed since the initial description of the disease in the 1860s - a lack of effective therapies. In part, the development of new treatments has been hampered by an imperfect understanding of the biological processes that trigger ALS and promote disease progression. Advances in our understanding of these biological processes, including the causative genetic mutations, and of the influence of environmental factors have deepened our appreciation of disease pathophysiology. The consequent identification of pathogenic targets means that the introduction of effective therapies is becoming a realistic prospect. Progress in precision medicine, including genetically targeted therapies, will undoubtedly change the natural history of ALS. The evolution of clinical trial designs combined with improved methods for patient stratification will facilitate the translation of novel therapies into the clinic. In addition, the refinement of emerging biomarkers of therapeutic benefits is critical to the streamlining of care for individuals. In this Review, we synthesize these developments in ALS and discuss the further developments and refinements needed to accelerate the introduction of effective therapeutic approaches.

Serial assessment of iron in the motor cortex in limb-onset amyotrophic lateral sclerosis using quantitative susceptibility mapping.

BACKGROUND: Dysregulation of iron in the cerebral motor areas has been hypothesized to occur in individuals with amyotrophic lateral sclerosis (ALS). There is still limited knowledge regarding iron dysregulation in the progression of ALS pathology. Our objectives were to use magnetic resonance based quantitative susceptibility mapping (QSM) to investigate the association between iron dysregulation in the motor cortex and clinical manifestations in patients with limb-onset ALS, and to examine changes in the iron concentration in the motor cortex in these patients over a 6-month period. METHODS: Iron concentration was investigated using magnetic resonance based QSM in the primary motor cortex and the pre-motor area in 13 limb-onset ALS patients (including five lumbar onset, six cervical onset and two flail arm patients), and 11 age- and sex-matched control subjects. Nine ALS patients underwent follow-up scans at 6 months. RESULTS: Significantly increased QSM values were observed in the left posterior primary motor area (P=0.02, Cohen's d =0.9) and right anterior primary motor area (P=0.02, Cohen's d =0.92) in the group of limb-onset ALS patients compared to that of control subjects. Increased QSM was observed in the primary motor and pre-motor area at baseline in patients with lumbar onset ALS patients, but not cervical limb-onset ALS patients, compared to control subjects. No significant change in QSM was observed at the 6-month follow-up scans in the ALS patients. CONCLUSIONS: The findings suggest that iron dysregulation can be detected in the motor cortex in limb-onset ALS, which does not appreciably change over a further 6 months. Individuals with lumbar onset ALS appear to be more susceptible to motor cortex iron dysregulation compared to the individuals with cervical onset ALS. Importantly, this study highlights the potential use of QSM as a quantitative radiological indicator in early disease diagnosis in limb-onset ALS and its subtypes. Our serial scans results suggest a longer period than 6 months is needed to detect significant quantitative changes in the motor cortex.

ALS is a multistep process in South Korean, Japanese, and Australian patients.

OBJECTIVE: To establish whether amyotrophic lateral sclerosis (ALS) is a multistep process in South Korean and Japanese populations when compared to Australian cohorts. METHODS: We generated incident data by age and sex for Japanese (collected between April 2009 and March 2010) and South Korean patients with ALS (collected between January 2011 and December 2015). Mortality rates were provided for Australian patients with ALS (collected between 2007 and 2016). We regressed the log of age-specific incidence against the log of age with least squares regression for each ALS population. RESULTS: We identified 11,834 cases of ALS from the 3 populations, including 6,524 Australian, 2,264 Japanese, and 3,049 South Korean ALS cases. We established a linear relation between the log incidence and log age in the 3 populations: Australia r 2 = 0.99, Japan r 2 = 0.99, South Korea r 2 = 0.99. The estimate slopes were similar across the 3 populations, being 5.4 (95% confidence interval [CI], 4.8-5.5) in Japanese, 5.4 (95% CI, 5.2-5.7) in Australian, and 4.4 (95% CI, 4.2-4.8) in South Korean patients. CONCLUSIONS: The linear relationship between log age and log incidence is consistent with a multistage model of disease, with slope estimated suggesting that 6 steps were required in Japanese and Australian patients with ALS while 5 steps were needed in South Korean patients. Identification of these steps could identify novel therapeutic strategies.

