Table 3.
Responses to Likert scale questions
| Question | Consensus agreement/disagreement | Percentage agreement/disagreement (%) | Number of panellists responding ‘insufficient expertise’ (n) | Delphi questionnaire round |
|---|---|---|---|---|
| Please indicate symptoms that paediatric patients (aged < 18 years old) present with, prior to a CTX diagnosis* | ||||
| Chronic diarrhoea | Agreement | 90 | – | Round 1 |
| Bilateral juvenile cataracts | Agreement | 90 | – | Round 1 |
| Mental retardation (e.g. learning difficulties)† | Agreement | 100 | – | Round 1 |
| Please indicate symptoms that adult patients (aged ≥ 18 years old) present with, prior to a CTX diagnosis* | ||||
| Infantile-onset diarrhoea | Agreement | 70 | – | Round 1 |
| Childhood-onset cataracts | Agreement | 90 | – | Round 1 |
| Tendon xanthomas | Agreement | 90 | – | Round 1 |
| Psychiatric symptoms | Agreement | 90 | – | Round 1 |
| Peripheral neuropathy | Agreement | 70 | – | Round 1 |
| Cerebellar signs | Agreement | 100 | – | Round 1 |
| Pyramidal signs | Agreement | 90 | – | Round 1 |
| All patients have elevated levels of serum cholestanol at the time of diagnosis | Agreement | 100 | – | Round 1 |
| Brain MRI should be performed at the diagnosis stage as they can contribute to the diagnosis of CTX by revealing abnormally increased or decreased signals with characteristics distribution, but also to exclude other conditions | Agreement | 70 | – | Round 1 |
| Measurement of serum cholestanol levels is the diagnostic marker of choice for CTX | Agreement | 100 | – | Round 1 |
| Movement disorders can be considered as late CTX manifestations, however, CTX should be considered in the differential diagnosis of movement disorders, particularly in case of an early onset and when associated with other neurological features and/or with systemic features | Agreement | 70 | – | Round 1 |
| DBS testing is the optimal method for screening of CTX in newborns | Agreement | 71 | 3 | Round 1 |
| CDCA is a lifetime replacement therapy | Agreement | 100 | – | Round 1 |
| The pathophysiological process in CTX patients may be reversed by CDCA, especially if treatment is initiated early in the disease process | Agreement | 100 | – | Round 1 |
| Transcranial magnetic stimulation (TMS) is a useful tool for evaluating improvements in pyramidal function in patients receiving CDCA | Disagreement | 71 | 3 | Round 1 |
| Treatment adherence can be improved by providing CTX patients with support and intensive education | Agreement | 90 | – | Round 1 |
| Pre-marital genetic counselling should be recommended to high-risk populations e.g. patients of Israeli or Moroccan origin | Agreement | 75 | 2 | Round 1 |
| Please indicate which of the below therapy options improves/stabilises prognosis in the majority of CTX patients | ||||
| CDCA alone | Agreement | 100 | – | Round 1 |
| CDCA and HMG-CoA reductase inhibitor | Agreement | 78 | 1 | Round 2 |
| LDL apheresis | Disagreement | 71 | 3 | Round 2 |
| Cholic acid alone | Consensus not reached | Agree (33) Disagree (50) | 3 | Round 3 |
| Cholic acid and HMG-CoA reductase inhibitor | Consensus not reached | Agree (20) Disagree (60) | 4 | Round 3 |
| Reducing plasma cholestanol concentrations slows down the progression of CTX | Agreement | 70 | – | Round 1 |
| CTX patients who start treatment after significant neurological pathology is established, have a worse prognosis compared to patients who started treatment as early as possible | Agreement | 100 | – | Round 1 |
| CTX patients showing MRI evidence of cerebellar vacuolation should be monitored more strictly over time as it is considered a prognostic marker | Agreement | 88 | 2 | Round 1 |
| During the early stages of treatment, paediatric patients should be monitored for the types of symptoms listed below 1–2 times per year | ||||
| Central and peripheral nervous system | Agreement | 100 | 1 | Round 2 |
| Ocular system | Agreement | 78 | 1 | Round 2 |
| Enterohepatic system | Agreement | 89 | 1 | Round 2 |
| Cognitive performance (e.g. learning difficulties) | Agreement | 100 | 1 | Round 2 |
| Cardiovascular system | Consensus not reached | Agree (44) Disagree (33) | – | Round 3 |
| Skeletal system | Consensus not reached | Agree (67) Disagree (0) | – | Round 3 |
| Pulmonary system | Consensus not reached | Agree (33) Disagree (11) | – | Round 3 |
| During the early stages of treatment, adult patients should be monitored for the types of symptoms listed below once per year | ||||
| Central and peripheral nervous system | Agreement | 100 | – | Round 2 |
