A Multidisciplinary Evaluation of Patients with DMD in An Italian Tertiary Care Center

With more widespread prolonged survival, Duchenne muscular dystrophy patients progressively experience multisystem complications. We retrospectively reviewed the charts of 132 Duchenne patients (112 alive/20 dead, age 3.5÷32.3 years) with the aims: 1) to provide a comprehensive description of the clinical status considering different aspects of the disease; 2) to propose a new scoring tool able to consider and pool together heterogeneous different functional. Five functions were analyzed: cardiac, respiratory, nutritional, ambulation and scoliosis. For each function, different items were considered and classified according to clinical severity (as indicated by international guidelines) and an incremental scoring was assigned.

In addition, a global score incorporating all functions was defined. The scoring system confirmed that despite the significant protective role of steroids, all functions deteriorated with age. The severity of the global score became significantly higher since the age of 13 years. The severity of cardiac, respiratory and nutritional dysfunction was higher since 18 years. Deceased patients were characterized by significantly worse cardiac function, absence of steroid therapy and later use of respiratory assistive devices. The index proposed in this pilot study is a promising tool able to aggregate and correlate heterogeneous functions. It could become either an individual prognostic indicator of decline or a global score to evaluate changes in clinical trials therefore allowing multicenter studies, optimizing the management of both the primary and the secondary complications of the disease and understanding their relative impact.

PATIENTS

We retrospectively reviewed the charts of all the patients with a diagnosis of Duchenne Muscular Dystrophy followed at the E. Medea Institute.

Patients not responding to international criteria for the diagnosis of DMD [10] , the ones who died before 2000 and the ones recruited in clinical trials (i.e., gene-modulating and deacetilase inhibitors studies) were excluded from our analysis. Therefore, only DMD patients with a certain diagnosis and regular records with neuromuscular and motor function evaluation, cardiac and respiratory, nutritional and swallowing evaluations, orthopedic and X-ray assessments were included in the study.   

Neurocognitive and neurodevelopment associated disorders and emotional condition were evaluated but not reported in these study [

The data collected and presented of both alive and dead boys are referred to the most recent clinic visit. The reported data of dead patients were collected less than 6 months before the exitus.

Informed consent for clinical data collection from the neuromuscular database, approved by the Institutional review board, was obtained by patients and relatives/tutors.

2.2          DATA COLLECTION

Genotype (deletion, duplication or point mutation in the DMD gene), age at last evaluation, ambulation if present, age at loss of ambulation, details about the use of steroid, in terms of age at which treatment started and/or stopped (when applicable) were collected for each boy.

According to steroid therapy patients were classified in naïve (never treated or treated for <1 year), past (not under treatment, but previously treated for >1 year), current (under treatment or stopped since <1 year before the visit).

According to the age at last evaluation, patients were divided in: ≤ 5 years (pre-symptomatic or early ambulatory stage), 6-9 (ambulatory stage), 10-12 years (late ambulatory stage), 13-17 years (early non ambulatory stage), 18-23 years (late non ambulatory stage), ≥24 years (advanced stage)

The indications for pharmacological therapy, use of devices, and in general the orthopaedic, respiratory, cardiac and nutritional management of the patients were performed according to the international guidelines specific for DMD (ALL DATA IN THE ATTACHED TABLE)

-INDEX DEFINITION

Five functions were considered at last observation: ambulation, range of scoliosis, cardiac function, respiratory function and nutrition. For each function, different functional items were considered. Each item was classified according to its clinical severity and an incremental scoring was assigned as described below In detail:

1.            Ambulation. If the patient was wheelchair bound, this function was assigned score 1. If the patient was ambulant, score 0. 

