Abstract
Background and purpose
Advances in multidisciplinary care are extending overall survival in Duchenne muscular dystrophy (DMD) patients. Our research objective was to delineate the clinical characteristics of this particular cohort and identify novel challenges associated with the disease.
Methods
Nineteen individuals aged 25–48 years (median 34 years) with a confirmed diagnosis of out‐of‐frame DMD gene mutation were selected.
Results
All patients were mechanically ventilated (5/19 via tracheostomy), with different patterns of cardiomyopathy. Swallowing and nutritional issues were frequent (median body mass index 18.95), with six cases requiring artificial enteral feeding (median age at start 29 years), as well as bone density alterations (11/19, 58%). Only 2/19 had been on long‐term prednisone therapy. Issues requiring at‐home/hospital assistance were respiratory infections (15/19, 79%), gastroenterological symptoms (9/19, 47%, including toxic megacolon and rectal perforation after repeated enemas), metabolic acidosis (2/19, 11%) and recurrent ischaemic strokes (1/19, 5%). From a social perspective, augmented‐alternative communication devices were necessary for 7/19 (37%), with most of the patients being assisted at home and 2/19 institutionalized. Eight/19 (42%) patients experienced psychiatric symptoms (median age at presentation 16 years) and 9/19 (47%) chronic pain (median age at onset 23 years), in both cases treated with psychoactive/analgesic drugs without major adverse events. The patients' subjective perception of physical health resulted in unfavourable scores, whilst the subjective assessment of mental health unexpectedly showed more positive values compared to other chronic neurological conditions.
Conclusions
The analysis of adults living with DMD reveals several new health‐related issues, such as the management of emergencies and safety of pharmacological treatments for psychiatric symptoms, chronic pain management, as well as an increasing caregivers burden.
Keywords: Duchenne muscular dystrophy, genetics, mental health, muscular dystrophy
INTRODUCTION
Duchenne muscular dystrophy (DMD) is an inherited recessive X‐linked muscular disorder determined by out‐of‐frame deletions/duplications or nonsense mutations in the DMD gene leading to dystrophin absence in skeletal muscle. It affects approximately 1 in 3500 live male births [1]. Most patients lose independent ambulation in their second decade and develop a progressive pulmonary function decline eventually leading to non‐invasive ventilation (NIV) or invasive ventilation dependence 24 h per day, alongside a growing risk of heart failure. In the past, DMD patients used to die mostly in their early 20s due to respiratory insufficiency or heart failure [2].
Nowadays, life expectancy has improved thanks to the implementation of multidisciplinary standards of care and interventions, including long‐term therapy with oral corticosteroids, early assisted mechanical ventilation and regular cardiomyopathy screening [3, 4]. Consequently, healthcare professionals are now dealing with a new population of individuals requiring highly specialized care, such as in emergency settings and mental and social health, often demanding prompt decisions [4, 5, 6, 7].
In addition, caregivers' physical and mental health requires particular attention considering the burden of looking after highly dependent individuals on a long‐term perspective. Throughout the course of the illness, caregivers encounter numerous and increasingly intricate challenges on a daily basis, such as enteral nutrition, mechanical ventilation and severe motor disabilities.
A cross‐sectional study of a single‐centre cohort of long‐surviving adults with DMD, aiming to describe their clinical features and to analyse under‐investigated aspects, including new late multisystem complications as well as their treatment and care setting issues, is presented.
METHODS
Study design
This is a cross‐sectional study. Data were retrieved from the medical records stored in the hospital database until September 2022. Written informed consent was obtained from all participants (or their legal guardians).
Study population
Currently, over 50 adults with DMD are followed at our Neuromuscular Unit. 19 patients aged ≥25 years were selected, because only limited comprehensive clinical data are available for patients surviving over their early 20s and reaching up to the fifth decade. All participants had a diagnosis of DMD defined by the demonstration of an out‐of‐frame mutation of the dystrophin gene via genetic analysis (multiplex ligation‐dependent probe amplification or DMD gene sequencing); dystrophin absence at immune histochemistry and western blot study on skeletal muscle biopsy (quadriceps) was reported when available.
Data collection
Overall clinical features
All patients underwent lifelong multidisciplinary periodic assessments according to the evolving standards of care and DMD consensus guidelines throughout the years [4]. In our study, data collected at the last clinical evaluation were reported, and the focus was on the following domains: corticosteroid treatment (including potential side effects); motor function (as measured by electronic wheelchair autonomous use and level of independence during activities of daily living); respiratory function (including ventilatory status and hours of mechanical ventilation per day); cardiac function (including left ventricular ejection fraction [LVEF], electrocardiogram, arterial blood pressure and heart rate, cardiac medications); nutrition (feeding status, body mass index [BMI]); communication strategies (verbal/non‐verbal, assistive device use such as eye‐tracking devices); bone health (as measured by bone density scan when available, vitamin D level and treatment).
