Clinical Controversies in Amyotrophic Lateral Sclerosis

Authors: Ruaridh Cameron Smail,1,2 Neil Simon2

1. Department of Neurology and Neurophysiology, Royal North Shore Hospital, Sydney, Australia 2. Northern Clinical School, The University of Sydney, Sydney, Australia *Correspondence to [email protected]

Disclosure: The authors have declared no conflicts of interest.

Received: 26.02.20

Accepted: 28.04.20

Keywords: Amyotrophic lateral sclerosis (ALS), biomarker, clinical phenotype, diagnosis, motor neurone disease (MND), pathology, ultrasound.

Citation: EMJ Neurol. 2020;8[1]:80-92.

Abstract Amyotrophic lateral sclerosis is a devastating neurodegenerative condition with few effective treatments. Current research is gathering momentum into the underlying pathology of this condition and how components of these pathological mechanisms affect individuals differently, leading to the broad manifestations encountered in clinical practice. We are moving away from considering this condition as merely an anterior horn cell disorder into a framework of a multisystem neurodegenerative condition in which early cortical hyperexcitability is key. The deposition of TAR DNA-binding protein 43 is also a relevant finding given the overlap with frontotemporal dysfunction. New techniques have been developed to provide a more accurate diagnosis, earlier in the disease course. This goes beyond the traditional nerve conduction studies and needle electromyography, to cortical excitability studies using transcranial magnetic stimulation, and the use of ultrasound. These ancillary tests are proposed for consideration of future diagnostic paradigms. As we learn more about this disease, future treatments need to ensure efficacy, safety, and a suitable target population to improve outcomes for these patients. In this time of active research into this condition, this paper highlights some of the areas of controversy to induce discussion surrounding these topics.

INTRODUCTION public consciousness, and increasing research funding, this is an excellent opportunity to improve outcomes for these patients. Motor neurone disease (MND) encompasses a group of disorders affecting the anterior horn While previously considered a neuromuscular cells and includes the most common form, disorder of the anterior horn cells, greater research termed amyotrophic lateral sclerosis (ALS). The in recent years into brain cortical dysfunction, inexorable decline in function leading to death and also identification of deposition of TAR for these conditions, in often otherwise healthy DNA-binding protein 43 (TDP-43) in the brain, people, has emphasised the unmet need for has altered the perception of this condition into better diagnostic and treatment paradigms. With the category of multisystem neurodegenerative awareness of these conditions increasing in the disease. On one end of the spectrum lies

