Accelerating patient access to oncology medicines with multiple indications in Europe.

Background: In recent years, innovation in oncology has created new challenges for pricing and reimbursement systems. Oncology medicines with multiple indications face a number of access challenges: (1) the number of assessments and administrative burden; (2) aligning price to different values of the same product; (3) managing clinical uncertainty at time of launch; and (4) managing budget uncertainty. These challenges impact a range of stakeholders and can result in delayed patient access to life-saving treatments. Consequently, countries have taken steps to facilitate patient access. Methods: Drawing on the experience across Europe we have reviewed different mechanisms countries have adopted that address these challenges. These include approaches aimed directly at the issue, multi-year-multi-indication (MYMI) agreements (BE, NL), and other approaches to manage access: flexible access agreements for new indications with clinical uncertainty (UK); development of a new agreement for each new indication (IT); and immediate access for new indications and bundled assessments (DE). Results: MYMI agreements are valuable where existing rules mean that every indication faces the same upfront evaluation process that delays patient access. They are also useful in managing budget impact and uncertainty. Other approaches that adopt an indication-specific approach helps manage clinical uncertainty at the time of launch and realise different values for the same product. They can help align price to value, even though indication-based pricing does not exist. Bundled assessments reduce the administrative burden for stakeholders, and the benefits of immediate reimbursement is that patient access is not delayed. Conclusion: The challenges for medicines with multiple indications impact a range of stakeholders and can result in delayed patient access to life-saving treatments. MYMI agreements have created a more pragmatic approach to HTA for medicines with multiple indications to ensure both fast and broad patient access. Continued innovation in oncology will require further innovative approaches in pricing and reimbursement. It is important that policymakers, payers and manufacturers engage in early discussions and are willing to find new solutions to help accelerate patient access to innovative therapies.

A long-term neuropsychological evaluation in Fabry disease.

Fabry disease (FD) is a X-linked multi-systemic metabolic disorder with mainly renal, cardiac and neurological dysfunction. The neuropsychological impact is still unclear, with previous study results ranging from disturbance of speed of information processing and executive functions to a normal cognitive profile. The aim of our study was to gain further insight into the neuropsychological involvement of FD. Patients with genetically proven FD were enrolled at the Ghent University Hospital by their treating neurologist. We evaluated the cognitive status of each patient by a thorough neuropsychological test battery and these exact same neuropsychological assessments were repeated after a follow-up period of 2-4 years and at a second follow-up moment 1-4 years after the first follow-up. Thirteen patients with FD were included (8 female) with mean age of 41.5 years (SD ± 13.9) at baseline. All patients had normal neuropsychological test results on the subtests included in the cognitive battery at baseline, according to age-, gender- and education matched normative data. At the first follow-up moment (2-4 years after baseline), six patients were included (3 male), mean age 45.3 years. At the second follow-up (1-4 years after first follow-up), four patients (2 male) were included, with mean age 45 years. Both at the first and second follow-up moments, all patients obtained normal scores on the subtests. The cognitive functioning appeared to be in the normal range at baseline and did not decline over a follow-up period of 3-8 years, suggesting that cognition in FD patients may be well-preserved in time.

Dysphagia, dysarthria and aphasia following a first acute ischaemic stroke: incidence and associated factors.

BACKGROUND AND PURPOSE: Dysphagia, dysarthria and aphasia are common symptoms following acute stroke; however, limited data are available from recent prospective clinical trials. The aim of this study was to determine the incidence and associated factors of dysphagia, dysarthria and aphasia following a first acute ischaemic stroke in patients admitted to a comprehensive stroke center. METHODS: All first ischaemic stroke patients admitted to the Stroke Unit of Ghent University Hospital within 48 h after symptom onset were enrolled in this prospective study between March 2018 and October 2019. Dysphagia and communication screenings were performed within 3 days after admission. When dysphagia, dysarthria and/or aphasia were assumed, standardized assessments were performed. Incidence rates were calculated as point estimates (%) with 95% confidence intervals (CI). Associated factors were calculated via multivariate binary logistic regression analyses. RESULTS: Dysphagia, dysarthria and aphasia were present in 23% (95% CI, 17-31), 44% (95% CI, 37-52) and 23% (95% CI, 17-30), respectively of 151 first ischaemic stroke patients [67 female, mean age 67 (SD 14) years]. Separate multivariate binary logistic regression analyses showed that dysphagia, dysarthria and aphasia were significantly associated with age-adjusted stroke severity at baseline [odds ratio (OR), 1.16; 95% CI, 1.09-1.23; OR, 1.13; 95% CI, 1.07-1.20 and OR, 1.11; 95% CI, 1.05-1.17 respectively]. Corrected for stroke severity, the risk for aphasia increased by 4% per year of age (OR, 1.04; 95% CI, 1.00-1.07). Adjusted for age and stroke severity, aphasia was significantly associated with large artery atherosclerosis as stroke etiology (OR, 3.91; 95% CI, 1.18-12.98). CONCLUSIONS: This trial showed a high incidence of dysphagia, dysarthria and aphasia following acute ischaemic stroke. Stroke severity was an associated factor for all three symptoms.