Emergency care
Data were also collected on health issues related to emergency care, including infectious diseases and abdominal symptoms. The patients' medical records were searched to retrieve data on the following events: calls to the emergency services from home, admissions to the Accident and Emergency (A&E) department, and hospitalizations. Open‐ended interviews with caregivers were used in the case of missing information.
Assistance needs
Assistance needs were investigated through the Muscular Dystrophy Care Schedule, which has already been applied to explore the burden of informal and formal assistance in Italian families of patients with muscular dystrophies [8]. The data collection process includes the gathering of information regarding the following aspects: (a) the patient's pharmacological treatments within the preceding 2 months; (b) the patient's rehabilitative procedures; (c) the psycho‐educational interventions involving the patient and their family members; and (d) the social and welfare support received by the patient and their family within the last 6 months. The data obtained through the Muscular Dystrophy Care Schedule were examined as binary ‘yes/no’ variables.
Mental health and pain
In the case of symptoms suggestive of significant struggle to cope with progressing disability, depression or anxiety, psychotic manifestations or social malfunctioning, patients were referred to a mental health specialist (psychologist and/or psychiatrist) to define the diagnosis based on the clinical criteria of the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition and to provide personalized treatment options. As regards pain, patients/caregivers were asked to provide information about episodic and/or chronic discomfort in everyday life, the latter defined as present for longer than 12 weeks. When pain was present, supplementary questions were included to inquire about the characteristics of the pain and determine the requisite treatments, encompassing both non‐pharmacological and pharmacological options.
Quality of life
The perception of patients' subjective quality of life was investigated through the Italian version of the Short Form 12‐item (SF‐12) health questionnaire [9], administered at last clinical evaluation. The SF‐12 is a concise health survey derived from the original SF‐36 and developed in the United States. It generates two summary measures, which assess individuals' subjective perceptions of their physical and mental health (physical component scale [PCS‐12] and mental component scale [MCS‐12] respectively), with PCS and MCS scores ranging from 0 to 100 and higher scores indicating a better health‐related quality of life. Reference values of PCS and MCS were selected from those calculated in an Italian cohort affected by five different neurological conditions, which have already been used as a reference in the neuromuscular field [10, 11].
Statistics
Statistical analysis primarily focused on descriptive statistics. In this study, also considering the skewed distribution and the presence of potential outliers, the median was therefore used as a measure of central tendency to summarize the data, together with the ranges of the data considered (i.e., range as the distance between minimum and maximum values).
RESULTS
Data collected in our study are summarized in Table 1.
TABLE 1.
Summary of study results.
| ID | Age/years | Muscle biopsy (Y/N) | Genetics | Corticosteroid treatment (ongoing/interrupted/never, age range of active treatment, regimen) | Autonomous control of wheelchair via joystick | Loss of independent walking (age/years) | Heart function (echocardiographic LVEF, HR and ABP at last evaluation (age/years) | Start of mechanical ventilation (age/years) and pattern of use (type, hours/day) at last evaluation (age/years) | Nutrition and body mass index at last evaluation (age/years) | Communication |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 25 | N | deletion exons 10–44 | Interrupted (from 5 to 10 years of age, alternate‐day prednisone) | Y | 11 | Normal (63%), 70 bpm, 110/70 mmHg (25) | 15 (NIV, 10 h/day) (25) | Oral, modified, 14.65 (25) | Verbal |
| 2 | 26 | Y | deletion exons 49–50 | Interrupted (from 5 to 15 years of age, alternate‐day prednisone) | Y | 11 | Reduced with diffuse hypokinesia (40%), 76 bpm, 100/60 mmHg (26) | 17 (NIV, 24 h/day) (26) | RIG (from 24 years of age), 13.74 (26) | Verbal (hypophonia) |
