Although neurologists are frequently faced with the management of rare diseases, there is little generic guidance for the approach to management. There are complexities with respect to diagnosis, counselling, treatment and monitoring which are idiosyncratic to rare diseases. Here we use a case report as the basis for discussion of the management of rare neurological diseases. We discuss current issues, guidance from regulatory bodies, and offer practical tips for diagnosis, treatment and monitoring, including the use of decision tree analysis. We offer a generic algorithm to aid neurologists when facing rare conditions.
- Rare Diseases
- Superficial Siderosis
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A case report
A 60-year-old woman, a retired research scientist, reported a 5-year history of progressive sensorineural hearing loss, a 2-year history of imbalance and mild difficulties in concentration. She had a history of depression and previously took mirtazapine. Her mother had developed Parkinson's disease and had died aged 89 years. She did not smoke and rarely drank alcohol.
On examination, the revised Addenbrooke's Cognitive Examination score was 77/100; there was particular deficit on memory (17/26) and fluency (9/14).1 There was mild dysarthria and bilateral dysdiachokinesia, without tremor or past pointing. Romberg's sign was positive and she had a wide-based ataxic gait.
The following blood tests were normal: full blood count, erythrocyte sedimentation rate, serum vitamin B12, folate, vitamins A and E, urea and electrolytes, liver function tests, serum C reactive protein, calcium and phosphate, thyroid function tests, ACE and antineuronal antibodies.
MRI of brain and cervical spine (figure 1) showed haemosiderin deposition, consistent with superficial siderosis of the central nervous system.2 CT scan of the intracranial arteries and MR time-resolved angiography of the spine showed no cause for this. At her next review appointment, following an internet search, she requested treatment with deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one), which is a bidentate ligand acting as an iron chelator. Since 1999, it has been approved for the treatment of iron overload in patients with thalassaemia major when deferoxamine therapy is contraindicated or inadequate. It is equivalent to the mainstay treatment, deferoxamine (desferrioxamine B), in the stabilisation of body iron levels in patients with thalassaemia.3 Its risk of agranulocytosis is 1% with 5% having less significant reductions in neutrophil count. Other side effects include nausea, vomiting and altered liver function. For superficial siderosis, deferiprone has the theoretical advantage over deferoxamine in that it crosses the blood–brain barrier. The patient based her request on a recent paper, which had reported the relative safety of the drug in 10 subjects with superficial siderosis followed up for 90 days.4 In this report, two of 10 patients had temporarily stopped deferiprone due to transient elevations in liver function. The study was not designed to test clinical efficacy. She was aware that the drug was not being used in routine clinical practice for her condition and that there was little evidence of clinical efficacy. Nonetheless, she was very keen to pursue any treatment that had even the slightest chance of helping her condition and long-term outcome, and thus she started the drug following a local approval process.
This case highlights the challenges that patients and clinicians encounter in managing rare neurological disorders. In this article, we discuss issues pertinent to the management of rare disorders where there is no established treatment, and use an algorithm that clinicians may find helpful. We refer to available guidance, emphasising advice from the UK General Medical Council, which is particularly applicable to our own working environment. A glossary of terms is included in box 2.
What does rare mean?
The exact prevalence of superficial siderosis is unknown but with a little over 100 cases of superficial siderosis in the literature, it can legitimately be considered to be rare. So how is ‘rare’ defined? The European Union suggests a disease is rare if its prevalence is less than or equal to 1 in 2000 of the European population, although most rare disorders have a prevalence of less than 1 in 10 000.5 The UK defines a disease as rare if its prevalence is less than 1 in 50 000 per population.6 The online portal for rare diseases, ‘Orphanet’, lists 5954 diseases, manifesting in up to 8% of the population.7 Rare diseases are sometimes referred to as ‘orphan’ diseases.