Neurological manifestations and neuro-invasive mechanisms of the severe acute respiratory syndrome coronavirus type 2.

BACKGROUND AND PURPOSE: Infections with coronaviruses are not always confined to the respiratory tract and various neurological manifestations have been reported. The aim of this study was to perform a review to describe neurological manifestations in patients with COVID-19 and possible neuro-invasive mechanisms of Sars-CoV-2. METHODS: PubMed, Web of Science and COVID-dedicated databases were searched for the combination of COVID-19 terminology and neurology terminology up to 10 May 2020. Social media channels were followed up between 15 March and 10 May 2020 for postings with the same scope. Neurological manifestations were extracted from the identified papers and combined to provide a useful summary for the neurologist in clinical practice. RESULTS: Neurological manifestations potentially related to COVID-19 have been reported in large studies, case series and case reports and include acute cerebrovascular diseases, impaired consciousness, cranial nerve manifestations and autoimmune disorders such as the Guillain-Barré syndrome often present in patients with more severe COVID-19. Cranial nerve symptoms such as olfactory and gustatory dysfunctions are highly prevalent in patients with mild to moderate COVID-19 even without associated nasal symptoms and often present in an early stage of the disease. CONCLUSION: Physicians should be aware of the neurological manifestations in patients with COVID-19, especially when rapid clinical deterioration occurs. The neurological symptoms in COVID-19 patients may be due to direct viral neurological injury or indirect neuroinflammatory and autoimmune mechanisms. No antiviral treatments against the virus or vaccines for its prevention are available and the long-term consequences of the infection on human health remain uncertain especially with regard to the neurological system.

Biotinidase deficiency: A treatable cause of opticospinal syndrome in young adults✰.

Diagnosis of biotinidase deficiency is rare and usually made in infancy, through newborn screening or after presenting symptoms. We present the case of 19-year old male with progressive optic atrophy and in a second phase spinal cord syndrome unresponsive to immunosuppressive therapies. After diagnosis of profound biotinidase deficiency, oral biotin substitution was started with partial visual improvement and normalization of gait. This case highlights the possibility of late-onset biotinidase deficiency and its treatable character.

Early-onset dementia, leukoencephalopathy and brain calcifications: a clinical, imaging and pathological comparison of ALSP and PLOSL/Nasu Hakola disease.

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia, and Nasu Hakola disease or polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy are both underrecognized progressive degenerative white matter diseases that can present with young dementia, leukoencephalopathy and brain calcifications. We report and compare three cases in terms of clinical phenotype, imaging and neuropathological findings. Both cases have led to the identification of two novel causal mutations.

Cerebral vasospasm in acute porphyria.

BACKGROUND AND PURPOSE: Porphyrias are a group of inherited metabolic disorders resulting from a specific deficiency along the pathway of haem biosynthesis. A clinical classification distinguishes acute from non-acute porphyrias considering the occurrence of life-threatening neurovisceral attacks, presenting with abdominal pain, neuropsychiatric disturbance and neuropathy. Vasospasm is a very rare complication that can occur in all major types of acute porphyria. METHODS: We describe a porphyric crisis with vasospasm in a woman with previously undiagnosed acute porphyria. Furthermore we performed a systematic review by searching the electronic database Pubmed/MEDLINE for additional data in published studies of vasospasm in acute porphyria. RESULTS: Overall, 9 case reports reporting on 11 patients who suffered vasospasm during an exacerbation of acute porphyria were identified. All of the reported patients were women and the mean age was 29.4 years. When brain MRI was performed, T2-hyperintense lesions, consistent with ischaemic changes, were observed in most patients (10/11, 91%). Although the genetic pathogenesis of the disease is well understood, the precise mechanisms to explain neurologic involvement in acute porphyria remain unclear. CONCLUSION: Acute porphyria is an unusual and rare cause of vasospasm. However, considering porphyria in patients with unexplained cerebral vasospasm, especially in women of childbearing age, is crucial given the severity of possible complications and the available treatment options.

Imaging Features of Hypertrophic Olivary Degeneration.

