Multidomain Fatigue, Cognitive, and Quality of Life Observations in Generalized Myasthenia Gravis Under Ravulizumab: A Case Series

Abstract

Introduction

This study aimed to explore fatigue and cognitive features as underrecognized non-motor dimensions in myasthenia gravis (MG), and to describe multidomain observations following initiation of ravulizumab in older adults with generalized myasthenia gravis (gMG).

Methods

Three acetylcholine receptor antibody-positive older adults with gMG underwent a standardized multidomain evaluation, including clinical outcomes, patient-reported measures of fatigue and quality of life, and performance-based cognitive assessment. Clinical severity was assessed using the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale and the Quantitative Myasthenia Gravis (QMG) score. Fatigue was assessed using the Neuro-QoL Fatigue scale and the Modified Fatigue Impact Scale (MFIS), and quality of life using the Myasthenia Gravis Quality of Life scale (MG-QoL). Cognitive performance was assessed using the Trail Making Test (TMT). Assessments were performed at baseline and repeated after approximately 12 months and analyzed descriptively.

Results

Three patients were enrolled. At baseline, MG-ADL scores ranged from 9 to 10 and QMG scores from 10 to 17. Neuro-QoL Fatigue T-scores ranged from 66 to 70, and MFIS total scores from 18 to 43, with MFIS cognitive subscores ranging from 5 to 21. TMT part B completion times ranged from 284 to 300 s in two patients, while one patient was not evaluable. At follow-up, MG-ADL scores were 7, MG-QoL scores ranged from 10 to 14 (from baseline 22–25), Neuro-QoL Fatigue T-scores were lower by 13–17 points, and MFIS total scores were lower by 3, 20, and 9 points across patients. Changes in MFIS cognitive subscores varied, with one patient showing a slight increase (5 → 6) and others showing reductions. One patient transitioned from non-evaluable to evaluable TMT part B performance, while switching cost showed heterogeneous changes across patients.

Conclusion

This exploratory case series describes heterogeneous multidomain trajectories across clinical, fatigue, and cognitive measures in gMG. The findings highlight the feasibility of integrating multidomain assessment of non-motor symptoms in this population, without supporting causal inferences regarding treatment effects.

Key Summary Points

Cognitive fatigue is an underrecognized non-motor feature in generalized myasthenia gravis.

This study explored fatigue, cognitive performance, and quality of life before and after ravulizumab using a multidomain assessment.

Clinical stabilization was accompanied by reductions in fatigue and lower quality-of-life burden, with heterogeneous changes in cognitive performance across patients.

Introduction

Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction characterized by fluctuating weakness and fatigability [1]. Clinical evaluation and treatment decisions primarily focus on motor manifestations, while non-motor symptoms are less systematically addressed. Nevertheless, many patients report cognitive complaints, including mental slowness, reduced attentional stamina, fluctuating clarity, and a subjective sense of “cognitive fog” [2]. These experiences are frequently described in clinical practice but remain poorly defined. Available evidence suggests that global cognitive impairment is uncommon in MG. However, subjective cognitive difficulties may arise from interacting factors such as fatigue, increased cognitive effort during motor fluctuation, sleep disturbance, medication effects, and emotional burden [2, 3]. These symptoms may therefore reflect functional inefficiency rather than structural cognitive decline. Complement inhibition has been associated with disease stabilization in generalized MG (gMG) and may be hypothesized to influence non-motor symptom burden by reducing fatigability and performance variability [4, 5].

This exploratory case series aims to characterize baseline multidomain profiles, including clinical, fatigue-related, and cognitive features, in older adults with gMG, and to describe multidomain observations following initiation of ravulizumab, with particular attention to cognitive fog as a patient-reported symptom.

Methods

Study Design and Setting

This observational exploratory case series was conducted at the BRAND Center, University of Foggia, Foggia, Italy. Ravulizumab, a long-acting anti-C5 complement inhibitor, was prescribed according to national regulatory indications and reimbursement criteria, in compliance with Italian Medicines Agency regulations for gMG. Patients were consecutively evaluated in a real-world clinical setting. Treatment decisions were made independently of this observational assessment.