Infrastructure for the management of rare diseases
Each European Union member state is in the process of adopting a plan to combat rare diseases by the end of 2013. In the UK, ministers from all four Departments of Health are signatories on the ‘UK Plan for Rare Diseases Consultation’, which recommends comprehensive and coordinated care for patients with rare diseases, including the use of specialist centres.8 In the meantime, patients with rare diseases surveyed by a patient support group, Rare Diseases UK, highlighted a frustration with delayed diagnosis, lack of information provision by the National Health Service (NHS) and lack of coordinated care.9 In all, 12% of surveyed patients reported waiting over 10 years for a diagnosis.
Diagnosis of rare diseases
Issues in current practice
Diagnostic error in medicine is common. For example, a study from an intensive care unit demonstrated nearly 20% discordance between the clinically-defined cause of death and findings at postmortem examination.10 Not surprisingly, therefore, the diagnosis of rare diseases is often delayed. Errors in diagnosis have been divided into three main categories.
‘No fault errors’ include misdiagnosing a rare condition that mimics a common one, and misdiagnosing a condition presenting in an atypical fashion.
‘System errors’, in which organisational deficiencies delay or negate the correct diagnosis, include factors such as faulty or inadequate equipment.
‘Physician cognitive errors’: clinicians make an initial diagnosis based on how closely their perception of available evidence (such as history and examination) matches typical presentations, for example, thunderclap headache suggests subarachnoid haemorrhage. The probability of this initial diagnosis is then modified in a Bayesian fashion based on test results. If the test results match the expectation, the diagnosis is typically confirmed and a search for alternative diagnoses will stop. However, at least 30 types of cognitive errors can impede this process and complicate diagnosis.11 Clinicians may commit an ‘anchoring error’ by focusing on a potential diagnostic clue prematurely, which may be compounded by ‘confirmation bias’, whereby the clinician looks for confirmatory evidence to confirm the diagnosis at the expense of searching for evidence to refute it. ‘Availability bias’ may play a role in this, with diagnoses appearing higher up the differential diagnosis if they come to mind more readily. This can, in turn, be compounded by a ‘search satisfaction’ error when the diagnostic pathway is prematurely terminated after an abnormal result is found. Although clinicians are educated to search for a unifying diagnosis according to the principle of ‘Occam's razor’, an abnormal result may lead to failure to diagnose a rare disease if there is, in fact, more than one pathology. All of these cognitive errors may be particularly problematic in the diagnosis of rare diseases.
The General Medical Council framework does not offer specific advice to manage rare diseases, but their advice relates equally to rare and common diseases.12 With respect to diagnosis, clinicians should provide ‘investigations…as necessary’ and ‘good use of the resources available to you’.
There are several proposed strategies to reduce cognitive errors in the diagnostic process.11 An awareness of the common cognitive biases is important. If a provisional diagnosis is achieved, clinicians should routinely reflect on this: ‘could this be anything else?’; ‘is there anything which is atypical?’; and ‘does the abnormal test result explain the clinical presentation or do I need to keep searching?’ Allocating an appropriate amount of time for complex diagnostic pathways is still important in an increasingly time pressured clinical environment.
If conventional investigation by first principles fails to achieve a diagnosis, there are several options. The portal ‘Orphanet’ (http://www.orpha.net) allows the input of symptoms to search for the diagnosis.7 A search string, including ‘deafness’, ‘ataxia’ and ‘dementia’, raised nine potential diagnoses but, as a limitation, superficial siderosis was not on the list, probably because it is the consequence of disease, rather than a primary disease.
Many countries have a well-developed tertiary and quarternary referral process for neurology, which likely facilitates the diagnosis of rare diseases. In the UK, about half of reference centres are disease based (eg, mitochondrial disease centre), with the remainder focusing on specific treatments. European reference centres can be found using the ‘Orphanet’ portal, with search options allowing the input of the disease (or class of diseases), the aspect of management (eg, medical management) and the country of practice to search for the appropriate reference centre. If a genetic disorder is suspected, then review by the local clinical genetics team may facilitate further counselling and advice for both patient and family. In the USA, the National Institutes of Health has an Office of Rare Diseases Research which provides accessible information on rare diseases (including links to relevant websites and trials) and stimulates research on the prevention, diagnosis, or treatment of rare diseases or conditions. Among many other activities, it runs the Underdiagnosed Diseases Program, which adopts a cross-specialty approach to the diagnosis of diseases that have eluded treating physicians, in a selected population.