| 3 | 28 | Y | deletion exons 10–44 | Interrupted (from 5 to 10 years of age, alternate‐day prednisone) | Y | 13 | Normal (60%), 66 bpm, NA (26) | 15 (NIV, 14 h/day) (28) | Oral, modified, 19.92 (28) | Verbal (hypophonia) |
| 4 | 30 | N | c.1033C>T (p.Gln345Ter) | Never | Y | 10 | Reduced with RWMA (40%), 76 bpm, 105/65 mmHg (30) | 18 (NIV, 14 h/day) (30) | Oral, modified, 23.43 (30) | Verbal |
| 5 | 30 | Y | deletion exon 45 | Ongoing (from 5 years of age, daily prednisone 25 mg) | Y | 12 | Normal (55%), 62 bpm, 110/70 mmHg (30) | 26 (NIV, 8 h/day) (30) | Oral, modified, 21.67 (30) | Verbal (hypophonia) |
| 6 | 31 | Y | deletion exon 73 (c.10386delT; p.Asn3462LysfsX3) | Interrupted (from 10 to 11 years of age, daily prednisone) | Y | 12 | Normal with RWMA (50%), 80 bpm, 100/70 mmHg (31) | 24 (NIV 8 h/at night) (31) | Oral, modified, 17.3 (31) | Verbal |
| 7 | 32 | N | deletion exons 46–51 | Interrupted (from 15 to 16 years of age, daily prednisone) | Y | 12 | Dilated‐hypokinetic (33%), 56 bpm, 90/70 mmHg (32) | 22 (NIV, 20 h/day) (32) | Oral, modified, 20.76 (32) | Verbal |
| 8 | 32 | N | deletion exons 49–50 | Never | N | 12 | Dilated‐hypokinetic (33%), 66 bpm, 120/70 mmHg (31) | 19 (IV tracheal tube) (32) | PEG (from 23 years of age), 18.95 (30) | Augmented and assistive communication devices |
| 9 | 33 | Y | c.6072T>A (p.Cys2024Ter) | Ongoing (from 7 years of age, daily prednisone 25 mg) | Y | 17 | Dilated‐hypokinetic (27%), 80 bpm, 100/65 mmHg (33) | 24 (NIV, 10 h/day) (33) | RIG (from 32 years of age), 17.51 (33) | Verbal (hypophonia) |
| 10 | 34 | Y | deletion exon 45 | Ongoing (from 16 years of age, alternate‐day prednisone) | Y | 13 | Reduced with RWMA (46%), 80 bpm, NA (34) | 26 (NIV, 18 h/day) (34) | Oral, modified, 20.45 (34) | Verbal |
| 11 | 35 | Y | c.1033C>T (p.Gln345Ter) | Never | N | 10 | Dilated‐hypokinetic (23%), 88 bpm, 100/60 mmHg (34) | 21 (NIV, 20 h/day) (35) | Oral, modified, 17.8 (35) | Verbal (hypophonia) |
| 12 | 35 | Y | deletion exons 46–51 | Never | Y | 10 | Normal (57%), 82 bpm, 105/75 mmHg (35) | 18 (IV tracheal tube) (35) | Jejunostomy (from 26 years of age), 15.57 (35) | Verbal (hypophonia) + augmented and assistive communication devices |
| 13 | 35 | N | deletion exons 47–50 | Never | N | 10 | Reduced with RWMA (38%), 76 bpm, NA (34) |
18 (IV tracheal tube) (35) |
Oral, modified, 17.7 (32) | Augmented and assistive communication devices |
| 14 | 36 | N | deletion exons 45–50 | Never | N | 13 | RWMA (42%), 82 bpm, 110/70 mmHg (36) | 22 (NIV, 24 h/day) (36) | Oral, modified, 27.06 (36) | Augmented and assistive communication devices |
| 15 | 39 | Y | exon 2 duplication | Interrupted (from 8 to 9 years of age, daily deflazacort) | Y | 13 |
Dilated‐hypokinetic (30%), 58 bpm, 100/70 mmHg (38) |
29 (NIV, 20 h/day) (39) | Oral, modified, 16.8 (39) | Verbal (hypophonia) |
| 16 | 40 | N | c.3151C>T (Arg1051Ter) | Interrupted (from 6 to 10 years of age, alternate‐day prednisone) | Y | 11 | Reduced with RWMA (45%), 80 bpm, 100/60 mmHg (39) |
21 (NIV, 8 h/at night) (40) |
Oral, modified, 22.66 (40) | Verbal (hypophonia) |
| 17 | 45 | Y | deletion exons 14–17 | Never | N | 8 | Reduced with RWMA (35%), 80 bpm, 90/60 mmHg (44) | 18 (IV tracheal tube) (45) | Jejunostomy (from 41 years of age), 19.4 (45) | Augmented and assistive communication devices |
| 18 | 47 | N | deletion exons 46–48 | Never | N | 10 | Reduced with RWMA (15%), 76 bpm, 85/45 mmHg (46) | 19 (IV tracheal tube) (47) | RIG (from 43 years of age), 9.18 (47) | Augmented and assistive communication devices |
| 19 | 48 | N | deletion exons 46–51 | Never | Y | 13 | Normal (58%), 80 bpm, 90/60 mmHg (46) | 26 (NIV, 24 h/day) (48) | Oral, modified, 20.81 (48) | Augmented and assistive communication devices |
| ID | Bone health status DEXA‐assessed and/or serum vitamin D level (current therapy, age at diagnosis) | Multisystem involvement and emergency care | Psychiatric comorbidities | Psychoactive medications | Chronic pain (Y/N) | Analgesic therapies | Assistance needs (at‐home family care/private resource in‐home care/home nursing/residential care) | PCS‐12 | MCS‐12 |
|---|---|---|---|---|---|---|---|---|---|
| 1 | Osteoporosis (cholecalciferol, 22) | Renal colic (3 at‐home calls) | Not reported | None |
N |
None | At‐home family care (parents, affected brother) | 38.017 | 49.380 |