Ethical Approval

The study protocol was approved by the local ethics committee (Comitato Etico Foggia, CE/47/2025/PO). This study was conducted in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments. All participants provided written informed consent for clinical and cognitive assessment and for the anonymized use of their data.

Participants

Three older adults with acetylcholine receptor antibody-positive gMG underwent a baseline multidomain evaluation prior to initiation of ravulizumab.

Assessments

All clinical, patient-reported, and cognitive assessments were performed at baseline (prior to ravulizumab initiation) and repeated at follow-up after approximately 12 months in all participants.

All clinical and patient-reported outcomes were available for all patients at both time points. Cognitive testing was performed in all patients; however, in one patient, the Trail Making Test partB (TMT-B) at baseline was attempted but not completed within the allowable time and was therefore considered non-evaluable.

Clinical Outcomes

Disease severity and functional impact were assessed using the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale [6] and the Quantitative Myasthenia Gravis (QMG) score [7]. Baseline body mass index (BMI) information was also collected.

Patient-Reported Outcomes

Patient-reported outcomes were used to assess quality of life (QoL) and fatigue.

Myasthenia Gravis QoL

Disease-specific quality of life was assessed using the MG-QoL. Higher scores indicate worse QoL [8].

Neuro-QoL Fatigue

The Neuro-QoL Fatigue scale was used to evaluate perceived fatigue severity. Scores are expressed as T-scores standardized to a reference population, in which 50 represents the mean and 10 the standard deviation; higher scores indicate greater fatigue. [9].

Modified Fatigue Impact Scale

The Modified Fatigue Impact Scale (MFIS) was used to assess the impact of fatigue on daily functioning across physical, cognitive, and psychosocial domains [10]. The MFIS yields a total score and domain-specific subscores, including a cognitive subscale, with higher scores indicating greater fatigue-related impact.

Cognitive Evaluation

Attention and cognitive flexibility were assessed using the TMT, a performance-based measure of processing speed (part A) and executive function, including cognitive flexibility, attentional set-shifting, and divided attention (part B), with analysis of total completion time and switching cost [7]. Memory recall task data were not included because of incomplete or non-standardized availability. Cognitive testing was administered under standardized conditions by trained personnel.

Statistical Analysis

Given the very small sample size (n = 3), analyses were purely descriptive. Data are presented at the individual patient level, with simple summaries where appropriate, and changes over time are described without formal statistical testing. To aid interpretation, observed changes were contextualized with reference to established benchmarks for clinical meaningfulness where available. In particular, a reduction of ≥ 2 points in MG-ADL was considered clinically meaningful [11]. For MG-QoL, changes exceeding approximately 3–4 points were interpreted as clinically meaningful [12]. For QMG, changes were interpreted descriptively without applying predefined thresholds for clinical meaningfulness. For Neuro-QoL Fatigue, in the absence of disease-specific minimally important differences, changes of approximately 0.5 standard deviations (approximately 5 T-score points) were considered indicative of clinically meaningful change [13]. For MFIS, minimally important differences are less well established, and changes were therefore interpreted descriptively [10].

The TMT performance was interpreted with reference to age-adjusted normative values, with markedly prolonged completion times considered indicative of impaired performance relative to expected ranges in older adults [14, 15].

Results

Patient Characteristics and Clinical Outcomes

Three patients with gMG were included in this exploratory case series. The main demographic and baseline clinical characteristics are summarized in Table 1. Mean age was 73 years (range 72–75), and mean BMI was 27.9 (range 24.7–34.2). Baseline disease severity was mild to moderate, with QMG scores ranging from 10 to 17 and MG-ADL scores ranging from 9 to 10.

Table 1.

