Rare neurologic diseases (RNDs) are illnesses with very low prevalence (2). In Europe, a low prevalence of rare diseases is defined as affecting fewer than 1 person per 2,000 individuals (3). There are over 6,000 rare diseases, of which more than 70% are of genetic etiology, approximately 70% are solely pediatric onset (4), and over half have neurologic or neuromuscular involvement (2). Although each rare disease has a relatively low prevalence individually, the cumulative point prevalence is substantial, at 3.5 to 5.9% globally, affecting approximately 260 to 450 million people (4).

Despite technological and therapeutic advances (5) and increased awareness (2), RNDs remain difficult to diagnose. First, since they are rare, a physician may consider more common illnesses of similar presentation before considering the RND, delaying a definitive diagnosis. For instance, the RND amyotrophic lateral sclerosis (ALS), that can present like several more common conditions, necessitates a lengthy differential diagnosis (6). Second, a general practitioner may misinterpret test results, misdiagnose, or fail to make a referral to a neurologist or neurologist specialist early enough in the diagnostic process (7), incurring additional delays. ALS can take between 10 to 16 months to diagnose due to such misdiagnoses and deferred referrals (8). Patients with other RNDs may wait 3 to 10 years before a diagnosis (7, 9). Lastly, although screening and diagnostic tests, such as genetic and genomic sequencing (10, 11), and specialist clinical care may facilitate diagnosis, availability may be limited due to high costs and lack of resources. Moreover, even when genetic or genomic testing are available, diagnostic yield is only 30 to 50% (12, 13), leading to undiagnosed RNDs.

Although once considered generally recalcitrant to treatment, an increasing number of disease-modifying therapies have become available for treating RNDs (14, 15). Moreover, some RND organizations have established guidelines for optimal multidisciplinary care of patients with RNDs (3, 16). Therefore, a timely diagnosis is crucial for earlier intervention. Nevertheless, many new disease-modifying therapies come with a hefty price tag, so treatment can be expensive (17), and, consequently, challenging if resources are limited, even when a diagnosis has been made.

We launched the current survey of neurologists to evaluate awareness and current diagnosis and care practices for RNDs. Specifically, we assessed neurologist attitudes and awareness towards RNDs, presence of RND specialty centers, and availability of diagnostic tests and treatments for RNDs in the home country of respondents. The survey was administered to senior neurologists involved in the different committees and boards of the World Federation of Neurology (WFN). We summarized survey responses stratified by practicing country by geographic region (Africa, Americas, Asia/Oceania, Europe), and income groups (higher, upper-middle, lower-middle, lower) as defined by the World Bank Classification.

In this study, we surveyed attitudes towards RNDs and diagnostic and care availability in the country of practice of eminent neurologists across the world. This was the first survey, to our knowledge, to assess the state of RND awareness and care practice among neurologists globally. We found that 89% of respondents agreed that RND patients deserved the same level of attention and care as patients with more common neurological conditions. Yet, 56% of respondents did not believe their country is well organized for diagnosis and care for patients with RNDs. Importantly, 35% of respondents from higher-income countries replied they did not know of a rare disease plan and there were also significant knowledge gaps regarding the availability of dedicated pediatric or adult RND centers, prenatal diagnosis, and treatment, across regions and income groups. Notably, there were significant differences by region and income groups, indicating there may be substantial disparities in terms of accessibility to RND diagnostic tools and treatments by geographic regions and income levels. Specifically, access to diagnostic tests and treatments were lower in respondents from Africa and access dropped as respondent’s country income level decreased.

Few surveys have been conducted of awareness of RNDs among neurologists or physicians more broadly. A 2021 survey of 239 members of the European Academy of Neurology (EAN) spanning 40 European countries found high levels of recognition of RNDs (19). On the other hand, a 2019 survey of Italian neurologists (n=104) found good awareness among members of the Italian Society of Neurology, Neurogenetics and Rare Neurologic Diseases Scientific Group, but relatively irregular awareness at the national and regional levels (20), underscoring knowledge gaps among neurologists despite national initiatives. In addition, surveys of awareness of rare diseases among medical (21, 22), nursing, and physiotherapy (22) students in Poland found knowledge gaps regarding RND prevalence, proportion ascribed to genetic etiology, and more frequent onset in pediatric patients. We also observed a significant knowledge gap relating to RND resources in the respondent’s countries. Taken together, these findings highlight the need for improved RND education to ensure patients with RND receive appropriate and timely care (19–22).