80 NEUROLOGY • July 2020 EMJ predominant anterior horn cell damage and entity, or to classify them as separate conditions.6 lower motor neuron (LMN) signs. On the Often with time, other UMN or LMN features other end is cortical TDP-43 deposition become apparent, and the diagnosis is revised to leading to behavioural-variant frontotemporal ALS.7,8 In the authors’ opinion, these conditions dementia (FTD). are likely to be the same pathophysiological condition, albeit with differing location of In this review, recent advances in the predominant pathology (and different emphasis understanding of the diagnosis and treatment on pathological processes) leading to the of this condition are discussed. This information spectrum of symptoms that they consider in is posed as a series of ‘controversial statements’ PMA, ALS, and PLS. Some have proposed that a for which evidence may be conflicting. While definite diagnosis of PMA or PLS is only made >4 the authors have no claim to answer these years after symptom onset to ensure that there questions, they hope this will encourage readers has been no emergence of ALS signs.6 Even if to question their own diagnostic and therapeutic patients exhibit solely UMN or LMN signs, often preconceptions and generate increased at biopsy there is evidence of more widespread consideration of the underlying issues. neural loss, which would support the hypothesis that this is all the same condition. Although CLASSIFICATION some distinction of the phenotypes is helpful to define prognosis, often the terminology can be Amyotrophic Lateral Sclerosis is the confusing for patients. Subjective interpretation Same Disease as Progressive Muscular of the criteria may impact patients’ entry into clinical trials. Others have proposed alternative Atrophy and Primary Lateral Sclerosis classifications to improve prognostic accuracy MND encompasses a family of disorders affecting and to allow clearer description of the patient’s the anterior horn cells, of which ALS is the status for other clinicians and in clinical trials. Not most common form, demonstrating both upper only would this classification involve a description motor neuron (UMN) and LMN features. Other of UMN or LMN predominance and El Escorial phenotypes of the disease such as primary category, but also diagnostic modifiers such as lateral sclerosis (PLS) and primary muscular genetic mutation, presence of frontotemporal 6 atrophy (PMA) are less common, featuring UMN dysfunction, and stage of disease. and LMN deficits, respectively. Even within ALS Amyotrophic Lateral Sclerosis and there is significant variation in the anatomical location and progression of the disease.1 Within Frontotemporal Dementia are on ALS, patients may have an UMN- or LMN- a Spectrum of TDP-43 Deposition predominant symptomatology. There are other Neurodegenerative Disease phenotypic variants such as the flail arm or flail leg syndrome, and rarer variants such as spinal There are conditions that have been associated or diaphragm onset.2,3 From the point of origin, with MND, such as FTD. Frontotemporal different patterns of disease spread have been dysfunction occurs in up to 50% of ALS patients, 9 characterised.1 Bulbar-onset disease accounts for reaching FTD criteria in 15%. TDP-43 has been approximately one-third of ALS cases, and carries found in both ALS and FTD. It is a RNA-binding a poorer prognosis. Specific genetic changes may protein which has been shown to be mislocalised influence phenotype and prognosis, but there is in ALS patients. Restoration of the stathmin 2 significant pleiotropy whereby a mutation may gene (STMN2) allows microtubule stabilisation, cause a variety of phenotypes, even within the and in turn allows recovery of axons in TDP-43- same family.4 Some have incorporated clinical, depleted motor neurons. This can indicate STMN2 10 phenotypic, and genetic factors into a prognostic as a target for future therapy. Some patients may model.5 A clear indication of prognosis is helpful also develop cerebellar or autonomic problems, for patients. possibly related to TDP-43 deposition in those areas of the nervous system. These associated In the absence of a distinguishing biomarker, features are not included in current clinical there has been controversy as to what extent classifications. There is again controversy as to ALS, PMA, and PLS should be defined as a single whether ALS–FTD is a separate entity compared