Demographic and clinical characteristics and Myasthenia Gravis Quality of Life (MG-QoL) scores

Patient no.	Age (years)	Sex	BMI	MG-ADL (baseline)	MG-ADL (follow-up)	MG-QoL (baseline)	MG-QoL (follow-up)
1	72	M	24.7	10	7	25	14
2	75	F	24.9	9	7	22	12
3	72	M	34.2	9	7	23	10

BMI body mass index, MG-ADL Myasthenia Gravis Activities of Daily Living, MG-QoL Myasthenia Gravis Quality of Life Scale

Following treatment with ravulizumab, MG-ADL scores declined from baseline values of 9–10 to a post-treatment score of 7 in all cases (Fig. 1a). QMG scores ranged from 8 to 15 at follow-up.

Fig. 1.

Individual paired changes from baseline to follow-up in a Myasthenia Gravis Activities of Daily Living (MG-ADL) scores, b Neuro-QoL Fatigue T-scores, and c Modified Fatigue Impact Scale (MFIS) total scores in patients with generalized myasthenia gravis treated with ravulizumab

Patient-Reported Outcomes

MG-QoL

MG-QoL scores ranged from 10 to 14 at follow-up, compared with baseline values ranging from 22 to 25 (Table 1).

Fatigue Outcomes

Neuro-QoL Fatigue

Neuro-QoL Fatigue T-scores were lower at follow-up compared with baseline (Fig. 1b). Individual reductions ranged from 13 to 17 points (Table 2).

Table 2.

Fatigue outcomes at baseline and follow-up

Patient no.	Neuro-QoL Fatigue (baseline)	Neuro-QoL Fatigue (follow-up)	MFIS total (baseline)	MFIS total (follow-up)	MFIS cognitive (baseline)	MFIS cognitive (follow-up)
1	70	54	18	15	5	6
2	66	53	43	23	21	4
3	69	52	42	33	20	16

Higher scores indicate greater fatigue severity for Neuro-QoL Fatigue T-scores and greater fatigue impact for MFIS. Neuro-QoL Fatigue is reported as standardized T-scores

MFIS Modified Fatigue Impact Scale, NeuroQoL Quality of Life in Neurological Disorders

MFIS

MFIS total scores were lower at follow-up in all three patients (Fig. 1c), with baseline values ranging from 18 to 43 and post-treatment values ranging from 15 to 33. MFIS cognitive subscores showed variable individual changes, with mean values of 15.3 at baseline to 8.7 at follow-up (Table 2).

Cognitive Evaluation

Individual TMT results are reported in Table 3, including part A, part B, and the switching cost (B − A difference, when evaluable).

Table 3.

Trail Making Test (TMT) at baseline and follow-up

Patient no.	TMT-A (baseline, s)	TMT-A (follow-up, s)	TMT-B (baseline, s)	TMT-B (follow-up, s)	Switching cost B − A (baseline, s)	Switching cost B − A (follow-up, s)
1	94	44	284	203	240	159
2	98	78	NE	350	NE	272
3	99	20	300	280	201	260

Trail Making Test (TMT) performance is reported as completion time in seconds. The B − A difference reflects attentional switching cost. NE not evaluable; indicates that a valid TMT-B score could not be obtained, and switching cost was therefore not defined

In one patient, TMT-B at baseline was attempted but not completed within the allowable time and was therefore considered non-evaluable. In the remaining patients, switching cost could be calculated at both time points.

At baseline, two patients showed prolonged TMT-B completion times and increased switching cost despite relatively preserved processing speed on TMT-A (Table 3). At follow-up, switching cost showed variable patterns, with one patient showing a reduction and one an increase despite lower TMT-A completion times.

Discussion

In the present case series, we describe multidomain observations in patients with gMG treated with ravulizumab, integrating clinical outcomes, patient-reported measures of QoL and fatigue, and performance-based cognitive measures. Given the small sample size and descriptive design, findings should be considered hypothesis-generating. Fatigue in neurological disorders is increasingly conceptualized as a multidimensional phenomenon, encompassing physical and cognitive and motivational components rather than a unidimensional symptom directly attributable to motor impairment alone [16, 17]. In this context, patients with MG frequently report subjective experiences of cognitive fog, characterized by reduced mental clarity, attentional stamina, and increased perceived cognitive effort [18]. These features may reflect altered efficiency under sustained demand rather than structural cognitive impairment, and provide a framework for interpreting non-motor outcomes in this population. In our cohort, MG-ADL scores were lower at follow-up across patients. These changes were accompanied by variable patterns in QoL and fatigue measures. Neuro-QoL Fatigue T-scores ranged from 13 to 17 points, a magnitude commonly considered clinically meaningful. Changes in MFIS total and cognitive subscores showed variability across patients, and are therefore interpreted descriptively. Overall, these findings support the importance of fatigue as a key non-motor domain in MG, while emphasizing individual variability.