We found that while 89% of neurologists believed patients with RNDs should receive timely access to care and treatment, only 44% believed their country was well-situated to do so. Global initiatives are needed to improve the ability to care for RNDs for neurologists in these countries. There are several organizations that promote RND awareness and/or advocate for patient representation, such as the European ORPHANET (4) and EAN (23) and the European Reference Networks, including the one for Rare Neurological Diseases (ERN-RND), EpiCare, EURO-NMD (24, 25). National organizations have also been established, such as the Italian National Network of Accredited Centres (20, 26). Registries are also an important step forward towards increasing RND visibility, and several such efforts have been launched, such as the Italian National Registry of Rare Diseases (26) and the US-led Global Rare Diseases Patient Registry Data Repository (27). Although these organizations’ efforts have borne fruit in raising awareness, nonetheless, knowledge gaps remain and access to RND diagnostic tools and care remains suboptimal, particularly in lower-income countries.

Neurologists practicing in Africa and in lower-middle- and lower-income countries reported their countries had the lowest preparedness and ability to diagnose and treat RND patients. This problem is not unique to Africa and lower-income countries; a survey of European EAN members found that almost one third of responders were dissatisfied with the protocol for ordering genetic tests in their country (19), which would hinder diagnostic capacity. In Italy, survey neurologists stated an RND diagnosis was possible in 75% of cases, but that it varied by specific RND (20). Therefore, diagnostic gaps remain for patients with RND, even in more resource rich settings. We also found that countries in Africa and of lower income lacked a national rare disease plan, and, we identified substantial knowledge gaps regarding availability of a national rare disease plan, even among respondents from higher-income countries. Our findings are aligned the Italian survey of neurologists that noted around 20% were unaware that coordinated care was available for RND patients through dedicated national centers (20). Thus, even knowledge of resources for RNDs is suboptimal.

Most RNDs, around 70%, have a pediatric onset (4), which makes the distinction between RND centers dedicated to children and adults important. However, our survey highlighted a lack of RND centers dedicated to pediatric patients in lower-income countries. Critically, a sizable number of respondents practicing in countries across all income groups were unaware whether RND centers dedicated to pediatric patients were available, indicating knowledge gaps more broadly. Findings were similar when we queried about adult RND centers, albeit the knowledge gap was less significant. A small survey of 20 ERN-RND members emphasized the challenges of transitioning pediatric RND patients to the care of an adult neurologist (28). Consequently, around half of pediatric health care providers continued to care for their RND patients well into adulthood. Although small, the study may suggest a disconnect in care between pediatric and adult RNDs, possibly the result of an on-going knowledge gap.

We also found suboptimal access to newborn screening and prenatal testing in countries in Africa and of lower-middle- to lower-income. However, this lack was by no means limited to these regions and socioeconomic groups, since availability was not 100% in higher- or upper-middle income countries for newborn screening and reached only 58% (higher-income) and 29% (upper-middle income) for prenatal screening. Moreover, 35% of neurologists practicing in higher- and 29% in upper-middle income countries replied they were unaware about availability of prenatal screening, a considerable knowledge gap. Our findings are similar to an EAN survey, which found that almost 10% of neurologists queried were unfamiliar with availability of prenatal diagnosis, while nearly 50% were uncertain about newborn screening programs (19). In an Italian survey, 40% of surveyed neurologists were unaware of newborn testing (20). Therefore, this issue is a global one, not limited only to some regions and income groups.

RND diagnoses are challenging because of their rare and complex nature. Several diagnostic tools are available to facilitate diagnosis, but they range greatly in cost, and, therefore, accessibility. Indeed, we observed that RND diagnostic tool availability differed by region and country income. Nevertheless, we identified a few diagnostic modalities that were widely adopted across all regions and income groups, which included routine blood and urine examination, tissue biopsy (brain biopsy to a lesser extent), neurophysiology (evoked potentials to a lesser extent), and some imaging methods. However, several more advanced imaging platforms as well as non-routine biochemical tests and molecular PCR and sequencing methods were generally less available in Africa and Asia/Oceania and lower-middle- and lower-income countries. Despite better availability in higher-income countries, the process may remain cumbersome; the EAN survey underscored the challenges of ordering genetic testing in Europe (19). In Italy, almost 30% of neurologists referred their patient to a center outside their region of practice and reported variability in diagnostic tool availability (12 to 99%) based on the RND center expertise (20). Therefore, lack in access to diagnostic tools remains broadly across the world, although some regions experience greater shortages.

