The experience of living with Niemann–Pick type C: a patient and caregiver perspective

To further our understanding of the impact of NPC, particularly the central phenotypes of the disease, qualitative interviews were held with a diverse spectrum of NPC patients and their caregivers. Our qualitative discussions with NPC patients and families centered around two objectives. The first objective was to assess the occurrence and variable manifestations of the signs and symptoms of NPC, as well as the impact they have on the lives of patients and caregivers. Relatedly, the second objective was to gain a deeper understanding of the various facets of NPC that are critical from the perspective of NPC patients and caregivers, as well as the challenges NPC families face when participating in clinical research. The information gathered from pursing these two objectives can be used in order to better shape the design of future studies on the central manifestations of NPC, specifically those incorporating structural and functional MRI.

The impact NPC has on the lives of affected individuals is variable but nonetheless deeply profound. Cognitive difficulties (memory deficits or executive dysfunction), motor function impairment, psychosocial challenges (verbal communication difficulties, loss of autonomy, and social exclusion), and other specific symptoms such as dysphagia, ataxia, dysarthria, and hearing loss were among the most important current and past concerns for patients and caregivers. These were also reported to be the most bothersome symptoms, as well as the most prioritized symptoms in need of treatment from the perspective of patients with NPC or their caregiver. Caregivers, primarily parents of individuals with NPC, noted that the outcome of NPC-related signs and symptoms combined with the fact that there remain limited treatment options for patients has brought on emotional difficulties that are perhaps unappreciated from an outside perspective. Mainly, it is not solely that there is a loss of cognitive or motor ability, but perhaps equally important, these and other central manifestations of the disease hinder a parents’ experience of seeing their children reach certain physical, educational, or social milestones in life or attain a basic level of independence or autonomy. In cases where a family consists of multiple NPC patients, the burden of the disease is understandably compounded and high for the caregiver as the clinical presentation and daily or long-term needs for each patient can vary.

In addition to concerns that arose and continue to persist following their NPC diagnosis, many individuals acknowledged their experiences and frustrations with delays in a correct NPC diagnosis. For the late-infantile and juvenile forms of NPC, diagnosis is, on average, delayed by ~ 4.1 years [14]. In our representative population, participants experienced, on average, a 7.6-year delay between symptom onset and receiving an NPC diagnosis. These lengthy diagnostic delays not only lead to years of uncertainty and misdiagnosis for families and individuals, but potentially result in lost opportunities for earlier disease management or targeted, symptom-specific treatment plans [4]. Participants cited heterogeneous presentation, early non-specific symptoms, and lack of clinician awareness about NPC as diagnostic hindrances. Patients in the study presented with a wide variability in symptom manifestation. Even among sibling groups (sibling set 1: patients 9 and 10; sibling set 2: patients 14–16; sibling set 3: patients 17 and 18), there exist diverse clinical presentations (Table 2). The lack of correlation between relatedness and symptom onset or disease severity is especially notable in the sibling group of patients 14–16. Patient 14 is non-ambulatory, non-verbal, and requires a GI-tube for feeding. Their siblings, in contrast, are ambulatory, verbally communicative, and eat without assistance, and instead experience psychiatric manifestations and memory impairment. Several participants noted a childhood diagnosis of attention-deficit hyperactivity disorder, difficulties in school, and poor memory at a young age as early clinical or behavioral indicators that went largely unrecognized or, at the very least, under-appreciated by caregivers, clinicians, or teachers. Others experienced gait impairment, uncontrollable twitches, and issues with tripping, falling, and poor balance. Additionally, multiple participants had severe psychiatric manifestations and were misdiagnosed with schizophrenia spectrum disorder, bipolar disorder, or other psychiatric syndromes, causing months-to-years long delays in proper diagnosis and likely exposure to unnecessary or non-efficacious treatments. A robust and unfortunate example of such a case is patient 11, who did not receive a correct NPC diagnosis for more than a decade after the parent noted symptom onset. These experiences of misdiagnoses or delays in diagnoses as reported by the patients and caregivers underscore the ongoing need for timely diagnosis and early intervention.

Several tools are available to aid clinicians in identifying the signs and symptoms of NPC and to measure overall disease burden and treatment efficacy. Clinical measures include the NPC Suspicion Index Tool [16], NPC Clinical Severity Scale (NPCCSS) [17], and the Assessment and Rating of Ataxia (SARA) scale [18, 19]. In addition to these benchmark clinical instruments, circulating biomarkers such as bile acids (of 3β-sulfooxy-7β-N-acetylglucosaminyl-5-cholen-24-oic acid and its glycine- and taurine-amides), and lysoSM-509 (N-palmitoyl-O-phosphocholineserine [PPCS]) are used for NPC diagnosis [20,21,22]. However, their ability to detect central therapeutic responses remains ambiguous [22, 23]. While benchmark clinical tools assess for cognition and decline in mobility [10, 24], multiple participants expressed a desire for a more tangible measure of disease progression and/or therapeutic response. Currently in NPC, there are no validated biomarkers that closely associate with central nervous system (CNS) manifestations or disease progression.

