{"id":384721,"date":"2024-08-30T00:01:00","date_gmt":"2024-08-29T22:01:00","guid":{"rendered":"https:\/\/medizinonline.com\/?p=384721"},"modified":"2024-08-26T16:08:06","modified_gmt":"2024-08-26T14:08:06","slug":"update-on-diagnostics-and-therapy","status":"publish","type":"post","link":"https:\/\/medizinonline.com\/en\/update-on-diagnostics-and-therapy\/","title":{"rendered":"Update on diagnostics and therapy"},"content":{"rendered":"\n

In addition to standard care for all forms of ALS, there has been significant progress, particularly for monogenetic forms of ALS, thanks to the development of specific gene-based treatment methods, currently ASO in particular.\nBasic genetic diagnostics, at least of the most common genes (SOD1, C9orf72, FUS, TARDP)<\/em>, are therefore recommended for all ALS patients at the time of diagnosis. <\/strong><\/p>\n\n\n\n

<\/p>\n\n

\n\t
\n\t\t\n\n

You can take the CME test in our learning platform after recommended review of the materials. Please click on the following button:<\/p>\n\n\n\n

<\/div>\n\n\n\n
\n
Start CME test<\/a><\/div>\n<\/div>\n\n\t<\/div>\n\t<\/div>\n\n

Cases of amyotrophic lateral sclerosis (ALS) were first described by Jean Martin Charcot in 1873 [1].\nCharcot already provided neuropathological evidence of an underlying motor system degeneration.\nIt is now known that amyotrophic lateral sclerosis, despite the predominant degeneration of the first and second motor neurons and the corticospinal tract, is a multisystemic neurodegeneration with numerous extramotor manifestations.\nWe have gained increasing knowledge about the underlying genetic factors, particularly in the last decade, which has also led to the first direct therapeutic consequences. <\/p>\n\n

Epidemiology<\/h3>\n\n

Based on data from the best-managed patient registry in Swabia, it can be estimated that there are around 8,000 to 9,000 people affected by ALS in Germany as a whole [2].\nWith an average age of onset of 70 to 75 years and a slight male predominance, an incidence of approx. 3\/100,000 patients is assumed.\nThe lifetime prevalence as the most descriptive statistical measure for the probability of developing ALS is 1:400.\nThese epidemiological figures are highly congruent with figures from other European countries.\nIn other parts of the world, such as Asia, the epidemiological data is different [3,4]. <\/p>\n\n

Clinical symptoms<\/h3>\n\n

The core symptoms of ALS are focal onset, progressive, atrophic paresis with frequent muscle spasms and fasciculations as a sign of increasing damage to the second motor neurons at the spinal level or in the brainstem area [5].\nThis is preceded or accompanied by an affection of the first motor neurons in the primary motor cortex and the corticospinal tract with increased and skipping muscle stretch reflexes and evidence of pathological reflexes or an increase in muscle tone in the sense of spasticity. <\/p>\n\n

Clinically and in everyday life relevant cognitive deficits and behavioral abnormalities in the sense of a frontotemporal dementia syndrome are found as extra-motor symptoms in approx. 5% of people with ALS [6,7].\nAccompanying disorders of the autonomic nervous system have been increasingly described in recent years [8].\nIn addition, pain of various origins is also important during the course of the disease [9]. <\/p>\n\n

Diagnostic procedures and diagnosis<\/h3>\n\n

The diagnosis is primarily made clinically after consistent and careful exclusion of alternative differential diagnoses.\nThe Gold Coast criteria [10] provide good guidance for clinical diagnosis.\nThe most important supporting diagnostic procedure is electromyography for the detection of active denervation or polytopic fasciculation potentials with simultaneous evidence of chronic neurogenic damage.\nElectromyography should examine different muscles in all four regions of the body (cranial nerves\/bulbar – cervical – thoracic – lumbosacral) [11].\nIn addition to electromyography, muscle sonography can also be performed to determine the presence of polytopic muscle fasciculations and to assess the muscular trophism and internal structure.\nMuscle sonography can be particularly advantageous for detecting muscle fasciculations in larger or deeper muscles, such as parts of the quadriceps femoris muscle or tongue base muscles, and can be an important complement to electromyography.\nElectroneurography of motor and sensory nerves as well as F-wave diagnostics on the upper and lower extremities is particularly necessary to rule out primary demyelinating neuropathy and, in particular, conduction blocks (CIDP or multifocal motor neuropathy\/MMN). <\/p>\n\n