After diagnosis, patients need counselling with respect to diagnosis, clinical issues, prognosis and management. This may be limited by paucity of evidence. In particular, clinicians should be aware of the inherent selection bias when evaluating case reports and series, which may skew interpretation of the severity and natural history of the disease. A good case series will have explicit inclusion and exclusion criteria, with consecutive patient enrolment, and a high follow-up rate of prospectively collected clinically relevant outcomes.13 Available information may be provided to patients in a variety of ways. It is important that it is timely and comprehensible, with the ability to discuss, reiterate and clarify over time, if needed. Written information including patient information leaflets may help patients with sufficient literacy skills. Disease specific information leaflets may be provided by healthcare organisations such as ‘NHS choices’ (http://www.nhs.uk), disease specific charities and patient support groups, and these should be assessed for appropriateness. Patients may also benefit from accessing the website run by EURORDIS (Rare Diseases Europe),14 a non-governmental organisation, which provides links to various patient-driven groups. Patients can also search ‘Orphanet’ for information on a large number of rare diseases and information about their relevant tests.7
Treatment and monitoring of rare diseases
Issues in current practice
Drugs developed specifically for rare diseases, the so-called ‘orphan drugs’, are scarce due to the high cost of drug development (up to nearly US$500 million),15 rarity of the disease and uncertain benefit. To this end, the US Orphan Drug Act and the European Union regulation 141/2000/EEC allows the designation of ‘orphan drug’ status for a rare disease for which there are financial and scientific incentives for the development, and extended patent protection for pharmaceutical companies taking on the developments of these agents. Without orphan drug status it would be unlikely that the revenue after marketing of the medicinal product would cover the investment in its development. In a minority of rare neurological diseases, there are such orphan drugs (box 1). Access arrangements for orphan medicines vary across between countries, even those within the UK. In England, the Advisory Group for National Specialised Services16 may recommend that a medicine is appropriate for commissioning at a national level. The Scottish Medicines Consortium and All Wales Medicines Strategy Group do this in Scotland and Wales, respectively.17 If medicines for rare conditions are approved by these organisations, clinicians usually have to submit an application on a ‘case by case’ basis to their health board or Primary Care Trust for consideration of approval and funding, especially where there is high cost.
Examples of drugs used in neurology
Categories are based upon UK practice
Examples of orphan drug use in neurology
Stiripentol for Dravet's syndrome
Alglucosidase-α for Pompe's disease
Amifampridine for Lambert–Eaton myasthenic syndrome
Examples of ‘off-label’ use in neurology
Deferiprone for superficial siderosis
Mitoxantrone and alemtuzumab for multiple sclerosis
Cyclophosphamide for cerebral vasculitis
Rituximab for myasthenia gravis and chronic inflammatory demyelinating polyradiculoneuropathy
Infliximab for neurosarcoidosis
Dosulepin and amitriptyline for headache disorders
Verapamil and lithum for cluster headache prophylaxis
Examples of unlicensed medicine use in neurology
3,4-diaminopyridine for Lambert–Eaton myasthenic syndrome
Flunarizine, dihydroergotamine and caffeine for headache
Coenzyme Q10 for mitochondrial disorders
Glossary of terms
Off-label drug: one with marketing authorisation for use for a separate indication
Orphan disease: rare disease
Orphan drug: a drug used to treat an orphan disease
Rare: the definition varies. The European Union defines a disease to be rare when it has a prevalence of <1 in 2000 per population
SPC: Summary of Product Characteristics
Unlicensed drug: a drug which does not have national market authorisation