| 2 | Osteoporosis (cholecalciferol, 24) | Bacterial pneumonias (2 ICU admissions), gastric distension (1 internal medicine ward admission) | Not reported | None | Y (from the age of 24) | None | At‐home family‐care (relatives: aunt, maternal grandmother) | 37.021 | 57.462 |
| 3 | Osteoporosis (cholecalciferol, 25) | Gastric distension (1 at‐home call, 1 internal medicine ward admission) | Not reported | None | N | None | At‐home family care (parents, affected brother) | 38.549 | 47.764 |
| 4 | Vitamin D deficiency (cholecalciferol, 28) | Upper respiratory ways infections (2 at‐home calls/year, 2 ER and 2 internal ward admissions) | Not reported | None | N | None | At‐home family care (mother and father) | 23.179 | 42.630 |
| 5 | Osteoporosis (cholecalciferol, risedronic acid, carbonate calcium, 24) | Upper respiratory ways infections (2 at‐home calls/year, 2 internal ward admissions) | Not reported | None | N | None | At‐home family‐care (father, mother and sister) | 38.676 | 52.077 |
| 6 | Osteoporosis (cholecalciferol, 25) | Upper respiratory ways infections (1 internal ward admission) | Anxiety (from the age of 14) | None | N | None | Private‐resource in‐home care (assistants) | 47.585 | 58.342 |
| 7 | Vitamin D deficiency (cholecalciferol, 30) | Bacterial pneumonia (1 ER and 1 internal ward admission) | Anxiety (from the age of 13), OCD (from the age of 18), depressive symptoms (from the age of 18) | BDZ + trazodone + low dose haloperidol | N | None | At‐home family care (father, stepmother, brother with DMD) | 23.431 | 38.179 |
| 8 | N/A (no ongoing therapy) | Bacterial pneumonia (3 ER and 2 ICU admissions), toxic megacolon (1 ICU admission), gastric distension (2 internal ward admissions) | Agitation (from the age of 12) visual/auditory hallucinations (from the age of 20) | BDZ, low dose haloperidol | N | None | Residential care (from 25 years—after permanent tracheostomy) | NA | NA |
| 9 | N/A (cholecalciferol, 20) | Gastric distension, paralytic ileus, rectal perforation after repetitive enemas (3 at‐home calls, 3 ER and 2 internal ward admissions, including rectal perforation episode), ischaemic cerebral stroke (2 ICU admission) | Panic attacks (from the age of 13) | None | Y (from the age of 23) | Pregabalin | Private‐resource in‐home care (assistants) | 32.799 | 54.625 |
| 10 | Osteoporosis (risedronic acid, cholecalciferol, calcium) | Upper respiratory ways infection (2 at‐home calls), bacterial pneumonias (2 ICU and 2 internal ward admissions), clinically relevant urinary tract infection (2 at‐home calls, 1 internal ward admission) | Autistic traits (from the age of 9), major depressive disorder (from the age of 22) | SSRI | N | None | Residential care (from 33 years, whilst scheduling jejunostomy) | 32.307 | 53.989 |
| 11 | Vitamin D deficiency (no ongoing therapy, 34) | Upper respiratory ways infection (2 at‐home calls/year) | Depressive symptoms (from the age of 18) | SSRI | Y (from the age of 19) | Acetaminophen/opioid | At‐home family care (mother, healthy sister, brother with DMD) | NA | NA |
| 12 | N/A (cholecalciferol, 32) | Bacterial pneumonias with sepsis (2 ICU admissions), bacterial pneumonia (2 internal ward admissions), metabolic acidosis in cachexia (1 ICU admission), gastric distension (5 at‐home calls), renal colic (2 ER admissions and 2 at‐home calls) | Not reported | None | Y (from the age of 23) | Acetaminophen | At‐home family care (parents) | 39.655 | 66.486 |
| 13 | NA (no ongoing therapy) | Bacterial pneumonias (1 ER, 3 ICUs and 2 internal ward admissions), gastric distension (2 ER admissions and 3 at‐home calls) | Not reported | None | N | None | At‐home family care (mother) + home nursing (from 31 years) | 29.316 | 59.614 |
| 14 | Osteopaenia (cholecalciferol, 32) | Bacterial pneumonia (1 internal ward admission), renal colic (1 ER admission, 3 at‐home calls, 1 internal ward admission) | Not reported | None | Y (from the age of 30) | None | At‐home family care (mother, healthy brother) | 39.598 | 63.805 |
| 15 | Osteoporosis (cholecalciferol, 32) | Metabolic alkalosis in nutritional hypokalaemia (1 ER and 2 internal ward admissions) | Not reported | None | Y (from the age of 18) | None | At‐home family care (parents) | 20.640 | 54.745 |
| 16 | Osteopaenia (cholecalciferol, 39) | Upper respiratory ways infection (1 at‐home call/year) | Not reported | None | N | None | At‐home family care (father, mother) | 36.113 | 44.533 |
