Rare Neurological Research Articles

Pharmacotherapy for behavioural manifestations in frontotemporal dementia: An expert consensus from the European Reference Network for Rare Neurological Diseases (ERN-RND).

Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by pervasive personality and behavioural disturbances with severe impact on patients and caregivers. In current clinical practice, treatment is based on nonpharmacological and pharmacological approaches. Unfortunately, trial-based evidence supporting symptomatic pharmacological treatment for the behavioural disturbances in FTD is scarce despite the significant burden this poses on the patients and caregivers. The study examined drug management decisions for several behavioural disturbances in patients with FTD by 21 experts across European expert centres affiliated with the European Reference Network for Rare Neurological Diseases (ERN-RND). The study revealed the highest consensus on drug treatments for physical and verbal aggression, impulsivity and obsessive delusions. Antipsychotics (primarily quetiapine) were recommended for behaviours posing safety risks to both patients and caregivers (aggression, self-injury and self-harm) and nightly unrest. Selective serotonin reuptake inhibitors were recommended for perseverative somatic complaints, rigidity of thought, hyperphagia, loss of empathy and for impulsivity. Trazodone was specifically recommended for motor unrest, mirtazapine for nightly unrest, and bupropion and methylphenidate for apathy. Additionally, bupropion was strongly advised against in 10 out of the 14 behavioural symptoms, emphasizing a clear recommendation against its use in the majority of cases. The survey data can provide expert guidance that is helpful for healthcare professionals involved in the treatment of behavioural symptoms. Additionally, they offer insights that may inform prioritization and design of therapeutic studies, particularly for existing drugs targeting behavioural disturbances in FTD.

Rural Medicine is not Permanently Paralyzed: A Systematic Online Review to Mitigate Misdiagnoses of Rare Neurological Syndromes such as Guillain-Barre Syndrome in Areas of Limited Healthcare Accessibility

Rural Medicine is not Permanently Paralyzed: A Systematic Online Review to Mitigate Misdiagnoses of Rare Neurological Syndromes such as Guillain-Barre Syndrome in Areas of Limited Healthcare Accessibility

Diet and Nutrients in Rare Neurological Disorders: Biological, Biochemical, and Pathophysiological Evidence.

Background/Objectives: Rare diseases are a wide and heterogeneous group of multisystem life-threatening or chronically debilitating clinical conditions with reduced life expectancy and a relevant mortality rate in childhood. Some of these disorders have typical neurological symptoms, presenting from birth to adulthood. Dietary patterns and nutritional compounds play key roles in the onset and progression of neurological disorders, and the impact of alimentary needs must be enlightened especially in rare neurological diseases. This work aims to collect the in vitro, in vivo, and clinical evidence on the effects of diet and of nutrient intake on some rare neurological disorders, including some genetic diseases, and rare brain tumors. Herein, those aspects are critically linked to the genetic, biological, biochemical, and pathophysiological hallmarks typical of each disorder. Methods: By searching the major web-based databases (PubMed, Web of Science Core Collection, DynaMed, and Clinicaltrials.gov), we try to sum up and improve our understanding of the emerging role of nutrition as both first-line therapy and risk factors in rare neurological diseases. Results: In line with the increasing number of consensus opinions suggesting that nutrients should receive the same attention as pharmacological treatments, the results of this work pointed out that a standard dietary recommendation in a specific rare disease is often limited by the heterogeneity of occurrent genetic mutations and by the variability of pathophysiological manifestation. Conclusions: In conclusion, we hope that the knowledge gaps identified here may inspire further research for a better evaluation of molecular mechanisms and long-term effects.

The Growing Role of Telerehabilitation and Teleassessment in the Management of Movement Disorders in Rare Neurological Diseases: A Scoping Review.