The diagnosis of rare diseases may be improved by recognising well-described physician cognitive errors, the appropriate use of web-based tools such as Orphanet and referral to reference centres
Many drugs for rare diseases are prescribed in off-label or unlicensed
Before prescribing for rare diseases, clinicians must consider the available evidence, cost implications of the drug (and any associated monitoring) and adverse effects, as well as patient opinion; decision tree analysis may help
Clinicians are not obliged to prescribe specific treatments simply because patients request them
Good channels of oral and written communication with the patient and general practitioner are mandatory before prescribing drugs for rare diseases
Patient decisions and rationale for management should be recorded
When there is no orphan drug, and no other drug licensed for its treatment, medications may be used off-label, or unlicensed medicines may be used if permitted by local legislation. Definitions of these drugs vary between countries. In the UK, an ‘unlicensed medicine’ is defined as one with no marketing authorisation for any indication. Unlicensed medicines have not been subject to the same scrutiny with respect to their quality, efficacy and safety, and therefore clinicians must carefully consider their risks and benefits before prescribing. In the USA, medications which lack approval by the Food and Drug Administration (FDA) are termed ‘unapproved’. An ‘off-label’ medicine in the UK is a medicine with marketing authorisation but where the licence does not cover the indication for which the medicine is being prescribed. Since they are not being used for their licensed indication, there may be limited knowledge and experience of their safety and efficacy in this setting. In the UK, the legal responsibility lies with the person signing the prescription. Pharmaceutical companies may be held to account for adverse events only if the product is defective, under the principle of strict liability. If the product is not defective, then clinicians may be called upon to justify their actions. Box 1 gives examples of drugs for rare neurological diseases.
There are important practical aspects of prescribing for rare diseases. Only 14% of British physicians responding to a commercially sponsored questionnaire-based study were familiar with General Medical Council guidance on unlicensed medicines; about three-quarters were concerned about a lack of safety data and legal implications.18 Budget concerns may be an issue with drugs for rare diseases, which are often expensive while helping only a few individuals. In addition, monitoring of the treatment of rare diseases may be costly and time consuming. With the ever-increasing drug expenditures of health systems, it is easy to appreciate the benefits of cost-effective prescribing. Finally, 71% of surveyed physicians were also concerned about safety monitoring of drugs used to treat rare diseases.
In the USA, there are still drugs available that are unapproved by the FDA, although federal law prohibits such drugs from being sold. The FDA advises against using such drugs on the basis on both safety and efficacy concerns, and are currently removing unapproved drugs or entering them into an approval process. If a drug has FDA approval, doctors in the USA are expected to use their clinical judgement but can prescribe drugs off-label if clinically justifiable. In Europe, laws governing off-label prescription vary between member states, but in general such practice is widespread.19 In the UK there is no legal framework prohibiting the prescription of off-licence of unlicensed medication. The General Medical Council addresses this issue directly in its ‘Prescribing’ guidance.20 It specifically allows the use of both unlicensed and off-licence medications if the clinician is satisfied that an alternative licensed treatment would not ‘meet the patient's needs’. The clinician must be satisfied that there is ‘sufficient evidence base and/or experience of using the medicine to demonstrate its safety and efficacy’ and must take responsibility for ‘overseeing the patient's care, monitoring and any follow-up treatment’. Finally, clinicians should consider the cost effectiveness of medicines, which are potentially very expensive.