The clinical interpretation of observed changes should be interpreted in light of available benchmarks (see “Methods”). Reductions in MG-ADL of 2–3 points are generally considered clinically relevant, and changes in MG-QoL exceed commonly reported minimally important differences (approximately 3–4 points). For Neuro-QoL Fatigue, observed reductions fall within a range generally considered important in clinical practice. For MFIS, minimally important differences are less well established, and results are therefore interpreted descriptively.

Cognitive assessment was intentionally focused on efficiency-based measures rather than global cognitive screening, in line with contemporary views distinguishing impaired performance from structural cognitive impairment. TMT performance revealed heterogeneous individual trajectories. At baseline, markedly prolonged TMT-B completion times and task non-completability in one patient were observed. In age-referenced normative samples, completion times in the range observed (approximately 280–300 s) correspond to performance within the lowest percentiles of healthy older adults. These findings may reflect impaired function rather than isolated inefficiency, and should therefore be interpreted with caution [14, 19]. At follow-up, one patient transitioned from non-completable to completable TMT-B performance, while switching cost showed variable changes across patients. Importantly, switching cost was only interpreted when both TMT-A and TMT-B were evaluable, and changes in task feasibility were considered separately from quantitative measures. Overall, the variability observed suggests that switching cost may have limited utility as a stable outcome measure in this context.

Changes in TMT performance should also be interpreted in light of potential confounding factors. Practice effects associated with repeated test administration and regression to the mean may contribute to apparent changes, particularly in small samples with extreme baseline values [20]. In the absence of a control group, these effects cannot be disentangled from potential treatment-related changes.

Taken together, the reported data on fatigue, QoL, and performance-based cognitive measures highlight the complexity of non-motor symptom assessment in gMG.

This study has important limitations, including the extremely small sample size, the descriptive analytic approach, partial non-evaluability of baseline cognitive data, and the absence of a control group. Additional factors such as concomitant treatments, psychological status, and educational level were not systematically assessed.

Conclusions

This case series highlights the feasibility and potential relevance of integrating multidomain assessment, including fatigue and performance-based cognitive measures, in gMG. Future prospective studies are needed to better characterize the relationship between fatigue, cognitive performance, and disease burden in this population.

Author Contribution

Aurora Zanghì: conceptualization; formal analysis; methodology; writing—original draft. Paola Sofia Di Filippo: methodology; data curation; writing—original draft. Claudia Rutigliano: methodology; data curation; writing—original draft. Carlo Avolio: methodology; data curation; writing—original draft. Emanuele D’Amico: conceptualization; methodology; investigation; data curation; supervision; project administration; writing—original draft; validation; visualization; final approval of the manuscript.

Funding

No funding or sponsorship was received for this study or publication of this article. The Rapid Service Fee was funded by the authors.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of Interest

Aurora Zanghì has nothing to disclose related to the submitted manuscript; Paola Sofia Di Filippo has nothing to disclose related to the submitted manuscript; Claudia Rutigliano has nothing to disclose related to the submitted manuscript; Carlo Avolio has nothing to disclose related to the submitted manuscript; Emanuele D’Amico has nothing to disclose related to the submitted manuscript.

Ethical Approval

The study protocol was approved by the local ethics committee (Comitato Etico Foggia, CE/47/2025/PO). This study was conducted in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments. All participants provided written informed consent for clinical and cognitive assessment and for the anonymized use of their data.

Consent for Publication

Written informed consent for publication of anonymized data was obtained from all participants.