2.            Range of scoliosis. It was evaluated by Cobb angle measurement on X-ray and classified as: absence of scoliosis (score 0), mild scoliosis (Cobb angle < 20°, score 1) moderate (Cobb angle 20-40°, score 2), severe (> 40°, score 3) and spinal fusion (score 4); 

3.            Cardiac function. It was evaluated through echocardiography, 24 hours electrocardiographic recording and electrocardiogram. Two functional parameters were considered to score the cardiac function: left ventricular ejection fraction (LVEF) and cardiac rhythm. The function of LVEF was considered normal when ≥60% (score 0), initial dysfunction when ≥50 and <60% (score 1), mild dysfunction when ≥40 and <50% (score 2), moderate-severe dysfunction when < 40% (score 3) . Cardiac rhythm analysis (were classified as: Sinus Tachycardia (score 1); SovraVentricular Extrasystolia (score 2); Ventricular Arrythmias (score 3); sustained Atrial flutter/Fibrillation (AF, score 4). The absence of arrhythmia was scored 0 while the presence of the implantable cardioverter-defibrillator (ICD) was given score 5 .

4.            Respiratory function. It was evaluated through spirometry and subdivisions of lung volume by the nitrogen washout technique (Vmax series 22, SensorMedics, Yorba Linda, CA) at last evaluation. Among these, forced vital capacity expressed as percentage of predicted values (FVC%pred) was considered and scored together with other two functional items: the effective use (and not the indication) of Cough Assist Device (CAD) and/or Mechanical Non Invasive Ventilation (MNIV). According to FVC%pred, three groups were defined: patients with FVC>50% (score 0), with FVC ≥ 30 and <50% (score 1); and FVC<30% (score 2) [19]. If CAD and/or MNIV were currently used, each of them received a score of 1, otherwise the score was 0. The age at start of both CAD and MNIV were also recorded. The indication for the use of both respiratory devices was based on the international guidelines for respiratory care in dystrophic patients .

5.            Nutrition.  It considered both the swallowing capabilities and the nutritional status (obesity or pathological thinness). Based on anthropometric measures and body mass index (BMI) in accordance with a report of a WHO Consultation, patients were classified as normal weight (BMI ranging from 18.50 to 24.99 kg*m2), pre-obese (BMI ranging from 25.00 to 29.99 kg*m2), obese (BMI > 30 kg*m2), pathological thinness (BMI < 18.5 Kg*m2) for adult patients[20–22]. For children (i.e. patients younger than 18 years old), BMI was calculated in relation to age and sex and interpreted through the use of growth curves (percentiles)[23]. The presence of altered nutritional status (preobesity/obesity or pathological thinness) was scored 1, otherwise the score was 0. Swallowing was evaluated in dedicated sessions with a speech and language therapist. According to food texture preparation, swallowing was classified as regular (all food, requiring regular chewing, score 0), mild dysphagia (soft food, requiring more chewing, score 1), moderate dysphagia (mechanically altered food, requiring some chewing, score 2), severe dysphagia (purees requiring no chewing, score 3) [24–27]. The presence of percutaneous endoscopic gastrostomy was scored 4. Age at placement of percutaneous gastrostomy (when present) was also reported.

Because the range of the scores varied among the different considered items, they were all normalized to a range of 0-1 by dividing each score by its maximal value (e.g.: FVC%pred score was divided by 2, scoliosis by 4).

Each function was given a score obtained as the mean of the normalized scores of all the itmes considered for it. Each item was therefore attributed the same weight for the final score of the function.

A global final index was defined as the resulting mean of the scores of the five functions. Each function therefore equally contributed to the global final index.

The normalized scores of each item, the score of each function and the global index thus ranged from 0 (less severe) to 1 (most severe).

STATISTICAL ANALYSIS

The age of patients and the age of ambulatory loss according to steroid therapy was tested by one-way non-parametric Kruskall-Wallis Analysis of Variance (ANOVA) with steroid use as independent factor. Similarly, the effect of age on the different indexes of alive patients was tested with age as independent factor. To investigate if the indexes differed between dead or alive patients, between naïve, past and current steroids treated patients or between patients with deletion, duplication or point mutation in the DMD gene, three separate one-way non-parametric Kruskall-Wallis ANOVA were performed with death, steroid intake or genetic analysis as independent factor. Post-hoc tests were based on Dunn’s method (SigmaStat 3.5, Systat Software, Inc, California-USA). In the comparison with dead patients, only alive patients older than 13 years old were considered to match the age of both groups. Significance was determined by p<0.05. In the text, data are presented as median (range).