The General Medical Council issues specific advice for UK physicians on the ‘Responsibility for prescribing medicines for hospital outpatients’.20 Note that liaison with the patient's general practitioner is mandatory, and ‘there should be full consultation and agreement between general practitioners and hospital doctors about the indications and need for particular therapies. The decision about who should take responsibility for continuing care or treatment after initial diagnosis or assessment should be based on the patient's best interests rather than on the healthcare professional's convenience or the cost of the medicine’. Finally, there is legal precedent in English Common Law to suggest that a clinician is not legally required to prescribe a medication which is felt to be inappropriate, even if the patient specifically requests it (Mr Leslie Burke vs GMC (2005)).21
The principles of good prescribing should guide all treatment decisions. These have been discussed extensively in the literature: efficacy should be balanced against side effects, and autonomy balanced with cost (figure 2).22
If there is no drug licensed for a particular disease, the clinician should review the literature and prescribe treatment only if there is potential benefit and an acceptable side effect profile. The evidence of efficacy may be limited to case series or reports. ‘Experts’ in the field may be consulted but any advice obtained should be regarded as ‘level 5’ evidence at best. The literature may also provide some safety information, in addition to the ‘Summary of Product Characteristics’ which contains updated information including serious and common side effects.23 If the clinician feels that requests for certain medications are not appropriate or justified, then there is no obligation to prescribe the medication and there is an ethical and legal basis for refusal to do so.21 Nonetheless, the basis for such a decision should be communicated clearly, since patients with rare diseases are a vulnerable group, at risk of being treated in private clinics offering unrealistic outcomes from expensive, ineffective and even harmful therapy.
A decision tree analysis is a potential method for making clinical decisions more explicit and structured. This aims to break down a decision into its component parts.24 Constructing a decision tree involves stating the possible outcomes after an intervention and the probability of them occurring (based on literature and experience). Each outcome is then assigned a value for ‘utility’ or worth which may be according to an arbitrary scale and defined in consultation with patient. The final value of an outcome—the expected utility—can then be calculated by multiplying the probability of the event with the subjective utility of the event. Logical decision making would assign the option with the highest value of expected utility as the preferable option. An advantage of this explicit and systematic approach is that it considers patient views and preferences. A potential limitation is that assigning an emotive value (the utility) to the decision may not be straightforward.25 In addition, estimates of probability are not always available or accurate. Estimates that are available may come from studies with small sample sizes, thereby increasing the confidence intervals of any probability. In addition, the probability of a particular outcome may vary widely between studies. If this is the case, one option is to calculate a decision tree using the extremes of the quoted probabilities in an effort to determine if the wide variation in predicted probabilities influences results. Figure 3 shows the decision tree analysis for treatment with deferiprone in our patient, with the basis for probabilities stated detailed in the figure legend. Although the side effect profile and the patient's wishes are well established, the probability of benefit is based on limited evidence and in this case should be interpreted with caution. When data are limited, one must remember the principle of ‘junk in, junk out’. Nevertheless, decision tree analyses allow for explicit consideration for all available data.
Regardless of the method used to make a decision, patients should be actively involved in the process. This involves the principle of shared decision making, whereby the potential benefits and harms of treatment are discussed after emphasising clinical equipoise. This is then followed by an exploration of ideas, concerns and expectations followed by joint decision making.26 Such an approach empowers the patient and respects autonomy, often with the patient preferring more conservative outcomes usually without the expense of an adverse effect on clinical outcome.27 We should not assume that patients will always opt for an expensive drug with limited evidence for efficacy. Given that the clinician may be called upon to justify actions after an adverse event for an off-label or unlicensed medication, the ultimate decision should be in keeping with the Bolam principle, whereby the common law duty to act responsibly is respected and the clinician prescribes in a fashion that would be supported by peers.
Next, if the clinician feels prescription is potentially worthwhile, the patient should then be presented with the literature in manageable volumes—preferably in summary form on a sheet of A4—with the emphasis that the prescription is ‘off-licence’ or unlicensed. The details of the discussion, including uncertainties, the use of unlicensed or off-label medications, and the patient's decision and consent, should be documented. Providing the patient a copy of the clinic letter in easily understandable language summarising the discussion is useful and in keeping with national guidelines such as the Health Improvement Scotland Clinical Standards for Neurological Health Services.17
If a decision to prescribe a medication is made in principle, it is important to consider cost. Both clinicians and patients may wish to make cost-effective decisions and to avoid very expensive medications with little proven benefit. However, while there are many robust cost-effectiveness analyses using indices such as the ‘quality adjusted life year’ for common neurological diseases such as stroke, epilepsy and Parkinson's disease, there are few such data for rarer neurological diseases and tests. In practice, factoring in costs often relies on patient preference and clinician judgement, and frequently requires institutional approval.