Background: People with rare neurological diseases (RNDs) often experience symptoms related to movement disorders, requiring a multidisciplinary approach, including rehabilitation. Telemedicine applied to rehabilitation and symptom monitoring may be suitable to ensure treatment consistency and personalized intervention. The objective of this scoping review aimed to emphasize the potential role of telerehabilitation and teleassessment in managing movement disorders within RNDs. By providing a systematic overview of the available literature, we sought to highlight potential interventions, outcomes, and critical issues. Methods: A literature search was conducted on PubMed, Google Scholar, IEEE, and Scopus up to March 2024. Two inclusion criteria were followed: (1) papers focusing on telerehabilitation and teleassessment and (2) papers dealing with movement disorders in RNDs. Results: Eighteen papers fulfilled the inclusion criteria. The main interventions were home-based software and training programs, exergames, wearable sensors, smartphone applications, virtual reality and digital music players for telerehabilitation; wearable sensors, mobile applications, and patient home video for teleassessment. Key findings revealed positive outcomes in gait, balance, limb disability, and in remote monitoring. Limitations include small sample sizes, short intervention durations, and the lack of standardized protocols. Conclusion: This review highlighted the potential of telerehabilitation and teleassessment in addressing movement disorders within RNDs. Data indicate that these modalities may play a major role in supporting conventional programs. Addressing limitations through multicenter studies, longer-term follow-ups, and standardized protocols is essential. These measures are essential for improving remote rehabilitation and assessment, contributing to an improved quality of life for people with RNDs.

Quality assurance for next-generation sequencing diagnostics of rare neurological diseases in the European Reference Network.

In the past decade, next-generation sequencing (NGS) has revolutionised genetic diagnostics for rare neurological disorders (RND). However, the lack of standardised technical, interpretative, and reporting standards poses a challenge for ensuring consistent and high-quality diagnostics globally. To address this, the European Reference Network for Rare Neurological Diseases (ERN-RND) collaborated with the European Molecular Genetics Quality Network (EMQN) to establish an external quality assessment scheme for NGS-based diagnostics in RNDs. The scheme, initiated in 2021 with a pilot involving 29 labs and followed by a second round in 2022 with 42 labs, aimed to evaluate the performance of laboratories in genetic testing for RNDs. Each participating lab analysed genetic data from three hypothetical cases, assessing genotyping, interpretation, and clerical accuracy. Despite a majority of labs using exome or genome sequencing, there was considerable variability in gene content, sequencing quality, adherence to standards, and clinical guidance provision. Results showed that while most labs provided correct molecular diagnoses, there was significant variability in reporting technical quality, adherence to interpretation standards, reporting strategies, and clinical commentary. Notably, some labs returned results with the potential for adverse medical outcomes. This underscores the need for further harmonisation, guideline development, and external quality assessment in the evolving landscape of genomic diagnostics for RNDs. Overall, the experience with the scheme highlighted the generally good quality of participating labs but emphasised the imperative for ongoing improvement in data analysis, interpretation, and reporting to enhance patient safety.

Metastatic Acute Myeloid Leukemia Presenting as Foot Drop: A Rare Neurological Manifestation (P11-11.018)

Metastatic Acute Myeloid Leukemia Presenting as Foot Drop: A Rare Neurological Manifestation (P11-11.018)

A Rare Neurological Presentation of Noonan Syndrome and Its Management—A Case Report

AbstractAlthough Noonan syndrome is a relatively common congenital disorder with autosomal dominant inheritance, its association with cerebrovascular anomalies is rare. We report a case of a 20-year-old with Noonan syndrome with cerebrovascular aneurysm, who underwent successful endovascular coiling. Only four cases of cerebrovascular aneurysms in Noonan syndrome have been reported in the literature so far. To the best of our knowledge, this is only the fifth reported case and the first one that has been treated successfully with endovascular coiling. We hereby discuss the management of this case, which had several comorbidities like congenital heart disease and craniovertebral junction anomaly.