It may be possible to tackle the lack of availability in diagnostic tools, for instance of molecular tests. A recent genetic testing study of adult RND patients (n=377) found that diagnostic yield was 32% overall, but varied by approach, and was actually highest by directed testing (50%), a less costly approach, than exome testing, which had only a 25% diagnostic yield (12). The outperformance of more targeted sequencing strategies, such as gene panels may be condition-dependent, e.g., muscle diseases, and could offer a cost-effective first-line solution for well-defined phenotypes (12, 13). However, next generation sequencing may be better geared for more phenotypically heterogeneous RNDs (13). By identifying what RND a patient may have can help prioritize targeted versus next generation sequencing, helping physicians allocate resources more effectively. Moreover, as next generation sequencing costs continue to drop, it will render the technology more accessible, even in lower resource settings.

Our last set of survey questions concerned RND treatment accessibility, which again showed variation by region and income groups, especially for newer therapies such as gene therapy and enzyme replacement therapy. Few surveys have been conducted of disease-modifying therapy for RNDs; a recent survey of Italian centers queried treatment for spinal muscular atrophy, noting higher disease prevalence possibly as a result of adoption of disease-modifying therapies, including gene replacement and antisense oligonucleotides (29). On the other hand, we found RND-specific drugs did not vary by region, although access significantly dropped step-wise with lower practice country income. Coverage of RND treatment cost was also variable, and less covered outside of Europe and within lower-income countries. Nevertheless, coverage was not universal in higher-income countries. Increasing access to disease-modifying therapies, even in higher-income countries, is a primary concern for patients because they significantly improve patient outcomes (30, 31). In a survey of patient representatives (n=95), almost half stated that developing therapies and preventive strategies was their main priority, given the direct impact of RNDs on their well-being, while professionals (n=61) favored investigation of disease mechanisms and models, with the ultimate goal of developing treatments (24). We highlight, herein, remaining work to be done to enhance access to disease-modifying therapies for RND patients.

Our study has some limitations. First, this was a scoping survey that was not validated. Moreover, respondents may have differed in their definitions, e.g., a “specific drug for RNDs”. Second, the study was relatively small overall, and even smaller by some regions and income groups. Consequently, responses by regions with few respondents may not be representative of the continent, which may be more heterogeneous and not reflected in this survey. Likewise, replies from the few respondents practicing in upper-middle-, middle-, and lower-income countries may not be characteristic of those income groups. This relatively small respondent sample size also precluded analysis of replies by country, but many respondents from one country within a region may have biased findings for that region. In addition, given our sample size, we were unable to account for differences between specific countries within a region. Furthermore, the response rate was low (34%), and regional disparities in participation were evident. Neurologists practicing in Europe were overrepresented among survey participants, constituting 51.6% of respondents compared to their estimated WFN membership proportion of 33.3%. However, participants from Asia-Oceania constituted 17.2% of respondents versus 23.5% of membership while participants from the Americas constituted 15.6% of respondents versus 27.5% of membership, and were, therefore, underrepresented in the survey. Participants from Africa constituted 15.6% of respondents and participated in proportion to their 15.7% of membership. Nevertheless, disparities in participation across Europe, Asia-Oceania, and the Americas may have biased results, and respondents more interested in sharing their knowledge and perspectives may have been more likely to participate in the survey.

Our study has some strengths and was a unique opportunity to query attitudes about care for RND patients and treatment and diagnostic availability in the country of practice of a cohort of esteemed neurologists. Our study highlighted some disparities in resource access, but also some strengths, for instance, in some diagnostic modalities, such as tissue biopsy and neurophysiology, even in lower resource settings. This suggests a potential approach for RND diagnosis in that context. Interestingly, our study also revealed some substantial knowledge gaps in RND care and diagnosis, even in higher- and upper-middle-income countries, signifying that, even among established neurologists, knowledge of RNDs and the infrastructure to care for patients remains suboptimal. Awareness campaigns may be warranted. Therefore, further research and initiatives are crucial to advance the diagnosis and care of RND worldwide, even in higher income countries (23, 25). Efforts should focus on improving diagnostic capabilities, fostering collaboration among neurology centers, and promoting education on the unique challenges and treatment options to improve outcomes and quality-of-life for RND patients.