Creative Commons Attribution-Non Commercial 4.0 July 2020 • NEUROLOGY 81 to ALS with some executive dysfunction, may be involved in a less obvious manner in because there appears to be differences in sporadic cases without obvious family history. TDP-43 deposition and microglial activation.11 The development of ALS has been shown to be Furthermore, TDP-43 deposition is variable, a multi-step process involving both genetic and and many ALS patients do not demonstrate environmental risk factors.20 Family history itself obvious cognitive impairment, most notably Prof may be difficult, since ALS is a disease of older Stephen Hawking. age, and family members may have died before symptoms manifested. A positive family history It is more easily conceivable to understand the is also affected by family size.21 Furthermore, TDP-43 deposition in the brain leading to UMN penetrance of some genetic forms, such as dysfunction. To what extent TDP-43 causes LMN the C9orf72 hexanucleotide repeat expansion, dysfunction, such as in PMA, is unknown. Several remains below 100%. The C9orf72 expansion is pathological processes have been proposed in the most common genetic abnormality, found ALS, affecting both UMN and LMN. It may be that in approximately 40% of familial cases. It is MND pathologies are numerous, and different also found in 4–8% of sporadic ALS cases (in a emphasis on pathological mechanisms leads to European and USA cohort).22 Approximately the different symptomatology experienced. one-third of ALS and FTD will have a pathogenic C9orf72 expansion.23 Other relevant conditions Further clarification about the description of the diagnosis and phenotype has been proposed.6 such as FTD may not be diagnosed or recalled This will assist in both research recruitment correctly when a family history is being sought. endeavours and being able to communicate It has been shown that the risk of ALS in relatives information about diagnosis and prognosis of patients with sporadic disease is higher than in to patients. those without affected relatives. Amyotrophic Lateral Sclerosis is Solely Some now advocate a broader genetic screening 23 A Motor Neuronopathy for ALS patients with apparent sporadic disease. With the advent of antisense oligonucleotide The concept of ALS only being a motor neuron therapy trials, identification of a mutation may condition has also been questioned. Not only lead to therapy. Greater adoption of genetic have there been significant cerebral cortex testing may also broaden the database of disease- changes mentioned above, there is recent causing mutations or expansions and increase research suggesting that sensory nerves are also our understanding of phenotypic presentations affected.12,13 Somatosensory evoked potentials are of different mutations. In the familial ALS cohort, also abnormal, suggesting sensory pathways in different phenotypes and prognoses are already the spinal cord or brain are affected.14 Small-fibre known: C9orf72 expansions are associated with neuropathy has also been demonstrated in ALS more cognitive (FTD-type) deficits, whereas patients, though it is unclear how this correlates SOD1 mutations less so. Certain mutations may with phenotype and prognosis.15,16 also confer a favourable prognosis.24 Amyotrophic Lateral Sclerosis Can DIAGNOSIS Be Split into Sporadic and Familial Subtypes Current Diagnostic Criteria Approximately 10% of ALS cases have been are Outdated and Do Not described as 'familial'.17 However, there remains Include Consideration of New significant numbers of so-called ‘sporadic’Diagnostic Techniques cases which have something of a genetic basis.18 Contributory genetic variations and mutations Correct diagnosis of ALS is essential to counsel are being identified, and their contribution to patients regarding their future. Other motor the pathway leading to ALS is gradually being neuromuscular disorders, such as multifocal understood.19 While cases such as those associated motor neuropathy (MMN), have effective with SOD1 mutations follow an autosomal- treatments and are important not to miss. Early on dominant pattern, other heritable genetic traits in the disease course, however, it is often difficult

82 NEUROLOGY • July 2020 EMJ to make a definite diagnosis of ALS; delays in the need for UMN and LMN degeneration in the diagnosis are common.25 The sensitivity of the same region. There must be disease progression revised El Escorial criteria may only be 57% at the in the affected region, and there must be spread time of diagnosis.26 Money and time can be spent of degeneration to other body areas. It divides on unnecessary treatments if the diagnosis is not diagnosis into four categories: definite, probable, made appropriately. First and foremost, diagnosis possible, and suspected. These criteria were is made on clinical grounds, with supporting revised in 1998.27 The principal change was to electrophysiological evidence. Imaging is used place more emphasis on electrophysiological for exclusion of mimics, such a monomelic evidence, allowing electromyography (EMG) amyotrophy or multi-level polyradiculopathy. evidence of denervation rather than clinical The El Escorial Criteria (1994) were formed evidence, i.e., muscle wasting. Further to standardise the diagnosis of ALS based on recommendations were made in Awaji, Japan, in principally clinical parameters. It emphasised 2008 to facilitate earlier diagnosis.28

Table 1: Advantages and disadvantages of various diagnostic modalities.

Diagnostic modality Pros Cons Nerve conduction study Exclude mimics Minimal UMN information, although 36-38 Simple indices H-reflex studies may provide some

Needle EMG The mainstay of diagnosis for No UMN information identifying widespread denervation Painful changes Time-consuming Peripheral nerve excitability Insights into axonal function Variability limits diagnostic specificity Requires hardware and operator experience Time-consuming Motor unit number estimation Allows monitoring of disease Patient-to-patient variability limits progression and prognosis diagnostic use Limited muscles able to be tested accurately Requires specific expertise and training Cortical excitability (transcranial Insight into UMN changes early in the Requires hardware and operator magnetic stimulation) disease process experience Differentiates ALS from mimics early in the disease Nerve and muscle ultrasound Quick, painless, body-wide screen for Hardware and operator experience fasciculations required Measurable muscle parameters allow Only limited information about UMN disease monitoring dysfunction Nerve ultrasound scan can distinguish ALS from mimics Blood and CSF biomarkers Simple to obtain CSF sampling difficult for longitudinal Good specificity versus controls, even study early in disease course Laboratory experience and equipment required, yet to be widespread May not distinguish easily from mimics

ALS: amyotrophic lateral sclerosis; CSF: cerebrospinal fluid; EMG: electromyography; UMN: upper motor neuron.