Hypertrophic olivary degeneration (HOD) is a unique form of transneuronal degeneration caused by a disruption of the dentato-rubro-olivary pathway, also known as the triangle of Guillain-Mollaret. The triangle of Guillain-Mollaret is involved in fine voluntary motor control and consists of both the inferior olivary nucleus and the red nucleus on one side and the contralateral dentate nucleus. Clinically, patients classically present with symptomatic palatal myoclonus. Typical magnetic resonance imaging findings include T2-hyperintensity and enlargement of the inferior olivary nucleus evolving over time to atrophy with residual T2-hyperintensity. In this article, we provide a case-based illustration of the anatomy of the Guillain-Mollaret-triangle and the typical imaging findings of hypertrophic olivary degeneration.

Tapia's syndrome in the intensive care unit: a rare cause of combined cranial nerve palsy following intubation.

Tapia's syndrome is characterized by unilateral paralysis of the tongue and vocal cord, and is caused by a concurrent lesion of both the recurrent laryngeal and hypoglossal nerves. The proposed mechanism in most patients is compression or stretching of these nerves on their extracranial course due to airway manipulation under general anaesthesia. As Tapia's syndrome is a rare and possibly devastating condition, recognition of the presence of concurrent paralyses is an important step in diagnosis and treatment. We report two cases of Tapia's syndrome as a complication of intubation in the intensive care unit.

Stroke Versus Seizure - Perfusion Computerized Tomography in a Patient with Aphasia.

Both stroke and seizures have varied clinical presentations and their differentiation in the acute setting is not always straightforward. We present the case of a patient who presented at the emergency room with acute onset aphasia. Clinically acute ischemic stroke was suspected. Perfusion CT was performed and demonstrated cortical hypervascularity in the left partietotemporal region. Additional MRI and EEG were performed and a final diagnosis of postictal aphasia was made. This case illustrates that perfusion CT is not only a useful tool for acute stroke management, but can also aid in the detection of seizures in patients presenting with stroke-like symptoms.

Questioning the Pathogenic Role of the GLA p.Ala143Thr "Mutation" in Fabry Disease: Implications for Screening Studies and ERT.

Fabry disease is an X-linked inborn error of glycosphingolipid metabolism caused by quantitative or qualitative defects in the lysosomal enzyme alfa-Galactosidase A (aGAL A), ultimately resulting in vital organ dysfunction. Mainly the kidneys, the heart, and the central nervous system are involved. While the classical phenotype of Fabry disease is readily recognizable, screening studies have identified clinical variants. Here, we report the phenotype associated with the GLA p.Ala143Thr (c.427G>A) mutation in 12 patients aged 42-83 years. None of the patients had classical Fabry signs or symptoms as angiokeratoma, hypohidrosis, acroparesthesia, or cornea verticillata. Possible Fabry manifestations were renal failure (5/12), stroke (7/12), and left ventricular hypertrophy (5/12), but these were not necessarily attributable to the p.Ala143Thr mutation, as a cardiac biopsy in one female and left ventricular hypertrophy and kidney biopsies in two males with renal failure and microalbuminuria lacked Gb-3 deposits. The literature data on this mutation as well as data collected in the Fabry Outcome Survey (FOS) database confirm these findings. The association of renal failure, stroke, and left ventricular hypertrophy with this mutation could be the result of selection bias, as most patients were detected in screening studies.We conclude that care should be taken with attribution of vital organ dysfunction to GLA sequence alterations. In case of the p.Ala143Thr mutation, and possibly also other mutations associated with an attenuated phenotype, diagnostic tools such as biopsy and imaging should critically evaluate the relation of end-organ failure with Fabry disease, as this has important consequences for enzyme replacement therapy.

Ischemic stroke and hyperhomocysteinemia: truth or myth?

Hyperhomocysteinemia is generally acknowledged as a treatable risk factor for atherotrombotic diseases, but a causal relationship between both is not yet definitively established. Hyperhomocysteinemia originates from a deviation in the methionine-homocysteine metabolism including disturbances of enzymes, vitamin deficiencies and different other factors. Observational studies, genetic polymorphism studies and several meta-analyses implicate already a causal relation between homocysteine and cerebrovascular diseases. It is useful to determine homocysteine levels for stroke who present no clue for vascular disease and thrombosis, who have an ischemic stroke at a young age and who have a family history of premature atherosclerosis. Because of the low cost and safety of the therapy, the American Heart and Stroke Association advises to treat patients with a stroke and hyperhomocysteinemia daily with 0,4 mg folic acid, 2,4 microg vitamin B12 and 1,7 mg vitamin B6. A significant benefit in secondary prevention is not yet proven. The results of larger follow-up trials have to be published.

Organisation of inhospital acute stroke care and minimum criteria for stroke care units. Recommendations of the Belgian Stroke Council.