Recommendations for optimal interdisciplinary management and healthcare settings for patients with rare neurological diseases

BackgroundIn 2017, the German Academy for Rare Neurological Diseases (Deutsche Akademie für Seltene Neurologische Erkrankungen; DASNE) was founded to pave the way for an optimized personalized management of patients with rare neurological diseases (RND) in all age groups. Since then a dynamic national network for rare neurological disorders has been established comprising renowned experts in neurology, pediatric neurology, (neuro-) genetics and neuroradiology. DASNE has successfully implemented case presentations and multidisciplinary discussions both at yearly symposia and monthly virtual case conferences, as well as further educational activities covering a broad spectrum of interdisciplinary expertise associated with RND. Here, we present recommendation statements for optimized personalized management of patients with RND, which have been developed and reviewed in a structured Delphi process by a group of experts.MethodsAn interdisciplinary group of 37 RND experts comprising DASNE experts, patient representatives, as well as healthcare professionals and managers was involved in the Delphi process. First, an online collection was performed of topics considered relevant for optimal patient care by the expert group. Second, a two-step Delphi process was carried out to rank the importance of the selected topics. Small interdisciplinary working groups then drafted recommendations. In two consensus meetings and one online review round these recommendations were finally consented.Results38 statements were consented and grouped into 11 topics: health care structure, core neurological expertise and core mission, interdisciplinary team composition, diagnostics, continuous care and therapy development, case conferences, exchange / cooperation between Centers for Rare Diseases and other healthcare partners, patient advocacy group, databases, translation and health policy.ConclusionsThis German interdisciplinary Delphi expert panel developed consented recommendations for optimal care of patients with RND in a structured Delphi process. These represent a basis for further developments and adjustments in the health care system to improve care for patients with RND and their families.

Inventory of current practices regarding hematopoietic stem cell transplantation in metachromatic leukodystrophy in Europe and neighboring countries

BackgroundFor decades, early allogeneic stem cell transplantation (HSCT) has been used to slow neurological decline in metachromatic leukodystrophy (MLD). There is lack of consensus regarding who may benefit, and guidelines are lacking. Clinical practice relies on limited literature and expert opinions. The European Reference Network for Rare Neurological Diseases (ERN-RND) and the MLD initiative facilitate expert panels for treatment advice, but some countries are underrepresented. This study explores organizational and clinical HSCT practices for MLD in Europe and neighboring countries to enhance optimization and harmonization of cross-border MLD care.MethodsA web-based EUSurvey was distributed through the ERN-RND and the European Society for Blood and Marrow Transplantation Inborn Errors Working Party. Personal invitations were sent to 89 physicians (43 countries) with neurological/metabolic/hematological expertise. The results were analyzed and visualized using Microsoft Excel and IBM SPSS statistics.ResultsOf the 30 countries represented by 42 respondents, 23 countries offer HSCT for MLD. The treatment is usually available in 1–3 centers per country (18/23, 78%). Most countries have no or very few MLD patients transplanted during the past 1–5 years. The eligibility criteria regarding MLD subtype, motor function, IQ, and MRI largely differ across countries.ConclusionHSCT for MLD is available in most European countries, but uncertainties exist in Eastern and South-Eastern Europe. Applied eligibility criteria and management vary and may not align with the latest scientific insights, indicating physicians’ struggle in providing evidence-based care. Interaction between local physicians and international experts is crucial for adequate treatment decision-making and cross-border care in the rapidly changing MLD field.

The Diagnostic Value of Whole-Exome Sequencing in a Spectrum of Rare Neurological Disorders Associated with Cerebellar Atrophy