Transcranial magnetic stimulation is available for recording motor-evoked potentials to objectify and, if necessary, quantify involvement of the first motor neurons.\nThis examination method can be used to examine the central motor conduction of the thickly myelinated axons of the corticospinal tract from the motor cortex as a stimulation site along the entire spinal cord [12].\nIt makes sense to examine one distal muscle each on the upper and lower extremities.\n Table 1<\/strong> provides a detailed overview of the proposed electrophysiological diagnostics for ALS and the Gold Coast diagnostic criteria .<\/strong> <\/p>\n

\n
\"\"<\/a><\/figure>\n<\/div>\n

Neurofilament light chains (NfL) are an important biomarker [13].\nThese can be easily determined in serum and cerebrospinal fluid.\nIt is important that the determination is carried out using a sufficiently sensitive detection method in an established laboratory with age-adjusted limit values.\nIt should be emphasized that although NfL can represent an additional important component for the diagnosis, an NfL within the normal range cannot rule out the diagnosis of ALS and elevated NfL values can also occur in other differential diagnoses of ALS (CIDP, vasculitic neuropathy, amlyoidosis-associated neuropathy, MMN) [14].\nThe significance of NfL as a prognostic progression marker appears to be even greater than in differential diagnostics, although here too no reliable statement can be made for the individual patient on the basis of the NfL value. <\/p>\n\n

While genetic diagnostics were still considered optional in the S1 guideline, which has been valid and available since 2021, the authors believe that this situation has changed as a result of developments over the last three years [5].\nIn view of therapeutic developments in this field, every ALS patient should undergo mandatory targeted genetic testing at least for the presence of a mutation in the Cu\/Zn superoxide dismutase 1 gene(SOD 1<\/em>) and young ALS patients under the age of 40 for the presence of a pathogenic mutation in the FUS gene<\/em> [15,16].\nOptionally, more extensive genetic diagnostics should also be carried out with the examination of other genes such as C9orf72, TARDP, TBK1<\/em> etc. [17].\nThe following sections on aetiology and genetics and, in particular, therapy will deal with this issue in more detail.\n Table 1<\/strong> provides an overview of the diagnostic procedures described and the Gold Coast diagnostic criteria recommended as a guide in clinical practice .<\/strong> <\/p>\n\n

With regard to further clinically relevant examinations for comprehensive differential and exclusion diagnostics depending on the initial clinical presentation (e.g. MRI imaging, ENT diagnostics, laboratory diagnostics) as well as relevant diagnostics in the course of prognosis assessment (e.g. pulmonary function test\/diaphragmatic function test, swallowing diagnostics using FEES, psychometrics using ECAS), we would like to explicitly refer to the very detailed and clear presentation of the S1 guideline [5].<\/p>\n\n

Phenotypic spectrum and pattern of muscle paresis against the background of neuroanatomy and pathophysiology of ALS<\/p>\n\n

The scientific findings of the last two decades, in particular neuroanatomical and neuropathological studies, have fundamentally changed the view of ALS.\nToday, ALS is no longer seen as a purely motor system degeneration, but as a multi-system degeneration [18,19]. <\/p>\n\n

ALS, like other neurodegenerative diseases such as Alzheimer’s or Parkinson’s disease, is a proteinopathy, i.e. pathological protein aggregates in the motor nerve cells as a neuropathological correlate lead to dysfunction of the affected motor nerve cells and ultimately to apoptosis and thus the loss of motor nerve cells.\nIn the case of ALS, this involves TDP-43 protein aggregates in more than 95% of cases [20].\nOnly in the case of underlying pathological SOD1<\/em> or FUS variants<\/em>does TDP-43-independent neurodegeneration occur [21].\nNeuropathological studies have established a stepwise, staged, cerebral propagation of TDP-43 pathology in ALS, comparable to \u03b1-synuclein pathology in Parkinson’s disease and tau pathology in Alzheimer’s disease [22].\nThese findings as well as the corticomotoneuronal pattern of paresis with the split hand sign (asymmetric atrophy of the C8\/T1 or ulnar-supplied hand muscles) as a very common clinical sign in ALS imply an origin of the neuropathological changes in the area of the primary motor cortex and a gradual spread of the TDP-43 pathology from there via axonal transport to the second motor neurons, i.e. the motor cranial nerve nuclei in the brain stem and the anterior horn cells of the spinal cord [23\u201326]. <\/p>\n\n

