The role of the pharmacist in motor neurone disease

Case scenario

Sarah, a regular customer in your community pharmacy, presents a prescription for riluzole tablets written by a neurologist for her husband David. It has been several months since David, aged 57, has been seen in the pharmacy. Sarah looks visibly upset and not her usual cheerful self.

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Introduction

Motor neurone disease (MND) is a group of progressive, degenerative disorders of the motor neurones.¹ Motor neurones are nerve cells which control the muscles that enable movement, speech, breathing and swallowing, and their degeneration results in muscle weakness and atrophy.^1–3

Patients diagnosed with MND have an average survival time of 2.5 years after diagnosis and usually die of respiratory failure.^1–3 The initial symptoms, rate and pattern of disease progression and survival times vary between patients.¹ In the vast majority of cases, the cause of the disease is unknown, and there is currently no cure.^1,2,4 Multidisciplinary care of patients is required as the disease progresses, and pharmacists can play an important role in patient care.³

The most common type of MND is known as amyotrophic lateral sclerosis (ALS).^1,4 In the United States, ALS is also colloquially known as Lou Gehrig’s disease.^3,5 Although there are other forms of MND that are not classified as ALS, ALS and MND are generally referred to interchangeably.² In the United Kingdom, some European countries, Australia and New Zealand, the disease is referred to as MND, but in most other countries it is simply referred to as ALS.⁵

Epidemiology

MND occurs globally. The lifetime risk of MND is approximately 1 in 300–400.^4,6 In Australia, on average, two people are diagnosed and two people die from MND each day.² It is estimated that over 2,000 Australians have MND at any time, of whom 60% are male and 40% female.² The prevalence in Australia is 8.7 per 100,000, with the highest prevalence in males aged 75–84 years.² However, 58% of patients are aged under 65 years.² 

Australia has a relatively high prevalence compared to other countries; for example, the prevalence rate in Europe is 7.9 per 100,000.² There is evidence that the prevalence of MND is increasing in some countries.^2,6

Although the average survival time following diagnosis is 2.5 years,¹ some patients die 3–12 months after diagnosis.⁴ However, in 5–10% of cases, patients may survive for 10 years or more.²

Aetiology and pathophysiology

Various mechanisms, such as protein aggregation, glutamate (a neurotransmitter) toxicity, oxidative stress and free radical or immune-mediated damage, may adversely impact the health of motor neurones in the body; these may contribute to the pathogenesis of MND.^1,2 However, the actual causes of MND are largely unknown. In 90% of cases, MND is sporadic where there are no clearly identifiable causes.² Approximately 10% of cases are inherited (familial) and the genetic mutation responsible for 60% of these cases in Australian families is now known.² From a clinical perspective, the inherited and sporadic forms of the disease are not distinguishable from each other.² Knowledge of genetic involvement in MND is increasing with further research, but the relationship between genetic and environmental risks, particularly in sporadic MND, is not well understood.²

Many risk factors have been proposed to be associated with the development of MND. However, the only factors that have been clearly identified are older age, male sex and family history.^3,6 Other factors that have been proposed include^1,6:

• smoking
• dietary factors
• physical fitness/exercise
• head trauma
• viral infections
• metabolic diseases
• occupational and environmental factors such as exposure to chemicals (e.g. pesticides), metals (e.g. lead) and ’electrical’ occupations (e.g. welding). 

These risk factors may act individually or in combination to contribute to the development of MND. Recent research suggests a six-step process with genes, environment and aging contributing to its development.^2,7

Proposed causes of MND, such as high-intensity exercise and blue green algae, often generate media interest, but it should be noted that an association is not the same as causality.² There may be interactions between non-genetic and genetic risk factors.^5,6 More research is required to understand how any underlying genetic mutations cause MND. Genetic testing of patients may become routine practice in the future as more MND-causing gene mutations are discovered in both familial and sporadic forms.² Also, targeted treatments and strategies which can prevent or delay the onset of disease in patients with an MND-related genetic mutation may be developed in the future, as knowledge of causative factors increases.²

Clinical features

The onset of MND is insidious. The site of initial symptoms varies from patient to patient, with symptoms typically occurring in one muscle group; for example, weakness and wasting of one hand or a unilateral foot drop.^1,2

Initial symptoms are usually mild and may include^1,2,8:

• stumbling due to weakness of the leg muscles
• difficulty holding objects due to weakness of the hand muscles
• slurring of speech and swallowing difficulties due to weakness of the tongue and throat muscles
• shortness of breath due to respiratory muscle involvement
• cramps and muscle twitching (fasciculations).