Creative Commons Attribution-Non Commercial 4.0 July 2020 • NEUROLOGY 83 It allowed fasciculations in a chronically from nerve conduction studies: increased H reinnervated muscle as evidence of LMN reflexes (relative to M wave) can indicate UMN dysfunction along with fibrillations and sharp dysfunction.36 A split-hand index can calculate waves. This change increases diagnostic sensitivity the ratio of median compound muscle action by 12–20% on revised El Escorial criteria, without potential (CMAP) compared to ulnar CMAP. changing specificity.29-31 A value <0.6 is indicative of the split hand phenomenon of ALS, and can be seen even when Diagnostic classification is useful for research symptoms arise in another anatomical area.1 purposes, but can be confusing when discussing Additionally, a split-leg index can also be used.39 the diagnosis with patients. For example, a Unfortunately, CMAP amplitudes themselves are patient may be defined by Awaji criteria as a blunt diagnostic indicator because they are ‘possible ALS', whereas the clinician is certain of preserved well into the disease course due to the diagnosis based on the clinical presentation compensatory reinnervation. Motor unit number and exclusion of mimics. In a retrospective study estimation provides more direct information of 399 standardised cases, there were large about motor neuron loss, and several techniques inter-rater variations in probable and possible have been developed for this. Some have the categories.32 Some patients were classified ability to distinguish ALS patients from controls at differently between revised El Escorial and Awaji diagnosis.40 Yet given the variability at diagnosis, Criteria in the probable-laboratory supported this technique may be more useful to monitor and possible categories. There is an inherent patients longitudinally, to monitor progress (more complexity in interpretation of both clinical and accurately than Revised Amyotrophic Lateral electrophysiological parameters for the different Sclerosis Functional Rating Scale [ALSFRS-R]) body regions. and provide prognostic information. Although The World Federation of Neurology (WFN) one study demonstrated the MScanFit program subgroup on ALS produced an updated to be most accurate for monitoring motor unit consensus statement in 2015 attempting to clarify decline, this requires software that may not be 41 the diagnostic classification.33,34 It took provided available to all neurologists. guidance on phenotypes not conforming to It is Likely that Cortical Excitability Will typical revised El Escorial criteria such as the flail arm or flail leg variant. Note was also made Prove To Be a Useful Diagnostic Tool that there is a negligible false-positive rate in the Motor evoked potentials (MEP) have been possible cohort, and these can be considered shown to be altered in ALS. MEP may be absent, for clinical trials (assuming appropriate exclusion decreased in amplitude, and may be delayed or of mimics). It also indicated that a pathogenic dispersed (prolonged central motor conduction mutation in a known gene can substitute for time [CMCT]).42 Absent MEP are seen in patients UMN or LMN signs. These are all pragmatic with more severe UMN dysfunction. Abnormal recommendations recognising the heterogeneity MEP may be helpful in differentiating ALS from of ALS and should allow easier access to a pure LMN disorder such as MMN; however, clinical trials for patients earlier in the disease early ALS patients may have CMCT that fall course. New consensus diagnostic criteria within normal limits (Figure 1).43 Additionally, have recently been published which have sought to simplify the diagnosis of ALS by differentiating ALS from hereditary spastic collapsing the previous definite, probable, and paraparesis cannot be done on CMCT values, 44 possible categories into a single diagnostic since both may be prolonged. The use of dual- entity to facilitate clinical management and stimulation transcranial magnetic stimulation trial design.35 (TMS) allows two magnetic impulses to be created in quick succession. How the cortex then responds Diagnostic Modalities to these impulses under different conditions, and whether a motor signal is generated, can provide Nerve conduction studies are necessary insights into what is occurring in the cortex on a during ALS diagnostic workup for exclusion of neuronal level. mimics such as MMN (Table 1).36-38 Some further diagnostic information may also be gained

84 NEUROLOGY • July 2020 EMJ A 20 MMA ALS Controls 10

0 Threshold change (%) Threshold

-10 0 10 20 30

Interstimulus interval (ms)

B C

* n.s. 15 8 n.s. n.s. *** n.s.

