ALS. In (a) and (b) T2-weighted images demonstrate slight hyperintensity along cortico-spinal tracts (arrows). In (c), note a slight hypointensity in both Rolando’s cortex (arrowheads)
No specific biomarker of the disease is available, with the exception of mutations of ALS-related genes. Delay from onset of the disease to confirmation of the diagnosis can vary from 10 to 18 months. Such delay creates considerable distress in patients and the risk to undergo unnecessary surgery.
188.8.131.52 Main Differential Diagnosis
Cervical and thoracolumbar radiculopathies, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN), myasthenia gravis (MG), multiple sclerosis (MS), multiple system atrophy (MSA).
184.108.40.206 Diagnostic Criteria
The revised El Escorial and the Awaji–Shima criteria were developed to increase the level of confidence of a diagnosis of ALS in order to facilitate inclusion criteria in clinical trials, classifying patients in different degrees of diagnostic certainty (definite, probable, probable with laboratory confirmation, possible). They both reflect the spread of the disease rather than diagnostic certainty, and therefore are not very useful in clinical practice. In fact they have been criticized because they are too restrictive, causing the exclusion of ∼ 20–30% of ALS patients from clinical trials. Besides, they do not have a clear correlation with ALS outcome.
Twin studies showed that about 60% of the risk of ALS is genetically determined, and the remaining 40% is environmentally determined. More than 20 genes are implicated in ALS pathogenesis. The four major ALS-related genes are C9ORF72, SOD1, TARDBP, and FUS. They account for 2/3 of familial and ∼ 10% of apparently sporadic ALS cases .
In 2011, another major advance in the understanding of ALS was the identification of a large GGGGCC hexanucleotide repeat expansion in the first intron C9ORF72 gene. This dominantly inherited condition causes both ALS and FTD. It is present in a high percentage of familial ALS and FTD, but it is also present in about 7% of apparently sporadic ALS cases. As for TARDBP and FUS, C9ORF72 points to defective RNA processing as a central mechanism in neuronal degeneration.
Other minor ALS-related genes have roles in RNA metabolism, while some rarer forms of ALS are caused by mutations in genes involved in protein degradation pathways.
The pathological characteristics of ALS are the presence of astrogliosis and degeneration of motor neuron cell bodies in the motor cortex, brain stem, and spinal cord. The remaining neurons contain cytoplasmic ubiquitin inclusions. In almost all cases, such inclusions stain for the protein TDP-43. Exceptions are SOD1 and FUS-related ALS cases in whom the inclusions contain respectively SOD1 and FUS proteins abnormally aggregated. The C9ORF72 genetic defect is associated with deposition of TDP-43 and p62, a protein involved in autophagy, in some cortical regions, and in the hippocampus. Moreover, there are ubiquitinated inclusions containing aggregates of abnormally translated dipeptide repeats derived from the hexanucleotide repeat expansion found in the cerebellum and hippocampus.
Current pathogenic hypotheses ascribe neurodegeneration to a combination of disrupted RNA metabolism and abnormal protein aggregation, partly due to clearance failure of the proteasome system and autophagy. These mechanisms are accompanied by an immune reaction with microglial activation. Other candidate pathogenic mechanisms include glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, and failure of axonal transport .
There are currently no specific therapies, with the exception of riluzole, which prolong survival, but only by a few months.
The mainstay of ALS management remains symptomatic treatment through a multidisciplinary approach. In the advanced phases, the use of percutaneous endoscopic gastrostomy (PEG) and of non-invasive (NIV) or invasive ventilation (IV) has demonstrated to be effective in treating malnutrition and respiratory failure.
In population-based studies, the median survival of ALS patients is 2–3 years from symptom onset, while ALS referral centers report survival times to 4–5 years . There is a considerable variability in survival; in fact, about 10 % of cases survive for more than 10 years . Most studies report no gender effect on ALS outcome.
Factors that predict rapid progression include an older age of onset, bulbar site of onset, short duration from first symptom to diagnosis, presence of cognitive impairment, and genotype.
Age is a strong prognostic factor, and survival is inversely related to age at onset both in males and in females; older patients have a significant short survival compared to younger patients, without a gender effect .
220.127.116.11 Diagnostic Delay
A shorter delay from symptom onset to diagnosis (6–9 months) carries a worse prognosis. This can be explained by a more aggressive disease, with earlier neurological evaluation and diagnosis .
18.104.22.168 Clinical phenotypes
One study demonstrated that clinical phenotypes have significantly different prognostic characteristics .