In some patients, there may be frontotemporal cognitive changes, and emotional responses such as laughing and crying may be easily triggered.

MND may be categorised according to the features of lower and upper motor neurone damage (see Table 1).^2,4 

Diagnosis

Diagnosis of MND is not straightforward, as initial symptoms may be confused with those of other diseases. The average time from the appearance of first symptoms to diagnosis is 12 months.² Several tests can be conducted to confirm the diagnosis
and rule out other diseases; these tests may include⁸:

• Creatine kinase blood test: elevated levels of this muscle enzyme may be indicative of MND.
• Magnetic resonance imaging (MRI) of the brain and spine: any abnormalities in the brain and spine as well as nerves will be shown.
• Electromyography (EMG): an electrical test of the muscle and nerves.
• Lumbar puncture: spinal fluid is generally normal with MND.
• Muscle biopsy: muscle tissue is generally normal with MND.
• Computed tomography (CT) scan: any brain abnormalities will be detected.

There are three main phenotypes of MND based on the sites of symptoms and involvement of upper and lower motor neurones:

1. ALS – This is the most common form of MND, affecting 70% of patients, where there is damage to both upper and lower motor neurones resulting in muscle stiffness and weakness in the limbs.^1,9,10 This typically occurs in patients aged over 55 years.⁸
2. Progressive bulbar palsy – This affects 8–25% of patients. There is damage to the lower motor neurones of head and neck nerves, resulting in swallowing and speech problems.^8–10
3. Progressive muscular atrophy – Affecting 5–10% of patients, 80% of whom are men, there is lower motor neurone damage resulting in muscle wasting and weakness, especially in the arms. This typically occurs in patients at an early age (under the age of 50 years).^8,10

Primary lateral sclerosis, where there is damage to the upper motor neurones only, is rare.^2,10 A small percentage of patients with MND may be diagnosed with ‘motor neurone disease with frontotemporal dementia’, where symptoms of dementia can develop several years prior to motor symptoms.²

Differentiation between the different MND clinical phenotypes is often blurred, and as the disease progresses, there may be considerable overlap, resulting in more generalised muscle wasting and weakness.² Patients exhibit different initial symptoms depending on the exact combination of nerves that are damaged, and as the disease progresses, the features of the disease become mixed.⁸ However, certain symptoms, such as loss of the senses, loss of bladder and bowel control, confusion or loss of mental functions, are rarely found in any patients with MND.⁸

Delays in diagnosis may result from various factors.¹¹ This may include patients not seeking immediate diagnosis, initial misdiagnosis, referral to non-neurological specialists and delayed referral to a neurologist.¹¹ General practitioners will probably only encounter one patient with MND in their careers.^1,11 Differential diagnoses may include a variety of other neurological conditions, including Kennedy’s disease, an inherited disorder which progresses very slowly, involves only lower motor neurones and exhibits similar symptoms to those of MND.^1,2

A diagnosis of MND, a debilitating and fatal disease, will have an enormous impact on the patient and the patient’s family.⁵ It is a difficult time for all, and many questions will arise. Because the symptoms and progression of the disease vary so much from one patient to another, it is impossible to predict exactly what will happen following diagnosis.⁸

Treatments

Because there is no curative therapy currently available, the focus of treatment for patients with MND is coordinated multidisciplinary care with timely interventions to help manage symptoms as they develop.^2,10

Pharmacological therapies

Currently there are only two neuroprotective, disease-modifying therapies available globally, both of which have only very limited effects on the course of the disease.²