| Ocular system | Agreement | 70 | – | Round 2 |
| Cardiovascular system | Agreement | 70 | – | Round 2 |
| Skeletal system | Agreement | 70 | – | Round 2 |
| Enterohepatic system | Agreement | 80 | – | Round 2 |
| Cognitive performance (e.g. learning difficulties) | Agreement | 100 | – | Round 2 |
| During the early stages of treatment, adult patients should be monitored for symptoms in the pulmonary system once per year | Consensus not reached | Agree (38) Disagree (13) | 1 | Round 3 |
| Paediatric patients should undergo the types of tests listed below 1–2 times per year | ||||
| Cholestanol plasma concentration | Agreement | 78 | 1 | Round 2 |
| Liver function tests | Agreement | 78 | 1 | Round 2 |
| Paediatric patients should undergo neurologic (and if necessary neuropsychologic evaluation) testing/examination twice per year | Agreement | 78 | 1 | Round 2 |
| Adult patients should undergo the types of tests/examinations listed below once per year | ||||
| Cholestanol plasma concentration | Agreement | 90 | – | Round 2 |
| Neurologic (and if necessary neuropsychologic evaluation) | Agreement | 100 | – | Round 2 |
| Liver function tests | Agreement | 90 | – | Round 2 |
| Urinary bile alcohol concentration | Consensus not reached | Agree (43) Disagree (14) | 2 | Round 3 |
| Brain MRI | Consensus not reached | Agree (22) Disagree (33) | – | Round 3 |
| The following healthcare professionals are important in the diagnosis of paediatric patients with CTX‡ | ||||
| Neurologist | Agreement | 100 | 1 | Round 2 |
| Paediatrician/Metabolic specialist | Agreement | 89 | 1 | Round 2 |
| Geneticist | Agreement | 78 | 1 | Round 2 |
| Ophthalmologist | Agreement | 100 | – | Round 3 |
| Neuroradiologist | Consensus not reached | Agree (44) Disagree (22) | – | Round 3 |
| Psychiatrist | Consensus not reached | Agree (33) Disagree (0) | – | Round 3 |
| Orthopaedic surgeon | Consensus not reached | Agree (22) Disagree (33) | – | Round 3 |
| Endocrinologist | Consensus not reached | Agree (11) Disagree (67) | – | Round 3 |
| Gastroenterologist | Consensus not reached | Agree (33) Disagree (11) | – | Round 3 |
| The following healthcare professionals are important in the diagnosis of adult patients with CTX‡ | ||||
| Neurologist | Agreement | 100 | – | Round 2 |
| Metabolic specialist | Agreement | 80 | – | Round 2 |
| Geneticist | Agreement | 80 | – | Round 2 |
| Ophthalmologist | Agreement | 78 | – | Round 3 |
| Neuroradiologist | Consensus not reached | Agree (56) Disagree (22) | – | Round 3 |
| Psychiatrist | Consensus not reached | Agree (67) Disagree (0) | – | Round 3 |
| Orthopaedic surgeon | Consensus not reached | Agree (22) Disagree (33) | – | Round 3 |
| Endocrinologist | Consensus not reached | Agree (22) Disagree (56) | – | Round 3 |
| Gastroenterologist | Consensus not reached | Agree (33) Disagree (22) | – | Round 3 |
| Cardiologist | Consensus not reached | Agree (22) Disagree (56) | – | Round 3 |
| The following healthcare professionals should be involved in prescribing treatment to paediatric patients‡ | ||||
| Neurologist | Agreement | 78 | 1 | Round 2 |
| Neuroradiologist | Disagreement | 78 | 1 | Round 2 |
| Paediatrician/Metabolic specialist | Agreement | 89 | 1 | Round 2 |
| Family doctor | Disagreement | 78 | 1 | Round 2 |
| Endocrinologist | Consensus not reached | Agree (11) Disagree (67) | – | Round 3 |
| Psychiatrist | Consensus not reached | Agree (22) Disagree (44) | – | Round 3 |
| The following healthcare professionals should be involved in prescribing treatment to adult patients with CTX‡ | ||||
| Neurologist | Agreement | 100 | – | Round 2 |
| Neuroradiologist | Disagreement | 80 | – | Round 2 |
| Metabolic specialist | Agreement | 80 | – | Round 2 |
| Cardiologist | Disagreement | 70 | – | Round 2 |
| Family doctor | Disagreement | 70 | – | Round 2 |
| Ophthalmologist | Disagreement | 70 | – | Round 2 |
| Endocrinologist | Disagreement | 78 | – | Round 3 |
| Gastroenterologist | Consensus not reached | Agree (0) Disagree (67) | – | Round 3 |
| Psychiatrist | Consensus not reached | Agree (22) Disagree (44) | – | Round 3 |
| The following healthcare professionals should be involved in the follow-up of paediatric patients with CTX‡ | ||||
| Neurologist | Agreement | 89 | 1 | Round 2 |
| Paediatrician/Metabolic specialist | Agreement | 100 | 1 | Round 2 |
| Ophthalmologist | Agreement | 100 | – | Round 3 |
| Neuroradiologist | Consensus not reached | Agree (33) Disagree (11) | – | Round 3 |
| Family doctor | Consensus not reached | Agree (56) Disagree (0) | – | Round 3 |