There is ample evidence from randomized trials that for patients with stroke, stroke unit care is superior to care in general medical or neurological wards. This evidence, which has been adopted by international guidelines has to be implemented into daily stroke care. This consensus document prepared by the Belgian Stroke Council provides a set of minimum criteria to meet international standards for stroke care. It is intended to provide help in the creation of stroke units in centers who do not currently have one and to provide a benchmark for centres already having organised stroke care.

The neurological illness of Friedrich Nietzsche.

BACKGROUND: Friedrich Nietzsche (1844-1900), one of the most profound and influential modern philosophers, suffered since his very childhood from severe migraine. At 44 he had a mental breakdown ending in a dementia with total physical dependence due to stroke. From the very beginning, Nietzsche's dementia was attributed to a neurosyphilitic infection. Recently, this tentative diagnosis has become controversial. OBJECTIVE: To use historical accounts and original materials including correspondence, biographical data and medical papers to document the clinical characteristics of Nietzsche's illness and, by using this pathography, to discuss formerly proposed diagnoses and to provide and support a new diagnostic hypothesis. MATERIALS: Original letters from Friedrich Nietzsche, descriptions by relatives and friends, and medical descriptions. Original German sources were investigated. Biographical papers published in medical journals were also consulted. RESULTS: Nietzsche suffered from migraine without aura which started in his childhood. In the second half of his life he suffered from a psychiatric illness with depression. During his last years, a progressive cognitive decline evolved and ended in a profound dementia with stroke. He died from pneumonia in 1900. The family history includes a possible vascular-related mental illness in his father who died from stroke at 36. CONCLUSIONS: Friedrich Nietzsche's disease consisted of migraine, psychiatric disturbances, cognitive decline with dementia, and stroke. Despite the prevalent opinion that neurosyphilis caused Nietzsche's illness, there is lack of evidence to support this diagnosis. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) accounts for all the signs and symptoms of Nietzsche's illness. This study adds new elements to the debate and controversy about Nietzsche's illness. We discuss former diagnoses, comment on the history of a diagnostic mistake, and integrate for the first time Nietzsche's medical problems.

Post-traumatic spontaneous recurrent hypothermia: a variant of Shapiro's syndrome.

A 49-year-old man presented with episodic hypothermia many years after sustaining a contusional brain injury. Brain magnetic resonance imaging demonstrated the destruction of the anterior parts of the corpus callosum without hypothalamic lesions. Nevertheless, delayed hypothalamic dysfunction at the neurotransmitter level is the probable pathophysiological key factor. Clomipramine treatment was beneficial. This case expands the spectrum of Shapiro's syndrome.

The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2.

BACKGROUND: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), or Nasu-Hakola disease, is a presenile dementia associated with loss of myelin, basal ganglia calcification, and bone cysts. It is caused by recessively inherited mutations in two genes encoding subunits of a cell membrane-associated receptor complex: TREM2 and DAP12. The clinical course of PLOSL has not been characterized in a series of patients with TREM2 mutations. METHODS: The authors compare neurologic and neuroradiologic follow-up data of six patients carrying TREM2 mutations with PLOSL due to defective DAP12 genes. The authors review the known mutations in these two genes. RESULTS: Mutations in DAP12 and TREM2 result in a uniform disease phenotype. In Finnish and Japanese patients with PLOSL, DAP12 mutations predominate, whereas TREM2 is mutated more frequently elsewhere. CONCLUSIONS: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy should be considered in adult patients under age 50 years with dementia and basal ganglia calcification. Radiographs of ankles and wrists, and DNA test in uncertain cases, confirm the diagnosis.

Positron emission tomographic study of post-ischaemic-hypoxic amnesia.

BACKGROUND: Despite extensive research, it still remains controversial as to what the precise location of the critical lesions underlying amnesia actually is. The amnesic syndrome is believed to be heterogeneous and due to several distinct functional deficits. PATIENTS AND METHODS: Two patients, a 45-year-old woman and a 56-year-old man, with sudden cardiopulmonary arrest and successful resuscitation, were left with a clear amnesic syndrome as main neurological sequela. During their revalidation period, they underwent a positron emission tomographic (PET) examination, utilizing the (13)NH(3) bolus technique at rest and after intravenous acetazolamide administration. RESULTS: Both PET studies showed more or less similar features with a decrease in regional cerebral blood flow (rCBF) in the frontal, temporal and parietal lobes. In addition, the rCBF was increased in both thalami of the 45-year-old woman and in the striata of the 56-year-old man. Acetazolamide vasoreactivity was most lost in the frontal lobes. CONCLUSIONS: In the present PET study, we demonstrated that destruction of the inhibitory pathways to the thalamus and basal ganglia by ischaemic-hypoxic frontal lesions could be one of the mechanisms leading to amnesia.