Our study examines the clinical drivers of healthcare resource utilization in adult patients with mitochondrial disease in Australia in the out-patient setting.

Our results show that neurological consultations and investigations are the leading driver of healthcare costs in the out-patient clinics in all the three groups of participants: those with mtDNA mutations, those with nDNA mutations, and those with no genetic cause identified. This is consistent with the high frequency (94.5%) of neurological symptoms in our study population necessitating a higher frequency of neurological investigations and consultations. Patient symptoms requiring outpatient care included muscle fatigue and weakness, exercise intolerance, migraines, seizures, stroke-like episodes, cognitive deterioration, gait impairment, paraesthesia and sensory deficits and incoordination.

Those patients with mtDNA point mutations (Group 1) accrued the highest per person per annum neurological-driven out-patient costs compared to Groups 2 and 3 (Fig. 2). This is not surprising, given that neurological symptoms and signs contribute significantly to the clinical manifestations in the patients with mtDNA mutations [2,3,4]. In these patients, neurological investigations such as MRI brain with MR spectroscopy and electroencephalogram (EEG) were carried out more frequently due to the higher prevalence of certain neurological symptoms such as stroke-like episodes and seizures.

Despite the clinical heterogeneity and variability in their disease course, neurological complaints constituted a high symptom burden in the other two groups as well (Group 2: 94.1%; Group 3: 93.1%). Similarly, neurological investigation was the most resource intensive field in Groups 2 and 3 as well (Fig. 3). Neurological symptoms due to myopathy and peripheral neuropathy were frequently investigated and treated in patients with OPA1 and TWNK mutations despite their features of optic atrophy, ptosis and ophthalmoplegia constituting the predominant phenotype [3, 21]. This higher frequency of neurological symptoms is similarly reflected in our study Group 3 which comprises participants with a clinical definite diagnosis but no confirmed genetic diagnosis to date, and is consistent with the study by Grier et al., where weakness, fatigue, difficulty in walking, incoordination, numbness and seizures were amongst the top ten self-reported symptoms in a cohort of patients with either a clinical diagnosis or biochemical deficiency or both [22].

Ophthalmological problems constituted the most frequent non-neurological symptoms (94.1%) and are consistent with outpatient monitoring of the ocular symptoms of participants stratified to Group2. Ophthalmological investigations and consultations are the second greatest driver of healthcare resource utilization. Ophthalmological costs were also attributed to day-only interventional procedures, of which surgery for correction of ptosis was most common. Surgical correction of ptosis in CPEO has shown safety and efficacy [23]. Eshaghi et al. have reported significant improvement in Margin-to-Reflex Distance 1 (MRD1) and chin-up posture at 1-year post-surgical follow up [24] and Doherty et al. demonstrated low complication rate and objective benefit following surgery in patients with ocular myopathy and ptosis [25]. In our cohort, 7 participants in Group 2 had ptosis correction surgery (41.2%) of which 3 patients required more than one operation. One participant in Group 1 and three participants in Group 3 also required ptosis correction surgery.

Gastroenterological and cardiac-related out-patient costs were also amongst the stronger drivers of healthcare resource utilization. Gastroenterological-related costs were the second most resource intensive field in Group 1 and third-most in Group 3. Almost three-quarters of the participants in Group 1 (73.9%) reported a high prevalence of gastrointestinal dysmotility and other symptoms associated with alimentary disorders. More than half of the participants in Group 3 (58.6%) also reported gastrointestinal symptoms. Similar to other studies [26,27,28,29], gastroenterological symptoms such as dysphagia, gastroesophageal reflux disease and feeding difficulties manifesting as delayed gastric emptying, constipation and intestinal pseudo-obstruction were observed and investigated with gastric motility and colonic transit studies and were main contributors to the higher out-patient costs. Gastroscopies and colonoscopies were performed at a lesser frequency. Consultations with gastroenterologists also contributed to the costs in this category especially for patients with severe or progressive symptoms.

Cardiac investigations and surveillance cardiac testing also contributed significantly to the healthcare resource utilization. The out-patient costs related to cardiac category are driven by surveillance investigations such as 12-lead electrocardiograms (ECGs), 24-h Holter monitoring and transthoracic echocardiograms (TTEs). Patients with mitochondrial disease are at an increased risk of cardiomyopathy and arrythmia as cardiac muscle is a high-energy-dependent tissue [30]. The progression to a high-grade AV block can be unpredictable in patients with mtDNA mutations, hence there is a need for regular monitoring despite minimal to no reported symptoms [31, 32]. Additionally, cardiac day procedures and investigations such as stress echocardiograms, electrophysiology studies (EPS) and myocardial perfusion scans (MIBI scans) are often more expensive compared to investigations in other specialties. Additional file 1: Table 1 lists the costs of specialty-based investigations and day-only procedures. Of the three groups, participants in Group 3 reported the highest prevalence of cardiac symptoms (48.3%), and investigations were more frequent because without a confirmed genetic diagnosis, the risks for cardiac complications are more difficult to ascertain.

When the health care costs were analyzed for the participants’ entire clinic duration, Group 3 showed the greatest healthcare resource utilization (Fig. 4). This observed difference is most likely due to the lack of a molecular diagnosis which can otherwise enable a more customized approach through utilization of streamlined standards of care and investigations [8, 9, 33] and undertaking further ancillary investigations to determine a potential molecular diagnosis.