4 10 0 5 -4

Threshold change (%) Threshold 0 change (%) Threshold -8 MMA Controls ALS MMA Controls ALS

Figure 1: Cortical excitability in patients with monomelic amyotrophy compares with healthy controls and amyotrophic lateral sclerosis patients. Whereas the mimic (MMA) demonstrates normal cortical excitability, patients with amyotrophic lateral sclerosis demonstrate cortical hyperexcitability. ALS: amyotrophic lateral sclerosis; MMA: monomelic amyotrophy; n.s.: nonsignificant. *p≤0.005 ***p≤0.001 Reproduced with permission from Matamala et al.43

Recent studies have focussed on cortical after one has been sent, and is indicative of a hyperexcitability as an integral component hyperexcitable motor cortex. This reduced SICI of ALS pathology. It is thought that cortical is the most robust TMS diagnostic variable.47-49 hyperexcitability occurs early in the disease This reduction in SICI occurs early in the disease process, and may result in anterior horn cell process, occurring prior to symptoms in familial degeneration in a ‘dying forward’ process.45,46 ALS50 and certainly when symptoms are subtle It has been established that a normal motor in sporadic cases.51 One series demonstrated that cortex has a refractory period (absolute then the number needed to test with TMS to diagnose relative) whereby a second motor signal cannot an extra case of ALS was 1.8, demonstrating be created. This is known as the short interval excellent diagnostic utility for the extra testing cortical inhibition period (SICI). In patients with time. This was not affected by site of symptom ALS, this SICI has been shown to be decreased. onset.46 The degree of reduced SICI has been In other words, the cortex is more ready to shown to be a prognostic marker for shorter generate a second motor impulse, only shortly life expectancy.52 A reduction in resting motor

Creative Commons Attribution-Non Commercial 4.0 July 2020 • NEUROLOGY 85 threshold and decreased cortical silent period clinical parameters in trials, and in some cases has duration have also been shown, consistent with shown to improve diagnostic accuracy compared cortical hyperexcitability for the symptomatic to clinical tests alone.64,65 side of the body.47,48,53 These techniques can differentiate ALS from mimics,43 and forms part Ultrasound has also been used to identify bulbar 66 of a proposed ALS diagnostic index to improve muscle dysfunction related to UMN dysfunction. early diagnosis.44,54 While the equipment may be The ratio of muscle thickness from contracted to expensive and requires operator experience, this relaxed was shown to differ between bulbar ALS will be a useful tool for earlier diagnosis. patients and controls. Further work is needed to determine how accurate this finding is on an Neuromuscular Ultrasound individual level, and whether this can be added as Complements Needle a criterion for UMN deficit in the bulbar region. In Electromyography and Should be a similar manner, thickness ratio changes of the diaphragm between inspiration and expiration Included in Future Diagnostic Criteria have been used to identify weakness. This Though not widely used when the El Escorial correlates with forced vital capacity, ALSFRS-R, or Awaji criteria were devised, neuromuscular and diaphragm CMAP. Diaphragm ultrasound ultrasound is emerging as a useful diagnostic and is an attractive alternative to other measures prognostic test modality (Table 1).55 Its attraction because of its noninvasive nature and lack of requirement for good bulbar control to perform comes from its noninvasive nature. It is also respiratory function tests.67 It should be noted, generally time-effective, being able to sample a however, that diaphragm thickness changes are wide variety of muscles in a short time. only one component of respiratory dysfunction For diagnosis, ultrasound can identify in ALS patients, with intercostal and bulbar fasciculations easily, and can identify fasciculations dysfunction as well as central drive impairment in deeper muscles compared to needle EMG.56,57 being important to consider as well. It can also be used for initial screening of likely As a disease progression monitoring tool, pathological muscles to increase needle EMG ultrasound has shown some promise, but yield. The distribution of fasciculations may demonstration of additional benefit to measures allow distinction of ALS compared to a benign of disability, such as the ALSFR-S score, is required fasciculation mimic or peripheral hyperexcitability before it becomes useful, and this is still lacking.4 syndrome.58 It has also been shown to facilitate differentiation of large fasciculations fromNerve ultrasound has also been studied in ALS. 59,60 myoclonus. However, it is inferior to EMG for Nerve cross-sectional area is reduced because defining the complexity of fasciculations, and of LMN loss. This differentiation can be used in fibrillations are better identified by needle EMG.61 clinical scenarios such as differentiating PLS Nevertheless, quantitative fasciculation analysis (solely UMN) from UMN-predominant ALS, allowed differentiation from mimics with high which shows nerve atrophy.68 Distal:proximal sensitivity and specificity.57 Muscle ultrasound is cross-sectional area ratios of peripheral nerves particularly useful for bulbar evaluation, for which have been shown to reflect motor neuron needle EMG of tongue muscles is painful and may atrophy typical of ALS and can be a diagnostic be hindered by incomplete relaxation.61,62 The use indicator.69 Other mimics such as MMN or chronic of muscle ultrasound scores may help simplify inflammatory demyelinating polyneuropathy use in diagnosis.63 often have enlarged nerves.