| 17 | N/A (no ongoing therapy) | Bacterial pneumonia (2 ER, 2 ICU and 2 internal ward admissions), upper respiratory ways infection (2 at‐home calls/year) | Panic attacks (from the age of 14) | BDZ | Y (from the age of 32) | Acetaminophen/opioids | At‐home family care (mother and father) | 35.717 | 51.562 |
| 18 | Osteoporosis (cholecalciferol, 46) | Bacterial pneumonias (3 ER, 1 ICU and 2 internal ward admissions), gastric distension (5 at‐home calls/year) | Panic attacks (from the age of 22), depressive symptoms (from the age of 22) | BDZ, antidepressant (SNRI) | Y (from the age of 33) | Acetaminophen/opioid | At‐home family care (parents) + home nursing (from 46 years—after tracheostomy and concurrent RIG) | NA | NA |
| 19 | Osteopaenia (cholecalciferol, 46) | Bacterial pneumonias (2 ICU and 3 internal ward admissions), upper respiratory ways infection (3 at‐home calls/year) | Not reported | None | Y (from the age of 22) | Acetaminophen | At‐home family care (father, stepmother, brother with DMD, stepsister) | 23.92 | 45.421 |
Abbreviations: ABP, arterial blood pressure; BDZ, benzodiazepines; DEXA, dual‐energy X‐ray absorptiometry; when deceased it was assumed to be the ‘last assistance setting’; ER, emergency room; HR, heart rate; ICU, intensive care unit; IV, invasive ventilation; when on IV setting, it was assumed as a 24‐h long ventilation regimen; LVEF, left ventricular ejection fraction; MCS‐12, mental component scale score; N, no; NA, not available; NIV, non‐invasive ventilation; OCD, obsessive‐compulsive disorder; PCS‐12, physical component scale score; PEG, percutaneous endoscopic gastrostomy; RIG, radiologically inserted gastrostomy; RWMA, regional wall movement abnormality; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; Y, yes.
Study population
The 19 patients selected in our study (aged ≥25 years) had a median age of 34 years (age range 25–48). Patients 1 and 3 and patients 4 and 11 were siblings. In all patients (100%) a causative out‐of‐frame mutation in the DMD gene was identified via multiplex ligation‐dependent probe amplification (deletions, 14/19, 74%; duplication, 1/19, 5%) or either via direct gene sequencing (AB PRISM 3130) or next‐generation sequencing of the DMD gene (nonsense point mutations 4/19, 21%). The most frequent deletions involved exons 46–51 (3/14, 21%), whilst the only duplication was observed on exon 2. Nonsense point mutations were all interpreted as either pathogenic or probably pathogenic based on their premature stop‐codon effect. In those individuals for whom it was available (10/19, 53%), dystrophin absence at immune histochemistry and western blot analysis on skeletal muscle biopsy (quadriceps) was demonstrated. Two patients (8 and 11) died after data collection due to respiratory failure (not related to SARS‐CoV‐2 infection).
Data collection
Corticosteroid treatment
Two of the 19 patients (patients 5 and 9, 11%) received daily oral prednisone at the suggested dosage of 0.75 mg/kg until loss of ambulation, after which the dose was maintained at 25 mg daily (median duration of therapy 25.5 years, range 25–26 years); 7/19 (37%) received corticosteroids either for a limited period of time only (e.g., during infancy/adolescence only) or not on a regular basis due to subjective perception of lack of efficacy or due to side effects. The remaining patients (9/19, 47%) never received corticosteroids.
Motor function
All patients were wheelchair‐bound; 13/19 (68%) were still able to autonomously control the wheelchair via a joystick, but were highly dependent in the activities of daily living (19/19, 100%) at last outpatient clinical evaluation; the median age at loss of ambulation was 12 years (range 8–17 years).
Cardiac function
At last clinical evaluation, all patients were on cardiac medication according to the cardiologist's indications. Fourteen of the 19 patients (74%) showed echocardiographic signs of cardiomyopathy, regional wall motion abnormalities in 8/14 (57%) and severe dilated‐hypokinetic cardiomyopathy with LVEF <35% in 5/14 (36%). The median LVEF was 40% (range 15%–63%), the median heart rate was 76 bpm (range 56–88 bpm) and the median arterial blood pressure was 100/67.5 mmHg (range 85–120 to 45–75 mmHg).
Respiratory function
All patients were mechanically ventilated at last clinical evaluation (19/19, 100%) with NIV in 14/19 (74%) or continuous invasive ventilation via tracheal tube in the remaining 5/19 (26%). The median age at the start of mechanical ventilation was 21 years (range 15–29 years). As for NIV daily use, the median value was 16 h (range 8–24 h).
