42 Motor Neurone Disease
Current Management of Motor Neurone Disease Professor Orla Hardiman BSc MD FRCPI FTCD MRIA Consultant Neurologist, Beaumont Hospital, Professor of Neurology, Trinity College Dublin
Motor Neuron Disease (MND), also known as Amyotrophic Lateral Sclerosis (ALS) is characterized by combined upper and lower motor neuron degeneration with progression to death within 3 years. There is now compelling evidence to indicate that MND should be classified as a heterogenous neurodegenerative disorder that primarily affects upper and lower motor neurons (corticospinal and anterior horn cells) but that also involves other parts of the neuroaxis. There is now extensive evidence from clinical, imaging, pathology and genetic studies of extensive overlap between ALS and Frontotemporal dementia (FTD). Indeed, up to 70% of incident MND patients develop cognitive and behavioural impairment, with 13% of patients presenting with co-morbid behavioural variant FTD. The most common cognitive impairment presents as executive and language function, with relative preservation of spatial domains. Social cognitive and behavioural change is common, and apathy occurs in up to 70% of patients. There is no individual test that provides a definitive diagnosis of MND. All investigations are aimed at confirming the presence of upper and lower motor neuron degeneration, while excluding other conditions that could mimic the clinical presentation, such as motor neuropathies (e.g. multifocal motor neuropathy with conduction block), cervical myelopathy with polyradiculopathy, multiple sclerosis and other rare metabolic
conditions. Neuroimaging is performed to exclude structural pathology, and neurophysiological studies are performed to confirm the presence of acute and chronic denervation, the absence of sensory findings, and to ensure that mimic syndromes are excluded. A series of diagnostic criteria have established for ALS/MND – the most recently published being the Gold Coast Criteria, requiring progressive upper and lower motor neuron signs in at least region, and exclusion of other possible causes (BOX 1). However, there remains an urgent need for diagnostic biomarkers for MND. Candidate markers include neurofilaments which are elevated in CSF and blood in MND, altered levels of circulating microRNA, imaging and neurophysiology based technologies, although additional studies are required before these can be used in clinical practice. For most patients, definitive diagnosis takes 12 -15 months, and most patients are seen by 3-5 different healthcare professionals before the diagnosis is entertained. “Red Flags” that should alert the clinician to the possibility of MND include progressive painless loss of function in bulbar or limb regions, unexplained weight associated with dyspnoea, and the presence of progress dysarthria with associated tongue fasciculations. A number of initiatives to increase awareness have been launched, including a recent policy paper presented to the European parliament in September 2023 https://www. alscoalition.eu/.
JANUARY 2024 • HPN | HOSPITALPROFESSIONALNEWS.IE
In Ireland, the diagnosis and management of MND has been included as part of the HSE Modernised Care pathways https://www.hse.ie/eng/about/ who/strategic-programmesoffice-overview/modernised-carepathways/. The pathway provides a streamlined approach from first symptom of MND through to ongoing management integrated by the specialist multidisciplinary team at the national centre for ALS/MND in Beaumont Hospital, with outreach to community and palliative care services, and with extensive links to the Irish Motor Neuron Disease Association. Epidemiology The epidemiology of MND has been tracked in Ireland since 1994, using the Irish ALS/MND population based register. Ongoing surveillance has shown that the mean age of onset of MND is in the early 60s. Although the disease can occur throughout life, the peak age of onset is in the early 70s. There has been slight increase in both the mean and peak age of onset in the past 10 years, the reasons for which are not clear, but may related to the improving overall health of the population. The incidence in Ireland is also increasing, partly as a result of the ageing population. At present, there are approximately 140 new diagnoses every year. The prevalence in Ireland is 8.5/100,000, or approximately 450 people living with the condition. Based on data from the Irish ALS/ MND Register, we estimate that the overall lifetime risk in
Ireland for developing ALS is approximately 1:350. Genomics Population based studies have suggested that the development of the disease occurs in 6 steps, the first of which is genetic predisposition, and the remainder are probably environmental factors that have not been fully elucidated. MND is sometimes segregated into “familial” and “sporadic” subtypes of disease, although heritability studies indicate that genetic factors account for up to 51% of overall risk. These genetic factors include single genes of major effect, and/or a polygenic risk that most likely interacts with as yet unknown environmental factors. In Ireland around 15-10% of probands report a family history of MND or FTD, albeit with incomplete penetrance in the majority of kindreds. Within populations of European origin (Europe and USA) four genes account for up to 70% of all cases of “familial” ALS, namely C9orf72, TARDBP (coding for TDP43), SOD1 and FUS. In Ireland, the C9orf72 variant comprising a hexanucleotide repeat expansion, accounts for around 10% of all ALS, and 50% of the familial form of the disease. The prevalence of the remaining gene variants is extremely low. Disease penetrance in families is incomplete – most recent estimates for C9orf72-related MND are in the region of 20%. This low penetrance is in part explained by evolving evidence that the presence of the repeat expansion, although associated with disease, may a require addition factors for disease to manifest. Irish studies have shown that in families of those with the C9orf72 repeat expansion, the disease may also occur more frequently than expected in family members who do not carry the repeat expansion. Additionally, recent studies from the Irish ALS/MND group has found that cognitive performance of families carrying the C9orf72 variant differs from controls, regardless of the presence of the mutation. This suggest that unaffected family members carry additional factors that increase their risk of both cognitive change and an overall risk of developing MND. There is also evolving evidence of wider disease “endophenotypes” among family members of MND probands which is most likely genetically determined.