Thereafter, it is important to liaise with the patient's general practitioner. First, this enables dissemination of information pertaining to the disease and the proposed drug. Such information should be provided to all healthcare professionals involved in the care of the patient and may include the community pharmacy if prescription and supply is provided from primary care. Second, it enables responsibilities for prescribing and monitoring of medications to be agreed. In situations where side effects are likely or special monitoring is required, the patient needs the appropriate arrangements in place before starting unlicensed or off-label medicines. The decision about who should take responsibility for continuing care or treatment after diagnosis or assessment should be based on the patient's best interest. Agreement to shared care with the general practitioner should not be expected as a right for complex specialist medicines. In the UK, general practitioners are free to decline to prescribe within primary care if they have not been given sufficient information to prescribe safely or if they consider that it is not within their level of expertise. However, in our experience, appropriate liaison between teams eliminates these issues.
The mechanism for distributing responsibilities for prescribing and monitoring drugs for rare diseases varies. For example, in the UK, immunosuppressants used in neurology, rheumatology and transplant medicine are usually started in secondary care by the hospital specialist, and are prescribed and monitored in primary care by the patient's general practitioner under a shared care agreement. This details the responsibilities for the hospital consultant, general practitioner, pharmacist and the patient with respect to prescription and, if relevant, monitoring. Decisions about whether a patient is appropriate for such shared care are based upon disease complexity, patient choice and the general practitioner's views. It is the responsibility of individual NHS Boards or primary care trusts to decide how a shared care agreement is funded, and this may require additional applications.
Once the strategies above have been implemented, the neurologist should agree a time frame for review with patient and GP, with clear stopping and continuation criteria. At review appointments, clinicians should ensure the patient has access to relevant support groups and, if appropriate, access to clinical trials which are often coordinated from reference centres.
Our approach to the patient with superficial siderosis
Deferiprone, when used for its licensed indication, has been considered by some NHS bodies to be inappropriate for prescribing in primary care. Thus, responsibility for prescribing this specialist medicine should remain with the hospital consultant and supply of this medicine should be organised via the hospital pharmacy. Our application to prescribe deferiprone from secondary care was approved by the hospital's senior management team. The cost of the drug before monitoring is approximately £1500 per annum. The neurology team liaised with the patient's general practitioner who agreed to provide venepuncture services, provided that the neurology team saw the blood results. However, eventually we reached a decision, in agreement with the patient, that the patient would attend the neurology ward weekly for venepuncture and at the same time collect the deferiprone for the following week. She agreed to contact the ward by telephone the next day before continuing the drug, with the ward doctor signing a pro forma when the blood results are checked and a decision relayed to the patient. We supplied a copy of our protocol to the patient (also stored on the ward), outlining the responsibilities of the medical staff, nursing staff and the patient.
In figure 4 we summarise, in an algorithm, the key points important for managing patients with rare diseases. These are not intended to be definitive or all-encompassing, and the precise management will vary with individual circumstances. They do, however, provide a framework for clinicians.
The diagnosis of rare diseases requires careful consideration and, often time, an awareness of common cognitive errors, and often the resources provided by reference centres. Optimal management of rare diseases should be in line with advice from relevant regulatory bodies such as the General Medical Council (UK), and requires a structured approach that considers both patient opinion and clinical evidence. It is mandatory that there is good communication among the neurologist, the patient and general practitioner. Key points are outlined in box 3.
We are grateful to Dr Celestine Santosh, Consultant Neuroradiologist, Southern General Hospital, Glasgow, for advice on imaging.
Competing interests None.
Provenance and peer review Commissioned. Externally peer reviewed. This paper was reviewed by Lionel Ginsberg, London, UK.
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