A prion-like propagation of the neuropathological changes appears to occur, which would explain the focal onset of the motor manifestation as well as a gradual spread to neighboring myotomes and body regions [27,28].\nAccordingly, depending on the initial manifestation of the neuropathology, the phenotypic spectrum of ALS – with regard to motor symptoms alone – is not uniform, but highly variable [29].\nThus, topographically distinct motor phenotypes alone can occur.\nIn addition, the phenotype is influenced by the usually different speed of degeneration of the first and second motor neurons and the associated clinical symptoms.\nWithout a precise understanding of the molecular mechanisms to date, the ratio of insoluble TDP-43 protein aggregates, which can no longer be transported axonally and thus accumulate locally, to soluble TDP-43 oligomers as precursors of the TDP-43 aggregates appears to be decisive here.\nObviously, these soluble precursors are then transported via axonal transport from the first motor neurons to the second motor neurons, where they are obligatory deposited as protein aggregates and lead to the death of these cells [23]. <\/p>\n\n

To date, there is no standardized classification of clinical phenotypes that would take into account the ratio or focus of damage to the first and second motor neuron, the clinical pattern or focus of atrophic paresis and its spread. <\/p>\n

\n
\"\"<\/a><\/figure>\n<\/div>\n

Figures 1 and 2<\/strong> provide a schematic overview of the neuroanatomy and pathophysiology of the disease as well as the clinical phenotypes and their classification.<\/p>\n

\n
\"\"<\/a><\/figure>\n<\/div>\n

Etiology and genetics<\/h3>\n\n

The etiology of ALS is still not sufficiently well understood.\nIn the sporadic form of the disease, which accounts for the vast majority of cases, a multifactorial genesis is assumed with the interaction of various unfavorable external environmental factors, epigenetic metabolic factors and a possible additional genetic susceptibility.\nChanges in nuclear-cytosolic protein transport, RNA metabolism, mitochondrial oxidative cell function, glutamatergic excitability, axonal protein transport and cellular autophagy are discussed as the underlying metabolic intracellular mechanisms, while functional disorders of atrocytes and oligodendrocytes as well as inflammatory processes are discussed as additive extracellular mechanisms [31].\nSignificant insights into the possible etiologic mechanisms of sporadic ALS have been gained primarily through genetic forms with distinct pathophysiologic processes. <\/p>\n\n

In 1993, pathogenic mutations in Cu\/Zn superoxide dismutase 1 (SOD1) <\/em>were described as a genetic cause of ALS for the first time [32].\nA large number of genetic mutations are now known to be the underlying etiology of ALS.\nIn the case of apparently sporadic ALS without a conspicuous family history in Germany, a monogenetic cause can be detected in slightly more than 10% of cases [17].\nThe most common genetic causes in Germany are pathological C9orf72 repeat expansions and mutations in the SOD1, TARDP<\/em> and FUS<\/em> genes [17]. <\/p>\n\n

Genetic diagnosis at the time of diagnosis should therefore be offered to every ALS patient, as this can have immediate therapeutic consequences, which we will discuss in detail in the following section. <\/p>\n\n

Therapy and prognosis<\/h3>\n\n

Riluzole has been approved in Germany since 1996 as the only pharmacological substance with a proven positive effect on the progression of ALS.\nA reduction in glutamate release and thus a reduction in excitotoxicity is postulated as the decisive mechanism of action.\nThis hypothesis has been given additional substance by evidence of primary degeneration of glutamatergic corticofugal pathways [18].\nA daily riluzole dose of 100 mg has the best efficacy\/side-effect profile.\nRetrospective analyses from a total of ten clinical ALS registries provide evidence of a median extension of survival time by up to 19 months with riluzole, and there are also clear indications that this substance is also effective in later stages of the disease [33\u201335].\nRiluzole is generally well tolerated; known side effects include an increase in transaminases, which must therefore be monitored regularly, and gastrointestinal complaints.\nAlternative dosage forms such as juice or orodispersible tablets are now also available for ALS patients with dysphagia. <\/p>\n\n

In addition to pharmacological therapy with riluzole, the prevention of a catabolic metabolic state with consecutive weight loss is considered to have an additional prognostic benefit.\nThe higher the body mass index (BMI), the more favorable the prognosis [36]. <\/p>\n\n