Nutrition
At last clinical evaluation, the median BMI was 18.95 (range 9.18–27.06). Thirteen of the 19 patients (68%) had preserved oral nutrition abilities, although in all cases with texture‐modified foods only, whereas enteral feeding was necessary for 6/19 patients (32%): 3/6 (50%) radiologically inserted gastrostomy; 2/6 (33%) jejunostomy; 1/6 (17%) percutaneous endoscopic gastrostomy. Regarding the patients on artificial enteral nutrition, the median age at introduction was 29 years (range 23–43 years).
Bone health
Three of the 19 patients (16%) presented isolated vitamin D deficiency, whilst 3/19 (16%) and 8/19 (42%) were diagnosed with osteopaenia and osteoporosis respectively. At last outpatient visit, 15/19 (79%) were prescribed cholecalciferol, whilst 2/19 (11%) individuals were prescribed bisphosphonates (in both cases risedronic acid) ± cholecalciferol for osteoporosis. Four/19 (21%) did not take any medication for bone mineral health.
Communication
At last clinical evaluation, 13/19 patients (68%) had preserved verbal communication skills, with 8/13 (62%) showing hypophonia. Seven/19 patients (37%) could rely on augmented and assistive communication devices (i.e., eye‐tracking technology for non‐verbal individuals) only or as a support for very limited verbal abilities.
Multisystem involvement and emergency care
In our cohort, 15/19 patients (79%) had recurrent upper and/or lower respiratory tract infections. Patients with upper respiratory tract infections (8/15, 53%) were usually managed at home, with follow‐up phone call appointments. Patients with lower respiratory tract infections often required access to the A&E department or admission to the internal medicine ward, sometimes followed by transfer to the intensive care unit (8/15, 53%), especially when sepsis developed as a complication of the respiratory infection. Nine/19 patients (47%) showed involvement of the renal (e.g., renal colic) and/or the gastrointestinal system (from minor abdominal discomfort successfully treated at home to gastric distension, paralytic ileus and toxic megacolon requiring intensive care unit admission). One patient (5%) suffered from two episodes of ischaemic stroke, the first one attributed to internal carotid dissection and the second one probably related to cardiac embolism. Two/19 individuals (11%) suffered from homeostasis imbalance (i.e., metabolic acidosis) due to severe nutritional issues.
Assistance needs
Within our study population, 15/19 (79%) patients were informally assisted at home by their family members, with 2/15 (13%) requiring additional support from home nursing programmes after specific events (e.g., after tracheostomy or gastrostomy insertion). Two/19 (11%) had personal assistants at home (private resources) and another 2/19 (11%) opted for assistance at residential care services. The median age at the initial need of home nursing support or respite institutional care was 32 years (range 25–46 years).
Mental health and pain
Psychiatric comorbidities were diagnosed in 8/19 patients (42%) showing the following persistent or frequently recurring symptoms: agitation (1/8, 13%); visual and/or auditory hallucinations (1/8, 13%); anxiety symptoms (5/8, 63%), including panic attacks (3/5, 60%); obsessive‐compulsive traits (1/8, 13%); depressive symptoms (4/8, 50%); autistic traits (1/8, 13%). No delirium episodes caused by infection or laboratory alterations were reported. Psychopharmacological treatments were indicated in 6/8 (75%): benzodiazepines in 4/6 (66%), antidepressants in 4/6 (66%) and low‐dose antipsychotics (e.g., haloperidol) in 2/6 (33%); no severe adverse effects were observed. The median age at presentation of the first mental health issues was 16 years (range 9–22 years). Nine/19 patients (47%) complained of chronic pain, with 6/9 (66%) requiring analgesic treatment: acetaminophen only (2/6, 33%), acetaminophen plus opioid (2/6, 33%), pregabalin (1/6, 17%). The median age at start of chronic pain was 23 years (range 18–33 years).
Quality of life
Based on SF‐12, PCS‐12 and MCS‐12 were calculated scoring a median value of 35.915 (range 20.640–47.585) and 53.033 (range 38.179–66.486) respectively.
DISCUSSION
Motor and cardiopulmonary function
Skeletal, respiratory and cardiac muscle functions in DMD classically follow a well‐known progressive pattern of worsening, although clinical variability is somewhat greater than expected. The phenotype may be influenced by the genotype, which could exert disease‐modifying effects [12, 13, 14], but further large‐scale studies are necessary to understand how genetic changes impact long‐term clinical outcomes. For instance, deletions in surrounding exon 44 and involving exons 3–7, including duplications of exon 2, have been linked to small amounts of dystrophin, and some mutations differentially affect specific dystrophin isoforms, potentially acting as a prognostic modifier [12, 15]. Given the intrinsic limitations associated with a small cohort, absolute conclusions regarding the correlation between genotype and phenotype cannot be drawn. Regarding steroid therapy, comparative statistical analyses between the group of patients receiving steroids and the steroid‐naïve group are not feasible due to the limited sample size. It should be noted that steroids were not diffusely prescribed in the 1980s and early 1990s.