Several neurological disorders, neurodevelopmental disorders, and neurodegenerative disorders have a genetic element with various clinical presentations ranging from mild to severe presentation. Neurological disorders are rare multifactorial disorders characterized by dysfunction and degeneration of synapses, neurons, and glial cells which are essential for movement, coordination, muscle strength, sensation, and cognition. The cerebellum might be involved at any time, either during development and maturation or later in life. Herein, we describe a spectrum of NDDs and NDs in seven patients from six Egyptian families. The core clinical and radiological features of our patients included dysmorphic features, neurodevelopmental delay or regression, gait abnormalities, skeletal deformities, visual impairment, seizures, and cerebellar atrophy. Previously unreported clinical phenotypic findings were recorded. Whole-exome sequencing (WES) was performed followed by an in silico analysis of the detected genetic variants’ effect on the protein structure. Three novel variants were identified in three genes MFSD8, AGTPBP1, and APTX, and other previously reported three variants have been detected in “TPP1, AGTPBP1, and PCDHGC4” genes. In this cohort, we described the detailed unique phenotypic characteristics given the identified genetic profile in patients with neurological “neurodevelopmental disorders and neurodegenerative disorders” disorders associated with cerebellar atrophy, hence expanding the mutational spectrum of such disorders.

Rare Neurological Complications in Thyroid Cancer Surgery

Rare Neurological Complications in Thyroid Cancer Surgery

Rare Neurological Manifestation of Thyroid Disorders – An Interesting Case Series

Background & Aims Disorders of thyroid gland are among the most common endocrine disorder. The neurologic disorders associated with thyroid dysfunction span the entire spectrum of neurology. Symptoms range from disorders of emotion and higher cognitive function to movement disorders, neuromuscular diseases and a range of rarer yet significant neurologic sequalae. Myopathy is the most common of the peripheral neurologic manifestations in both hypothyroidism and hyperthyroidism. Compressive mononeuropathies, namely carpal tunnel syndrome, are a major feature in hypothyroidism. At the level of the central nervous system, psychosis, personality change, mood disorder, confusion, dementia, coma, and seizures can occur in either hypothyroidism or hyperthyroidism. Movement disorders occur in hyperthyroidism, whereas ataxia and headaches are associated with hypothyroidism.

Child-to-adult transition: a survey of current practices within the European Reference Network for Rare Neurological Diseases (ERN-RND).

Transition from child-centered to adult-centered healthcare is a gradual process that addresses the medical, psychological, and educational needs of young people in the management of their autonomy in making decisions about their health and their future clinical assistance. This transfer is challenging across all chronic diseases but can be particularly arduous in rare neurological conditions. To describe the current practice on the transition process for young patients in centers participating in the European Reference Network for Rare Neurological Diseases (ERN-RND). Members of the ERN-RND working group developed a questionnaire considering child-to-adult transition issues and procedures in current clinical practice. The questionnaire included 20 questions and was sent to members of the health care providers (HCPs) participating in the network. Twenty ERN-RND members (75% adult neurologists; 25% pediatricians; 5% nurses or study coordinators) responded to the survey, representing 10 European countries. Transition usually occurs between 16 and 18years of age, but 55% of pediatric HCPs continue to care for their patients until they reach 40years of age or older. In 5/20 ERN-RND centers, a standardized procedure managing transition is currently adopted, whereas in the remaining centers, the transition from youth to adult service is usually assisted by pediatricians as part of their clinical practice. This survey demonstrated significant variations in clinical practice between different centers within the ERN-RND network. It provided valuable data on existing transition programs and highlighted key challenges in managing transitions for patients with rare neurological disorders.

Zebrafish Models of Rare Neurological Diseases like Spinocerebellar Ataxias (SCAs): Advantages and Limitations.

Spinocerebellar ataxia (SCA) is a heterogeneous group of rare familial neurodegenerative disorders that share the key feature of cerebellar ataxia. Clinical heterogeneity, diverse gene mutations and complex neuropathology pose significant challenges for developing effective disease-modifying therapies in SCAs. Without a deep understanding of the molecular mechanisms involved for each SCA, we cannot succeed in developing targeted therapies. Animal models are our best tool to address these issues and several have been generated to study the pathological conditions of SCAs. Among them, zebrafish (Danio rerio) models are emerging as a powerful tool for in vivo study of SCAs, as well as rapid drug screens. In this review, we will summarize recent progress in using zebrafish to study the pathology of SCAs. We will discuss recent advancements on how zebrafish models can further clarify underlying genetic, neuroanatomical, and behavioral pathogenic mechanisms of disease. We highlight their usefulness in rapid drug discovery and large screens. Finally, we will discuss the advantages and limitations of this in vivo model to develop tailored therapeutic strategies for SCA.