Despite a strong desire and interest towards participating in research studies, NPC patients and caregivers may hesitate to become involved in clinical investigations, particularly those encompassing potentially demanding methods such as MRI or other forms of neuroimaging. On one hand, identifying and validating new tools or approaches that can accurately inform on CNS disease in NPC are critically needed, while on the other hand, newly developed tools should be feasible to employ across a broad spectrum of patients with NPC who can vary according to age, disease severity, and overall clinical presentation. From our focus group discussions, there was an openness to participate in a wide range of studies. However, barriers to do so were mainly logistical in nature for a subpopulation of the current NPC cohort. Caregivers or NPC patients themselves reported that transportation comes with many challenges, due largely in part to patients travelling with medical equipment, being non-ambulatory, or requiring some level of supervision from a caregiver due to cognitive or motor-related impairments. However, provided that logistical support and resources (for patient and caregiver) are well-organized ahead of time by members of the study team, study participation to even distant study sites were not considered a major hurdle. With regards to undergoing MRI procedures, most focus group participants noted no prior issue undergoing imaging, while some noted that sedation was necessary during MRI and at earlier stages of the disease when the NPC patient was in a less stable mental and physical state. Experiencing claustrophobia, anxiety, or involuntary movements in an MRI environment was noted by several caregivers, but most expressed that this challenge could be overcome using non-sedative means (i.e., music, having someone within the MRI room, or undergoing some preparations in a mock MRI environment).

The presence of cognitive impairment was a very common symptom that diminished the quality of life for NPC patients or represented a common source of concern for all study participants. This was true independent of past or current status of disease or symptom severity. Although many individuals in our cohort were considered to have adult-onset NPC, for which cognitive impairment is often present [6, 8], concerns related to cognition also extend to younger patients and their caregivers. Both patients and caregivers expressed worry about the decline of cognitive abilities and described this loss of function as greatly contributing to reductions in independence. Understanding the biobehavioral basis of cognitive dysfunction in NPC is paramount, but also a challenging task in NPC. For example, although there are numerous neuropsychological tests such as the N-Back, Stroop, or Go-No Go tasks, which are frequently employed as strictly behavioral methods or in combinations with fMRI data acquisition, their incorporation in an NPC study may be challenging as the cognitive capabilities and a basic understanding of task procedures can be difficult for many low functioning NPC patients with progressive disease [25,26,27]. Therefore, an implementation of behavioral assessments and batteries such as the Kaufman Assessment Battery for Children (KABC-II) or the Vineland Adaptive Behavior Scale should be considered as these tools are better suited for individuals with intellectual or developmental disabilities [28]. Additionally, use of low burden, resting-state fMRI procedures might also be considered for studies aiming to uncover and characterize functionally affected CNS circuitry in NPC patients [29,30,31,32,33].

Given the overall framework of focus groups, discussions occurring in this context generally offer an opportunity for study teams to perform a deep dive into severe, complex, and heterogeneous diseases such as NPC. Dialogue occurring during focus groups can facilitate an engaging and flexible conversation, where patients and caregivers can communicate various aspects of living with a chronic disease without the constraints of, for example, clinical questionnaires or behavioral tasks. Nonetheless, this focus group consisted of multiple limitations. Firstly, information gathered from this focus group is primarily qualitative or semi-quantitative in nature at best. In our experience, participants were open and forthcoming, but we recognize that some aspects of living with NPC or having a child or partner with NPC may be emotionally challenging, making certain elements of NPC difficult to articulate. Secondly, the participants in our focus group had variable access to informed clinical care, either prior to or during the time of diagnosis, as well as presently; some individuals had access to physicians and clinical care staff intimately familiar with NPC, while others in a different geographical setting had more limited access. This variable access to healthcare relevant to NPC may have contributed to the heterogeneity of concerns raised by patients and caregivers. Unfortunately, the current study could not disentangle the exact causes underlying the issues raised during the focus group. Finally, the sample size of this study (N = 19) was also moderate, which limited our ability to make distinctions between, for example, early vs. late diagnosis. Yet, this study provides the impetus for designing studies to identify certain phenotypes and further developing more detailed hypotheses to test in future investigations.

While the current study findings were derived from NPC patients and families, there are indeed parallels with other rare disease populations in terms of the impact that the illness has on primary caregivers [34,35,36,37]. Given the wide range of emotional, physical, and logistical demands that family members or caregivers often face daily, there are universal problems imposed on the caregiver that reduce their overall health-related quality of life, ability to pursue personal goals and objectives, or productivity. Moreover, when planning prospective investigations involving NPC patients and other rare disease populations, the burden on caregivers should also be considered and steps taken to minimize challenges these individuals may face throughout the study.

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