In addition to a predictable high level of dependence in activities of daily living stemming from the severe physical limitations, most patients displayed echocardiographic signs of cardiomyopathy of varying degrees, alongside an elevated need for prolonged mechanical ventilation. It is noteworthy that 17 patients achieved significant survival outcomes without receiving regular chronic treatment with steroids, presumably according to the application of multidisciplinary standards of care and specific favourable genetic backgrounds. Furthermore, the impact of steroids on cardiopulmonary function is still under investigation, although a potentially positive effect can be anticipated [16, 17]. On top of that, 6/19 patients, including steroid‐naïve patients, did not experience any reduction in ejection fraction (LVEF), which is particularly remarkable in the case of the longest‐surviving patient. Such individual (patient 19) received regular cardiac medications only including angiotensin‐converting enzyme inhibitor and presented a deletion of exons 46–51. Recent observations over cardiopulmonary phenotypic discordance in adults with DMD with performant LVEF values and ventilatory capacities confirm the role of certain genetic modifiers which in the future could be useful to develop specific potential prognostic trajectories alongside the DMD gene mutation [13, 18].
Nutritional issues
Duchenne muscular dystrophy patients are frequently affected by metabolic imbalances (e.g., weight gain or loss depending on disease stages, insufficient fluid intake, progressive dysphagia) [19]. In our cohort, most patients had a low‐to‐normal BMI at their last outpatient evaluation, except for one severely compromised patient who had long refused artificial enteral nutrition (patient 18). Besides, artificial enteral nutrition was necessary for six patients, four of them requiring tracheostomy. Patients with tracheostomy, on continuous ventilation, reported frequent cases of gastric and intestinal distension. This condition is presumed to be caused by air swallowing through mechanical ventilation. From the perspective of bone health, ageing and immobility, coupled with nutritional issues, are emerging concerns in most adults with DMD, even in the absence of chronic steroid treatment, as demonstrated in our cohort. Almost all of our patients have been treated with cholecalciferol, with only two on bisphosphonates prescribed for osteoporosis. According to reports, bisphosphonates have a greater effect on increasing bone mineral density compared to cholecalciferol and calcium, and should be taken into consideration for all cases requiring treatment with the guidance of bone metabolism experts [20].
Communication
Most of the orally communicating patients in our cohort exhibited hypophonia when speaking, and occasionally relied on augmented communication technology, particularly when tracheostomized or 24‐h non‐invasively ventilated. A recent cross‐sectional study involving 15 DMD patients demonstrated no apparent affection of muscular tone and mobility of laryngeal muscles as assessed through videolaryngoscopy, which supported previous in vivo findings [21]. The data presented in Fonseca et al.'s [21] study contradict our own observations, and could perhaps be attributed to the relatively younger age of the patients included in the study, with only three of them being over 18 years old. Consequently, it is possible that the intrinsic muscles of the larynx may experience delayed impairment, although detailed findings in this regard are still lacking.
Emergency care
Systemic involvement in adults with DMD is a growing challenge, with for instance expected infectious episodes in already compromised respiratory settings. Nonetheless, further issues may be encountered such as gastrointestinal complaints. Our experience shows that emergency department visits were primarily due to ventilatory, infectious, abdominal or metabolic issues. Even life‐threatening conditions such as paralytic ileus, rectal perforation after repeated enemas and toxic megacolon necessitated ER and ICU admissions, representing a significant cause of urgent medical assistance. These manifestations broaden the spectrum of already known gastrointestinal complications, such as gastro‐oesophageal reflux, chronic constipation and gastric bloating [22]. Additionally, atypical clinical scenarios like ischaemic cerebral strokes can occur, confirming earlier retrospective studies that showed an elevated risk of neurovascular accidents in these populations [23].
Mental health and pain
Cognitive network dysfunction is well described in DMD patients from infancy, ranging from intellectual disabilities to impaired verbal and memory skills, attention‐deficit hyperactivity disorder, autism spectrum disorder and obsessive‐compulsive disorder [8, 9, 24, 25, 26, 27, 28, 29, 30, 31, 32]. It can be inferred from our study cohort that the cognitive and psychiatric profile may continue to have an impact on the overall health and care requirements of DMD patients in their adulthood. The scientific literature suggests that anxiety and depression may be more common in adults with DMD, potentially due to several consistent factors, including the use of corticosteroids and increasing awareness of the disease and its frequently unaddressed needs [33]. In our study, mental health specialists, including psychiatrists and psychologists, were involved in managing nearly half of the cohort, especially in cases where psychoactive medications were required to treat major symptoms such as obsessive‐compulsive behaviour and hallucinations. However, the lack of literature on the safety of psychoactive drugs in the DMD population often limits their use in such contexts [34]. Amongst our patients, only two were treated with low‐dose oral haloperidol, whilst the others experienced antidepressive/anxiolytic treatments, with constant monitoring of routine blood tests and QT interval and no major side effects. On the other hand, chronic pain also represented a major issue in our population, affecting almost half of the adults and increasing in frequency at later ages. As expected, late non‐ambulatory patients often complained of more pain in terms of intensity and sites of symptoms [35]. To address this situation, common analgesics (e.g., acetaminophen) and anti‐epileptic drugs used for chronic pain treatment (e.g., pregabalin) were administered. No significant adverse reactions were reported, although only partial pain control was achieved with the mentioned molecules.