The current recommendations for ALS patients are therefore to maintain a stable weight and avoid weight loss.\nIn this context, the insertion of a PEG tube also plays an important role in progressive dysphagia, with a prolonged survival time as a result of this measure [37].\nWhether and to what extent specific anti-catabolic therapeutic approaches such as targeted high-fat, high-calorie nutritional interventions or ketogenic nutritional interventions can improve the prognosis is currently being intensively investigated in studies.\nIn this context, the Germany-wide LIPCAL-ALS 2 study as an Investigator Initiated Trial <\/em>(IIT) by colleagues from Ulm, which is scheduled to start in 2024 to 2025, is of great importance. <\/p>\n\n

Non-invasive (NIV) and invasive ventilation by means of a tracheostoma is another important measure for prolonging survival in ALS with ventilatory insufficiency [38,39].\nThis is also plausible, as alveolar hypoventilation with consecutive hypercapnia due to diaphragmatic involvement is typically a significant factor in the death of ALS patients after three to five years of disease progression. <\/p>\n\n

The development of antisense oligonucleotides (ASO) for specific genetically induced forms of ALS can be seen as a milestone.\nIn particular, the intrathecally administered ASO Tofersen should be mentioned here, which binds the SOD1 mRNA<\/em>in patients with pathogenic SOD1 variants<\/em>(around 1-2% of all ALS cases) and thus prevents the cytotoxic expression of the SOD1 protein<\/em>.\nIt has been shown that the mechanistic effect of a significant reduction in SOD1 expression<\/em>by approx. 30% in humans occurs very rapidly within days of starting therapy with Tofersen, followed by a significant drop in NfL in CSF and serum, before finally a slowdown in the decline in the ALSFRS-R score [16,40].\nAfter a longer-term observation of twelve months, further positive signals with clinical relevance such as effects on muscle function and weight stabilization were also observed. <\/p>\n\n

In the USA, Tofersen was approved by the FDA in April 2023 solely on the basis of the convincing biomarker data with a significant drop in NfL values.\nIn Germany, Tofersen was made available as part of an open access program.\nInitial real-world application data from the German motor neuron network impressively confirmed Tofersen’s study data with even better data in terms of clinical progression parameters [41].\nIn this context, it was only logical that the EMA decided to approve Tofersen in February 2024. <\/p>\n\n

In addition to the Tofersen ASO for SOD1-associated<\/em>ALS, ASOs are currently being developed or have already been investigated in studies, particularly against C9orf72 <\/em>and FUS <\/em> [15,42].\nIn particular, the ASO Jacifusen (ION363) should be mentioned here in the detection of a pathogenic FUS variant<\/em> as the cause of juvenile ALS, which is currently being tested in a multicenter, multinational study with two study sites (Rostock and Ulm) in Germany. <\/p>\n\n

The revised ALS-Functional Rating Scale<\/em> (ALSFRS-R) is a proven and well-established score for evaluating the motor functions of all four body regions and is not only an important endpoint for clinical studies, but has also proven to be an easily feasible follow-up parameter in clinical practice [43].\nThe ALSFRS-SE (SE: “self-explanatory”), which was only recently agreed within the German MND network in German with corresponding concrete and exemplary explanations for the individual items and functional impairments, is expected to have an additional advantage in terms of practical handling and, in particular, diagnostic accuracy [44]. <\/p>\n\n

Conclusion for practice<\/h3>\n\n

In addition to standard care for all forms of ALS (Riluzole, prevention of catabolic metabolic state including timely insertion of a PEG tube, early non-invasive and, if necessary, invasive ventilation in the event of ventilatory insufficiency), there has been significant progress, particularly for monogenetic forms of ALS, thanks to the development of specific gene-based treatment methods, currently ASO in particular.\nTofersen should be mentioned here as a very effective, specific therapy for SOD1-associated<\/em>ALS, which is now also available in Germany. <\/p>\n\n

Basic genetic diagnostics, at least of the most common genes (SOD1, C9orf72, FUS, TARDP)<\/em>, are therefore recommended for all ALS patients at the time of diagnosis.\nThe extent to which targeted, anti-catabolic, high-calorie interventions can favorably influence the course of sporadic ALS will hopefully be shown by upcoming studies in this area. <\/p>\n\n

Take-Home-Messages<\/strong><\/p>\n\n