Not only do muscles atrophy, their characteristics There is a building body of evidence to support are changed as the disease progresses, with the use of ultrasound in both diagnosis and increased deposition of fibrous-fatty tissue. monitoring of ALS patients. Some uses, such as These changes can be quantified with ultrasound fasciculation identification, are simply diagnostic. measures of echo intensity, echovariation, grey- Other measures may not be useful in the early level co-occurrence matrix, and increased muscle stages, such as muscle atrophy, but may be stiffness on elastography Figure( 2). These have useful to monitor for disease progression and been demonstrated to be useful adjuncts to assist prognosis.

86 NEUROLOGY • July 2020 EMJ A B C

Figure 2: Ultrasound of the first dorsal interosseous muscle. A) A healthy control; B) an ALS patient with minimal clinical hand weakness; and C) an ALS patient with severe hand weakness. Ultrasound demonstrates reduced muscle thickness/cross-sectional area and increased echogenicity with progressive denervation. ALS: amyotrophic lateral sclerosis.

Standardisation of testing techniques for particularly in the premotor cortex. Changes quantitative measures will be useful for both appear to be most prominent in the ALS-FTD research and longitudinal patient monitoring. cohort.71 The corticospinal pathways are also With machines improving in portability and disrupted. As the disease progresses, further loss cost, use of ultrasound is likely to become more is seen in frontotemporal areas outside the motor widespread, and incorporation of ultrasound pathways.72 These techniques allow ALS patients parameters in future diagnostic and prognostic to be differentiated from controls with a 65% paradigms is recommended. sensitivity and 67% specificity for ALS. However, this is only on a group level and no definite MRI is a Useful Research Tool, But conclusions can be drawn on an individual level.73 Adds Little to an Individual Diagnosis of Amyotrophic Lateral Sclerosis Blood Biomarkers Will Support a Diagnosis of Amyotrophic Lateral MRI can be used for exclusion of mimics and is Sclerosis in the Future, and performed on most patients undergoing ALS diagnostic workup. Identification of corticospinal Can Be Used for Monitoring of tract hyperintensity on T2-weighted imaging, as Disease Progression well as hypodensity on susceptibility-weighted Neurofilament light chain (NfL) protein is imaging (SWI) in the motor cortex (the ‘motor emerging as a potentially useful biomarker in band sign’) can be indicators for a diagnosis of many neurological conditions. It is released from ALS. One study identified the motor band sign in 78% of ALS patients on whom the SWI sequence neurons undergoing axonal damage. Studies was used, however numbers were small, and have shown increased levels in ALS patients further research is required.70 With SWI or gradient compared to controls, but more importantly has 74-76 echo sequences becoming standard, this may be shown the ability to differentiate from mimics. a helpful piece in the diagnostic puzzle. Both of The titre has also been shown to vary with clinical these MRI findings are nonspecific however, so stage, and therefore may aid in identifying should not be overemphasised. disease progression. It appears to be higher in patients with UMN features and the level in MRI has been a useful research tool to evaluate cerebrospinal fluid (CSF) correlates with time to the cortical changes seen in ALS. Voxel-based death, indicating use as a prognostic marker.74 morphometry and diffusion tensor imaging Further work is required on this, however, because have shown accelerated loss of grey matter, levels will vary on a patient-to-patient basis,