Riluzole is available on the Pharmaceutical Benefits Scheme (PBS) for eligible patients (authority required). The exact mechanism of action is unknown, but it is thought to target glutamate by inhibiting its accumulation and neurotransmission.^6,12 Tablets containing 50 mg (Rilutek, Pharmacor Riluzole, Riluzole Sandoz, APO-Riluzole) are available, as well as a liquid containing 5 mg/mL (Teglutik) for ease of swallowing or use via a percutaneous endoscopic gastrostomy (PEG) tube.³ The dosage is 50 mg twice daily, taken at the same time each day, 1 hour before or 2 hours after food.³ In the initial clinical trials comparing riluzole with placebo, there was no clinically significant benefit on muscle strength, but survival for patients was increased by up to 3 months compared with placebo.^13,14 However, recent analyses of population studies may indicate that survival for patients taking riluzole may be extended by as much as 6–19 months.^9,13

Riluzole is generally well tolerated, but common adverse effects may include nausea, dizziness, headache, abdominal pain, weakness, drowsiness and vomiting.^2,12 Aminotransferases may become elevated, and regular liver function tests are recommended.^1,4,12 Some cases of fatal hepatic failure and pancreatitis have been reported.¹⁴

Treatment should be initiated as early as possible after diagnosis. Realistic expectations for treatment effects and potential adverse effects should be discussed with both patients and carers.¹⁵

Edaravone (Radicava) has recently been approved for use in Australia; however, it is not yet available, as it is pending PBS listing (as of September 2024). In a small number of patients, it provides limited extensions in survival time. It works by suppressing oxidative stress as a free radical scavenger, although its exact mechanism in MND is yet to be elucidated.^2,9 Edaravone is administered as an intravenous infusion, and treatment should be initiated within 2 years of disease onset.^2,3

Numerous other pharmacological therapies have been investigated but have not been proven to be effective in mitigating MND, and currently there is insufficient evidence to recommend them. Some of these include²:

• ceftriaxone
• glatiramer acetate
• cyclosporin
• intravenous immunoglobulin therapy
• KDI tripeptide
• minocycline
• neurotrophic factors
• gabapentin
• lithium
• stem cells
• complementary medicines such as gingko biloba, coenzyme Q10 and creatine.

Other pharmacological therapies are used to manage individual symptoms such as pain, anxiety, depression, insomnia, cramps, mucosal secretions, drooling (sialorrhea), spasticity, dysphagia, constipation, emotional lability and fatigue.^1,3,9 Anticoagulants are not routinely recommended for prevention of venous thromboembolism in MND unless there are additional risk factors.³

Non-pharmacological therapies

As various symptoms develop, interventions will be required for each. Nutritional management is important throughout the disease.^9,15 Nutritional status should be monitored regularly, and high-calorie diets can be used to improve nutrition. PEG feeding may be required in some patients; PEG tubes should be placed before respiratory insufficiency develops.⁸

Similarly, respiratory management is important, and respiration should be monitored regularly.^1,9 To treat respiratory insufficiency, non-invasive positive-pressure ventilation can be used to improve survival and quality of life.^1,9,15

Difficulties with speech (dysarthria) may require the use of special communication devices.⁹

Caring for patients

Patients are generally cared for at home by family members. MND clinics housing multidisciplinary health professionals are available around Australia to support patients and their carers.¹⁰ The clinics are often held in outpatient clinics at a hospital and are usually staffed by a neurologist, other specialist doctors, nurses and allied health professionals.^1,2,10

Care of patients requires involvement of various health professionals, not all of whom may be based at a clinic. This may include a general practitioner, neurologist, nurse, psychologist, physiotherapist, speech therapist, occupational therapist and dietitian.^8,10

Pharmacists can have positive impacts in the management of MND and have been shown to play an important role in multidisciplinary clinics. A US study reported that pharmacists contributed to optimising medicine use, minimising medicine-induced adverse effects and supporting patient and carer education.¹⁶ Additionally, pharmacists can assist by providing advice regarding non-pharmacological management of symptoms as well as vaccines such as influenza and pneumococcal vaccines.³ Pharmacists may also participate in the provision of palliative care as required in the terminal stages of the disease.³ Above all, pharmacists should be compassionate with both patients and their carers.⁴

Information and support for patients and carers are available from MND Australia and from the various state MND associations.