| Endocrinologist | Consensus not reached | Agree (22) Disagree (33) | – | Round 3 |
| Gastroenterologist | Consensus not reached | Agree (22) Disagree (11) | – | Round 3 |
| Psychiatrist | Consensus not reached | Agree (44) Disagree (11) | – | Round 3 |
| The following healthcare professionals should be involved in the follow-up of adult patients with CTX‡ | ||||
| Neurologist | Agreement | 100 | – | Round 2 |
| Ophthalmologist | Agreement | 70 | – | Round 2 |
| Metabolic specialist | Agreement | 80 | – | Round 2 |
| Neuroradiologist | Consensus not reached | Agree (33) Disagree (22) | – | Round 3 |
| Cardiologist | Consensus not reached | Agree (33) Disagree (0) | – | Round 3 |
| Gastroenterologist | Consensus not reached | Agree (33) Disagree (22) | – | Round 3 |
| Family doctor | Consensus not reached | Agree (56) Disagree (0) | – | Round 3 |
| Endocrinologist | Consensus not reached | Agree (33) Disagree (22) | – | Round 3 |
| Psychiatrist | Consensus not reached | Agree (56) Disagree (11) | – | Round 3 |
| A specialist CTX centre/department should be visited once per year by: | ||||
| Adult patients with CTX | Agreement | 100 | – | Round 2 |
| Paediatric patients with CTX | Agreement | 89 | 1 | Round 2 |
| A local CTX centre/department should be visited twice per year by: | ||||
| Adult patients with CTX | Agreement | 90 | – | Round 2 |
| Paediatric patients with CTX | Agreement | 100 | 1 | Round 2 |
| In patients with CTX, the absence of dentate nuclei signal alteration in brain MRI may be an indicator of better prognosis | Agreement | 75 | 2 | Round 2 |
| Increased atrophy and/or signal alteration, identified through brain MRI examinations, may be present in patients who have deteriorating neurological symptoms | Agreement | 78 | 1 | Round 2 |
| Research indicates that treating CTX mothers with CDCA during pregnancy acts as an important means of protection against damage to the fetus and miscarriage | Consensus not reached | Agree (67) Disagree (0) | 3 | Round 3 |
| Paediatric patients should undergo testing for urinary bile alcohol concentrations once per year | Consensus not reached | Agree (57) Disagree (14) | 2 | Round 3 |
| Paediatric patients should undergo brain MRI at the time of diagnosis, then once per year during follow-up | Consensus not reached | Agree (11) Disagree (11) | – | Round 3 |
| Disease progression in patients with CTX is better monitored using brain MRI compared with clinical evaluation alone | Consensus not reached | Agree (22) Disagree (44) | – | Round 3 |
| CDCA alone is a preferred first line treatment compared to CDCA and HMG-CoA reductase inhibitor for treating the underlying biochemical abnormalities in CTX | Agreement | 78 | – | Round 3 |
| There is a positive correlation between the progression of clinical and neuroradiological symptoms in patients with CTX | Consensus not reached | Agree (50) Disagree (0) | 1 | Round 3 |
| Brain MRI can be used to determine neurological stability in patients with CTX | Consensus not reached | Agree (25) Disagree (25) | 1 | Round 3 |
A total of 10 panellists answered questions in Rounds 1 and 2, and 9 in Round 3. Questions achieving consensus (≥ 70% panellists agreeing/disagreeing with the statement) are shown for the round in which consensus was reached and are highlighted in bold. Where questions did not achieve consensus throughout the study, the results are shown for Round 3 only. The proportion of panellists responding neutrally to the questions (responding ‘3’,‘4’ or ‘DNW’) are not presented. In all rounds, ‘insufficient expertise’ responses were removed prior to analysis. *Options that did not achieve consensus in Round 1 were rephrased as a proportion question in Round 2. Please refer to Table 5 for the rephrased questions and responses
†Phrased as in the original survey question; ‘mental retardation’ referred to as ‘intellectual disability’ in the text
‡Some panellists noted in their comments that alternative roles/names for certain healthcare specialists exist in different countries (e.g. metabolic specialists are often the same as geneticists in some countries). Therefore, panellists may have answered questions about healthcare professionals differently depending on the role they perceive each of the healthcare professionals’ specialism to be in their country
CDCA: chenodeoxycholic acid; CTX: Cerebrotendinous xanthomatosis; DBS: dried bloodspot; DNW: do not wish to answer; HMG-CoA: 5-hydroxy-3-methylglutaryl-coenzyme A; LDL: low-density lipoprotein; MRI: magnetic resonance imaging; TMS: transcranial magnetic stimulation