Clinical phenotypes and natural progression for motor neuron disease: analysis from an Australian database.

From 1997 to 2003 we prospectively followed a cohort of ALS/MND patients. Patients were allocated to predetermined clinical phenotypes using the principles established in the modified El Escorial criteria. The date and region of symptom onset were carefully determined and their progression was scored using the Appel ALS rating scale. The four distinct clinical phenotypes: Global, Flail Arm, Flail Leg and Primary Lateral Sclerosis (PLS) demonstrated significantly different rates of progression and survival times. The Global ALS/MND phenotype can present with initial symptoms in any region and rapidly progresses to involve all segments, with symptoms due to a mixture of combined corticospinal tract and anterior horn cell dysfunction. The Global phenotype has the shortest survival and most rapid rate of disease progression. There was a significant difference in survival between Global bulbar onset and cervical onset disease but no significant difference in the rate of disease progression between the three Global subgroups as determined by the Appel/ALS rating scale. Flail patients had much slower rates of progression and significantly longer survival compared to the Global phenotype. Patients with Primary Lateral Sclerosis as expected progressed the slowest and survived the longest compared to the other clinical phenotypes. The utility of developing a method of assigning clinical phenotypes with similar survival and disease progression rates is discussed in relation to therapeutic trial design, practice benchmarking and clinico-pathological correlations.

Amyotrophic lateral sclerosis as a multi-step process: an Australia population study.

Objective: This study sought to investigate whether a multistep process was also evident in an Australian amyotrophic lateral sclerosis (ALS) population. Methods: Mortality rates for ALS patients (years 2007-2016) were obtained from the Australian Institute of Health and Welfare (AIHW). The log incidence of ALS, as reflected by crude mortality rates, was regressed against log of age disease onset. Results: From a total population of 24 million, 6524 cases of ALS were identified. A linear relation between the log incidence and log age was identified, with r2 value of 0.99, indicating that ALS is a multistep process. The linear slope estimate was 5.0, suggesting that six steps were required for development of ALS. Conclusions: This study established a linear relationship between log incidence and log age onset in an Australia ALS population, consistent with a multistep process. Identification of these steps will likely be of therapeutic benefit in ALS.

Identification and outcomes of clinical phenotypes in amyotrophic lateral sclerosis/motor neuron disease: Australian National Motor Neuron Disease observational cohort.

OBJECTIVE: To capture the clinical patterns, timing of key milestones and survival of patients presenting with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) within Australia. METHODS: Data were prospectively collected and were timed to normal clinical assessments. An initial registration clinical report form (CRF) and subsequent ongoing assessment CRFs were submitted with a completion CRF at the time of death. DESIGN: Prospective observational cohort study. PARTICIPANTS: 1834 patients with a diagnosis of ALS/MND were registered and followed in ALS/MND clinics between 2005 and 2015. RESULTS: 5 major clinical phenotypes were determined and included ALS bulbar onset, ALS cervical onset and ALS lumbar onset, flail arm and leg and primary lateral sclerosis (PLS). Of the 1834 registered patients, 1677 (90%) could be allocated a clinical phenotype. ALS bulbar onset had a significantly lower length of survival when compared with all other clinical phenotypes (p<0.004). There were delays in the median time to diagnosis of up to 12 months for the ALS phenotypes, 18 months for the flail limb phenotypes and 19 months for PLS. Riluzole treatment was started in 78-85% of cases. The median delays in initiating riluzole therapy, from symptom onset, varied from 10 to 12 months in the ALS phenotypes and 15-18 months in the flail limb phenotypes. Percutaneous endoscopic gastrostomy was implemented in 8-36% of ALS phenotypes and 2-9% of the flail phenotypes. Non-invasive ventilation was started in 16-22% of ALS phenotypes and 21-29% of flail phenotypes. CONCLUSIONS: The establishment of a cohort registry for ALS/MND is able to determine clinical phenotypes, survival and monitor time to key milestones in disease progression. It is intended to expand the cohort to a more population-based registry using opt-out methodology and facilitate data linkage to other national registries.