Systematic review of drug therapy for chorea in NXK2-1-related disorders: Efficacy and safety evidence from case studies and series.

The NKX2-1-related disorders (NKX2-1-RD) is a rare disorder characterized by choreiform movements along with respiratory and endocrine abnormalities. The European Reference Network of Rare Neurological Disorders funded by the European Commission conducted a systematic review to assess drug treatment of chorea in NKX2-1-RD, aiming to provide clinical recommendations for its management. A systematic pairwise review using various databases, including MEDLINE, Embase, Cochrane, CINAHL, and PsycInfo, was conducted. The review included patients diagnosed with chorea and NKX2-1-RD genetic diagnosis, drug therapy as intervention, no comparator, and outcomes of chorea improvement and adverse events. The methodological quality of the studies was assessed, and the study protocol was registered in PROSPERO. Of the 1417 studies examined, 28 studies met the selection criteria, consisting of 68 patients. The studies reported 22 different treatments for chorea, including carbidopa/levodopa, tetrabenazine, clonazepam, methylphenidate, carbamazepine, topiramate, trihexyphenidyl, haloperidol, propranolol, risperidone, and valproate. No clinical improvements were observed with carbidopa/levodopa, tetrabenazine, or clonazepam, and various adverse effects were reported. However, most patients treated with methylphenidate experienced improvements in chorea and reported only a few negative effects. The quality of evidence was determined to be low. The management of chorea in individuals with NKX2-1-RD presents significant heterogeneity and lack of clarity. While the available evidence suggests that methylphenidate may be effective in improving chorea symptoms, the findings should be interpreted with caution due to the limitations of the studies reviewed. Nonetheless, more rigorous and comprehensive studies are necessary to provide sufficient evidence for clinical recommendations.

Wernicke's Encephalopathy: A Rare but Avoidable Neurological Complication Associated with Allogeneic Stem Cell Transplant

Wernicke's Encephalopathy: A Rare but Avoidable Neurological Complication Associated with Allogeneic Stem Cell Transplant

Diagnosis and Management of Marchiafava-Bignami Disease, a Rare Neurological Complication of Long-term Alcohol Abuse.

Marchiafava Bignami disease (MBD) is a neurological disorder characterized by myelin degeneration and tissue necrosis within the central nervous system. This condition predominantly afflicts individuals with chronic alcohol abuse and malnutrition. The most distinctive pathological feature of MBD is the necrotic degeneration specifically observed in the corpus callosum; however, emerging evidence also indicates the potential involvement of other brain regions. The main pathophysiological mechanisms involve alcohol consumption, which leads to thiamine depletion and disrupts various metabolic pathways. This, in turn, hinders myelin synthesis and impairs signal transmission, resulting in a wide range of symptoms and signs. MBD can manifest in different stages, including acute, subacute, and chronic, each with varying severity. Diagnosing MBD can be challenging due to its presenting symptoms being nonspecific. In the era preceding the development of sophisticated imaging methodologies, the diagnosis of MBD was primarily established through postmortem examination conducted during autopsies. However, with a detailed medical history and imaging modalities such as magnetic resonance imaging (MRI) and computed tomography (CT), it is now possible to diagnose MBD and differentiate it from other diseases with similar clinical presentations. MRI is considered the gold standard for visualizing lesions in the corpus callosum and other affected areas. Also, positron emission tomography (PET), single photon emission computed tomography (SPECT), and magnetic resonance spectroscopy (MRS) could show brain damage in the corpus callosum associated with MBD. MRI-diffusion-weighted imaging (DWI) detects early lesions, while diffusion tensor imaging (DTI) investigates clinical manifestations and recovery. Poor prognostic indicators for MBD include extensive cerebral cortex involvement and severe disturbances in consciousness. Differential diagnosis involves ruling out other alcohol-related disorders, such as neoplastic conditions, Wernicke's encephalopathy, and multiple sclerosis, among others, through careful evaluation. The therapeutic strategies for the management of MBD are currently lacking definitive establishment; however, available evidence indicates that targeted interventions have the potential to induce amelioration. Corticosteroids offer prospective advantages in addressing brain edema, demyelination, and inflammation; research findings present a heterogeneous outcome pattern. Notably, thiamine treatment reduces the likelihood of unfavorable consequences, particularly when administered promptly, and thus is endorsed as the primary therapeutic approach for MBD. This review will highlight this rare disease that many healthcare providers might not be familiar with. By understanding its clinical presentation, differential diagnosis, imaging, and management, medical providers might better identify and diagnose MBD. Raising awareness about this condition can lead to better prevention, early detection, and timely intervention.