Knowledge to practice

The care of patients with MND requires a multidisciplinary team. Multidisciplinary teams benefit from a pharmacist’s involvement, as they can compassionately assist patients and carers by providing advice regarding symptom management, medicine use and adverse reactions.

Conclusion

MND is a fatal disorder of motor neurones. The rate and pattern of the disease varies in each patient, as does the survival time. In 90% of cases the cause is unknown, but regardless there is no known cure. Management of MND requires a multidisciplinary approach. A pharmacist’s knowledge of medicines and symptom management can
help improve a patient’s quality of life.

Key points

• In MND there is progressive destruction of motor neurones leading to death due to respiratory failure.
• The rate and pattern of the disease, and survival time, vary in each patient.
• A multidisciplinary team is required for optimal care of patients.
• Pharmacists can address any deficiencies in knowledge and provide advice regarding the management of symptoms and the use and expectations of various pharmacological therapies, including possible adverse effects.    

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References

1. Lau FS, Brennan FP, Gardiner MD. Multidisciplinary management of motor neurone disease. Aust J Gen Pract 2018;47(9):593–6. 
2. MND Australia. Overview of MND: this information is for health professionals and service providers. 2021. At: www.mndaustralia.org.au/mnd-connect/for-health-professionals-service-providers/overview-of-mnd-for-health-professionals 
3. Thompson E. Pharmacist considerations for treating patients with ALS. US Pharm 2019;44(8):HS-1-HS-10. 
4. Gauld N. Living with motor neurone disease. Pharmacy today. 2023. At: www.pharmacytoday.co.nz/article/opinion/columns/living-motor-neurone-disease 
5. The International Alliance of ALS/MND Associations. What is ALS/MND? 2024. At: www.als-mnd.org/what-is-alsmnd/ 
6. Ingre C, Roos PM, Piehl F, et al. Risk factors for amyotrophic lateral sclerosis. Clin Epidemiol 2015;7:181–93. 
7. Al-Chalabi A, Calvo A, Chio A, et al. Analysis of amyotrophic lateral sclerosis as a multistep process: a population-based modelling study. Lancet Neurol 2014;13(11):1108–13. 
8. Oliver D. Motor Neurone Disease: a family affair. 3rd edn. London: Sheldon Press; 2011. 
9. Shoesmith C, Abrahao A, Benstead T, et al. Canadian best practice recommendations for the management of amyotrophic lateral sclerosis. CMAJ 2020;192(46):e1453–68. 
10. Dharmadasa T, Henderson RD, Talman PS, et al. Motor neurone disease: progress and challenges. Med J Aust 2017;206(8):357–62. 
11. Gwathmey KG, Corcia P, McDermott CJ, et al. Diagnostic delay in amyotrophic lateral sclerosis. Eur J Neurol 2023;30:2595–601. 
12. Rossi S, ed. Riluzole. Australian medicines handbook; [updated Jan 2024]. At: https://amhonline.amh.net.au/chapters/neurological-drugs/drugs-other-neurological-conditions/riluzole?menu=hints 
13. Andrews J, Jackson CE, Heiman-Patterson TD, et al. Real-world evidence of riluzole effectiveness in treating amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 2020;21(7–8):509–18. 
14. Hardiman O, Al-Chalabi A, Chio A. et al. Amyotrophic lateral sclerosis. Nat Rev Primers 2017;3:17071. 
15. Anderson P, Abrahams S, Borasio GD, et al. EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS) – revised report of an EFNS task force. Eur J Neurol 2012;19(3):360–75. 
16. Jefferies KA, Bromberg MB. The role of the clinical pharmacist in a multidisciplinary amyotrophic lateral sclerosis clinic. Amyotroph Lateral Scler 2012;13(2):233–36. 

Our author

Dr Barry L Werth BPharm (Hons), MBA, PhD, MPS is a member of the Lived Experience Research Advisory Panel and the Research Collective at MND Australia and is a pharmaceutical industry consultant.