An unusual case of hypertensive encephalopathy.

This case report describes a 59-year-old male who presented with headaches, seizures and hypertension followed by coma. Initial magnetic resonance imaging showed T2 hyperintensities typical of Hypertensive Encephalopathy (HE), the follow up scans showed diffusion-weighted imaging (DWI) hyperintensities which is a rare finding in HE. DWI hyperintensities are typically suggestive of areas of cytotoxic damage, and the presence of these changes makes this case unusual, since the pathogenesis of HE is usually due to vasogenic oedema rather than cytotoxic damage of the brain tissue.

Motor neurone disease: disability profile and service needs in an Australian cohort.

Motor neurone disease (MND) places considerable burden upon patients and caregivers. This is the first study, which describes the disability profile and healthcare needs for persons with MND (pwMND) in an Australian sample from the perspective of the patients and caregivers to identify current gaps in the knowledge and service provision. A prospective cross-sectional community survey of pwMND (n=44) and their caregivers (n=37) was conducted, to determine symptoms and problems affecting daily living. Standardized assessments were carried out to determine the disease severity for stratification purposes, service needs and gaps. The mean age was 61 years with more men affected than women (3 : 2). The severity of disease was high (n=18; 41%) based on the Amyotrophic Lateral Sclerosis Functional Rating Scale. Despite the high level of disability, 11 (25%) solely relied on their families for all assistance. Caregivers were mostly partners (mean age: 57 years). PwMND reported more pain, emotional disturbance and spasticity/cramps/spasms. Caregivers focused more on psychosocial issues. Nineteen (43%) pwMND reported gaps in the service in rehabilitation therapy and respite. Significantly proportionally, more caregivers (n=19; 51%) reported gaps particularly in the area of psychosocial support. The gaps identified in the MND care should be prioritized for future service development using the 'neuropalliative rehabilitation' model of care. For improved consensus of care and communication among treating clinicians, the framework of International Classification of Functioning, Disability and Health should be explored in this population.

The SEIQoL-DW is a valid method for measuring individual quality of life in stroke survivors attending a secondary prevention clinic.

OBJECTIVES: This paper examines the applicability and construct validity of the Schedule for the Evaluation of Individual Quality of Life-Direct Weight (SEIQoL-DW) for measuring quality of life in stroke survivors living at home that attend a secondary prevention clinic. PARTICIPANTS AND METHODS: Forty-six individuals attending a secondary prevention clinic following a stroke or transient ischaemic attack participated in a semi-structured interview to complete a range of outcome measures. Assessments of cognitive impairment, disability, and handicap were conducted using the Mini mental State Examination (MMSE), Barthel Index (BI), and Rankin Scale (RS). Measures to assess quality of life included perceived health status (PHS), Visual Analogue Mood Scale (VAMS), the Hospital Anxiety and Depression Scale (HADS), and the SEIQoL-DW. The construct validity of the SEIQoL-DW was assessed by correlation with the other measures. RESULTS: According to the cues elicited from the SEIQoL-DW, participants nominated 'relationships with family and friends' as the most important life domain, followed by 'social and leisure activities', and 'health'. Spearman's rho correlation coefficients demonstrated significant relationships between the SEIQoL-DW index scores, PHS (r = 0.35, p = 0.016), VAMS (r = 0.419, p = 0.004), and the HADS anxiety (r = -0.546, p < 0.0001) and depression (r = -0.701, p < 0.0001) subscale scores. CONCLUSIONS: The SEIQoL-DW demonstrated reasonable construct validity for use in assessing individual quality of life in a group of individuals following stroke or TIA that attend a secondary prevention clinic.