Assistance setting and caregiving
Prolonged survival is almost invariably proportional to increased caregiving demands for family members. Paediatric DMD assistance setting and the influence of caregiving on informal carers have been extensively characterized throughout the years [36, 37]. In our study, it is noteworthy that most patients received home‐based care from elderly caregivers, with or without the support of home nursing programmes or private assistants. Regarding institutionalized or both informally and professionally home‐cared patients, such caregiving programmes have typically been initiated when more invasive procedures were approached. Our findings, in line with Pangalila et al. [33] and other published reports, suggest that tracheostomy was perceived as particularly challenging and uncomfortable by informal caregivers, often leading them to seek professional support [37, 38]. Additionally, major behavioural and psychiatric disorders, such as those exhibited by patient 8 and patient 10 (i.e., psychosis, autistic traits and depressive symptoms), may have contributed to the family's decision to opt for professional institutional care.
Quality of life
Within our cohort, when comparing the median values of SF‐12 PCS and MCS to the reference values for neurological conditions such as epilepsy, migraine, multiple sclerosis, stroke and Parkinson's disease, it was observed that adults with DMD exhibited lower PCS scores, which aligns with expectations for a progressive and highly limiting condition. However, unexpectedly, these patients demonstrated better MCS scores. This intriguing finding prompts further investigation of the data presented by Pangalila et al. [33], who discovered a relationship between fatigue and overall quality of life, as well as the quality‐of‐life domains of physical health and environment. By dissecting the overall quality of life into the domains of PCS and MCS, a disparity wherein the perception of poor physical health coexisting with a positive subjective mental health status was uncovered, despite the presence of severe motor limitations. This observation is particularly interesting considering the patients' relatively satisfactory social participation, an aspect explored through specific items in the SF‐12 questionnaire. To gain deeper insights, it is essential to expand the study to include larger cohorts. This would enable the correlation between PCS and MCS values across different age groups, individuals utilizing tracheostomy/feeding tubes, institutionalized patients and those affected by psychiatric disorders and chronic pain to be explored.
Limitations of the study
It is acknowledged that our study has limitations attributed to the cross‐sectional approach and the limited sample size, precluding the application of inferential statistics and hypothesis testing, thus limiting the generalizability of the findings. Nevertheless, it is important to note that the condition under investigation pertains to a rare cohort of adults with DMD reaching considerable ages, for which there is still little evidence in the medical literature.
CONCLUSIONS
Adults with DMD show complex clinical phenotypes, characterized by multisystemic complications in addition to the well‐known motor, respiratory, cardiac and bulbar decline. Emergency care needs require great consideration for these cohorts and standardized protocols should be encouraged, in particular for non‐referral centres. Emerging, under‐investigated aspects such as gastroenterological complications, the burden perceived by parents/caregivers of adults living with DMD, the presence of psychiatric symptoms and/or chronic pain represent unmet care needs that would require regular assessments with standardized outcome measures. Future, multicentric experiences and studies would help to better define the unique phenotypes observed in this population, which in turn would further improve the currently available care recommendations for adults with DMD.
FUNDING INFORMATION
This research received no external funding.
CONFLICT OF INTEREST STATEMENT
The authors state that they have no conflict of interest.
ETHICAL STATEMENT
The present study was approved for publication in a scientific journal by the institutional ethical committee (Prot. no. 0120543, 2 November 2022). The local ethical committee also reviewed the written informed consent form (ICF) which was presented to the patient and collected for the same purpose.
ACKNOWLEDGEMENTS
This study was initiated by the investigators without other external funding. It is confirmed that the journal's position on issues involved in ethical publication have been read and that this report is consistent with those guidelines. The authors of this publication are members of the European Reference Network for rare neuromuscular diseases (ERN EURO‐NMD)—Project ID No. 739543.
Gadaleta G, Urbano G, Brusa C, et al. Adults living with Duchenne muscular dystrophy: old and new challenges in a cohort of 19 patients in their third to fifth decade. Eur J Neurol. 2024;31:e16060. doi: 10.1111/ene.16060
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.