Creative Commons Attribution-Non Commercial 4.0 July 2020 • NEUROLOGY 87 and may also vary based on the site of disease had some correlation with disease progression. manifestation. There is still an overlap between Other CSF biomarkers of inflammation have values in the ALS and mimic populations, therefore also shown correlation with disease progression other diagnostic techniques should be used. and some ability to delineate ALS cases from Laboratory techniques have now improved to neurological controls.83 Whether these research allow detection of NfL in the blood as well as CSF, techniques are able to be replicated in other labs, and this will be important for its use to monitor and can be used on a more general basis, remains disease progression, since serial CSF sampling is to be seen. Furthermore, as with most tests, on impractical. Though not as sensitive or specific an individual level there may not be sufficient as CSF for ALS diagnosis, serum or plasma levels separation between an ALS patient and a mimic. still demonstrated good positive and negative- predictive values.75,76 TREATMENT Phosphorylated neurofilament heavy chain The role of the multidisciplinary team, and the use (pNfH) has also been studied and is similar to of symptomatic management including palliative NfL with respects to sensitivity and specificity. A care, are recommended for all ALS patients cut-off of 560 pg/mL yielded a sensitivity of 83% and are incontrovertibly beneficial. American and a specificity of 80%. NfH did not change with guidelines were published on the topics of disease progression in one small study, whereas symptomatic treatment, nutritional support, a drop of NfH levels correlated with disease and respiratory support in 2009,84,85 and similar progression in another.77 A small study has also guidelines exist in the UK (National Institute for indicated that pNfH concentrations in the CSF Health and Care Excellence [NICE]) and Europe.86 can help differentiate UMN-predominant ALS Appropriate feeding and breathing adjuncts such from common mimics such as hereditary spastic as percutaneous gastrostomy and noninvasive paraparesis and PLS on a group level.78 There ventilation should also be discussed with patient was significant overlap in groups on an individual and family. These have been shown to prolong level and therefore, again, this biomarker can only survival, and the only controversy arises as to provide some supportive evidence for diagnosis. when these adjuncts should be instigated. A limitation remains in the availability of a suitably Commonly, this is a decision led by the patient validated immunofluorescence assay. Currently and their family. Significant variation occurs with used at research centres, it may take time to regards to the uptake of respiratory support, and become more widely available. this variation is sometimes unexplained though may relate to cultural and patient factors.87 Numerous other blood and CSF biomarkers have The role of pharmaceutical agents for disease been proposed for ALS.79 Given the relationship modification is more debatable. to FTD, CSF levels of TDP-43 have been tested in ALS patients. The CSF level could differentiate Riluzole Should be Ceased in Later ALS patients from neurological controls with Stages of the Disease a sensitivity of 59.3% and specificity of 96.0%. The indication that lower levels of TDP-43 Riluzole is a glutamate release inhibitor which heralded a poorer prognosis, and that there has been used for more than 20 years. It has was no correlation with disease duration, needs demonstrated tracheostomy-free survival benefit further investigation in a larger trial. Plasma TDP- of between 2 and 3 months.88,89 It remains 43 levels have also been found to be higher in generally well tolerated, but may cause increased ALS patients than controls, although there was fatigue and transaminase abnormalities. Since significant overlap of the two groups.80 Another the original studies, the extent of drug effect study has shown that CSF metabolomics (eight has been questioned, with only some study selected metabolites) coupled with clinical outcome measures being positive, and lack of parameters provided prognostic information cost-effectiveness limiting previous use in some in ALS patients.81 Using a proteomic method jurisdictions.90,91 Some studies only identified a to identify CSF biomarkers, Thompson et al.82 survival benefit in bulbar-onset rather than limb- identified three macrophage-derived chitinases onset ALS.92 Some showed bulbar-onset ALS to that were more abundant in ALS patients and be more responsive,89,93 but this was contradicted