The Importance of Implementing a Transition Strategy for Patients with Muscular Dystrophy: From Child to Adult-Insights from a Tertiary Centre for Rare Neurological Diseases.

Progress in the field of muscular dystrophy (MD) using a multidisciplinary approach based on international standards of care has led to a significant increase in the life expectancy of patients. The challenge of transitioning from pediatric to adult healthcare has been acknowledged for over a decade, yet it continues to be a last-minute concern. Currently, there is no established consensus on how to evaluate the effectiveness of the transition process. Our study aimed to identify how well patients are prepared for the transition and to determine their needs. We conducted a descriptive, cross-sectional study on 15 patients aged 14 to 21 years. The patients completed a sociodemographic and a Transition Readiness Assessment Questionnaire (TRAQ). We also analyzed the comorbidities of these patients. Our study revealed that only 46.7% of the patients had engaged in a conversation with a medical professional, namely, a child neurologist, about transitioning. A total of 60% of the participants expressed having confidence in their self-care ability. However, the median TRAQ score of 3.6 shows that these patients overestimate themselves. We emphasize the necessity for a slow, personalized transition led by a multidisciplinary team to ensure the continuity of state-of-the-art care from pediatric to adult healthcare services and the achievement of the highest possible quality of life for these patients.

Two Cases of TMEM151A-Associated Paroxysmal Dyskinesia in a Single-Center Series of PRRT2-Negative Patients.

Two Cases of TMEM151A-Associated Paroxysmal Dyskinesia in a Single-Center Series of PRRT2-Negative Patients.

Exploring the values, preferences, and information needs of patients with NKX2-1-related disorders: A qualitative study protocol.

NKX2-1-related disorders have a prevalence of 1:500,000 and are therefore considered a rare condition according to the European Commission's definition. The European Reference Network of Rare Neurological Disorders is developing the first clinical practice guideline on the management of this condition, with the support of the Andalusian Health Technology Assessment Area, Endo-ERN, ERN-Lung and Imegen, within the framework of the ERNs Guidelines programme (DG SANTE/2018/B3/030). Within the scope of this programme, it becomes necessary to explore the patient perspective in order to include it in the ongoing clinical practice guideline and accompanying patient information booklet. This study will use qualitative methods to explore the values, preferences and information needs of patient with NKX2-1-related disorders and their caregivers. Participants will come from a variety of countries throughout Europe. One focus group and four semi-structured interviews will be conducted. Pairs will analyse the data using Grounded Theory. The Andalusian Regional Ministry of Health's Ethics Coordinating Committee for Biomedical Research (Sevilla, Andalucía, Spain) has approved this study protocol (29/03/2022). This is the first study to explore the values, preferences, and information needs of patients with NKX2-1-related disorders. The proposed study's findings will contribute to the generation of useful knowledge that will provide guidance to improve the care given to patients with the studied condition. While this study will provide valuable insights into the perspectives of patients with NKX2-1-related disorders, the findings are unlikely to be generalizable to patients with other conditions.