88 NEUROLOGY • July 2020 EMJ in other studies.94 Its use at later stages of A recently published study with appropriately the disease is unclear and debated.94 Riluzole standardised protocols using autologous was shown to have an effect on cortical and bone-marrow-derived mesenchymal stem cell peripheral axon excitability, but it was transient.95 transplant found a small benefit in a cohort Furthermore, studies suggest that riluzole is not of ALS patients demonstrating rapid disease effective following treatment for longer than progression.103 This was a Phase II study, and 12 months.89,93 further studies are required before this onerous therapy becomes more mainstream. Patients More recent retrospective trials, however, have should be encouraged to enrol in approved indicated that riluzole works in advanced stages clinical trials to undertake experimental of disease, whereas the middle stages (King’s therapies, otherwise currently it is considered Stages 2 and 3) did not demonstrate a benefit.96,97 that potential harms of stem-cell therapy Given the possibility that riluzole is working in outweigh benefits. different ways at different stages of disease, some advocate continuing riluzole into the advanced stages and remains a preferred approach of many CONCLUSION neurologists if the medication is tolerated.98,99 This is an exciting time for ALS research, with No Other Medications for Amyotrophic understanding of pathological mechanisms Lateral Sclerosis Have Been Shown To increasing and diagnostic armamentarium Be of Benefit evolving. Clinical trials for new therapeutics will come soon, and it is therefore important to The antioxidant drug edaravone has been improve diagnostic certainty early in the disease approved in Japan and the USA. Although course for timely treatment. In this review, 100 the initial trial was negative, a subsequent many of the uncertainties in the understanding randomised trial in a subgroup of rapid of this heterogeneous condition have been 101 progressors was positive. Its use is limited by demonstrated. It is clear that no single diagnostic the requirement for intravenous infusion, its test will identify all ALS cases. The diagnostic cost, and uncertainty regarding which patients modalities described represent pieces of a will benefit. Other medications trialled have not puzzle, with each patient being sufficiently demonstrated benefit, but hopefully there are different to require a personalised diagnostic more in the pipeline.102 approach. The authors endorse the use of a Stem-Cell Therapy Represents the proposed personalised diagnostic ALS index54 Future of Amyotrophic Lateral and propose the utilisation of these diagnostic techniques to be included in future diagnostic Sclerosis Treatment criteria. Specifically, they recommend the As patients strive to find any effective therapy additional incorporation of cortical excitability and to slow or reverse their decline, they become ultrasound evidence into laboratory-supported susceptible to strong marketing for therapies diagnosis in future consensus guidelines. Blood which may be promising but have no evidence and CSF biomarkers may play a role if uptake for benefit. Autologous stem-cell therapyis widespread, but greater certainty regarding (‘transplants’) has been used for immune diagnostic accuracy is required. Incorporation reconstitution in multiple sclerosis and systemic of genetic information (where available) should sclerosis with good results, albeit with significant also be considered. From a therapeutics point of potential side effects. Patients are drawn to the view, disease-modifying treatments are still some idea of stem cells for its intuitive mechanism way off, and there remains controversy as to how of action, and as a ‘nonpharmacological’ way beneficial, and in whom, the current treatments of inducing their own body to repair itself. work. There is a need to adequately test therapies Private clinics are providing treatments to ALS in a well-defined patient population prior to patients with varying methods and standards.17 approval to ensure cost-effectiveness.

Creative Commons Attribution-Non Commercial 4.0 July 2020 • NEUROLOGY 89 References

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