PLS has a benign outcome with a median survival of more than 12 years. Also pyramidal phenotype has a relative benign prognosis, with the longest survival among ALS phenotypes, and similar to PMA. Flail arm phenotype has a median survival time of 4 years. Classic and flail leg phenotype carry an intermediate survival time. At the end of the spectrum, bulbar and respiratory phenotypes have the worst prognosis, less than 2 years. In this study, ALS phenotype was independently related to survival.
22.214.171.124 Cognitive functions
It is now clearly evident that 10 to 15% of ALS patients develop an overt FTD and that another 30–35% have a mild to moderate impairment of frontotemporal function with dysexecutive syndromes or behavioral changes. Some recent population-based studies found that patients with ALS-FTD have a shorter survival than those with normal executive and behavioral function (median survival, 28 months vs. 39 months) . This difference could be explained in part to a poor compliance of these patients for procedures (PEG, NIV) in the advanced phases of the disease. A mild cognitive impairment, on the contrary, seems to have little or no effect on ALS outcome.
126.96.36.199 Nutritional status
It is widely accepted that malnourishment carries a poor prognosis in ALS. Body Mass Index is a marker of nutritional status; it has been repeatedly found to be an independent prognostic factor for death .
188.8.131.52 Respiratory status
Respiratory function is generally considered a critical aspect in ALS, as most patients die for respiratory failure.
Prognostic indices include: (1) percent predicted forced vital capacity; (2) upright and supine forced vital capacity; (3) percent predicted vital capacity; (4) slope of decline of vital capacity; (5) sniff nasal pressure; (6) maximal inspiratory pressure and maximal expiratory pressure. All these indices were significantly correlated to survival .
184.108.40.206 Functional scores
The ALS Functional Rating Scale-Revised (ALSFRS-R) is the most widely used functional scale for ALS. It has been shown to be significantly related to outcome, particularly its respiratory subscore . The progression rate of the ALSFRS-R, calculated as the ratio between points of score lost from disease onset to diagnosis/months of disease duration, resulted also to be significantly related to prognosis.
220.127.116.11 Multidisciplinary approach
The interdisciplinary care approach performed in tertiary ALS centers can modify patients’ outcome. Increasingly, ALS patients are referred to tertiary ALS centers, whose practice is based on the interdisciplinary care paradigm. ALS patients followed by a multidisciplinary clinic have a better prognosis than those attending general neurology clinics, with a median survival from onset ~10 months longer . Moreover, the hospitalization rate is markedly reduced, and the hospital stay is shorter for patients attending tertiary ALS centers. These effects were independent from all other known prognostic factors (e.g., PEG and NIV) and could be explained with a better provision of supportive care of all problems related to the disease.
PEG is widely used for avoiding starvation and dehydration and improving quality of life. Nevertheless, whether enteral nutrition has a positive effect on survival is still a matter of debate (see also Chap. 11).
NIV is the treatment of choice in the management of respiratory disturbances in ALS. One controlled trial performed in ALS demonstrated a significantly longer survival in spinal-onset patients and only a better quality of life in bulbar-onset patients . A population-based study confirmed that NIV has positive effects on survival, in particular among patients followed by tertiary ALS centers compared to patients followed by general neurological clinics (316 vs 229 days) . This positive effect was present also in patients with mild to moderate bulbar signs, while patients’ age at the time of NIV determined a significant difference in survival (≤49, 451 days; 50–69, 268 days; ≥70, 164 days).
Recent genotype–phenotype studies have demonstrated that gene mutations can influence age at onset and outcome .
Cases carrying C9ORF72 repeat expansion have a median survival from onset of ~3 years. Patients carrying TARDBP mutations have a median survival of ~5 years, while FUS mutations are often characterized by a rapid progression and death occurring in less than 2 years.
SOD1 mutations are extremely heterogeneous in outcome. There are mutations such as the Ala4Val, which has a rapidly progressive course, whereas the Asp90Ala recessive variant is associated with a very slow course.
There are genes not causing ALS but modulating its clinical expression. They are sought with the genome wide association screening approach. The common variant rs12608932, located within an intron of UNC13A gene on chromosome 19, was found to be significantly associated with the risk of developing ALS but homozygosity for the minor allele of rs12608932 also shortens survival by approximately 12 months . Another example is NI-PA1, also associated to a shorter survival.
One of the most critical aspects in ALS is the lack of biological markers of disease progression to be used in clinical trials to evaluate therapeutic response.
The search of protein biomarkers has focused mostly on blood and cerebrospinal fluid, but also on muscle and other tissues. Inflammatory cytokines and chemokines (MCP-1 and IL-8), phosphorylated neurofilament heavy chain (pNfH), CD14, S100β have been proposed but with contrasting results in terms of correlation with disease progression.
A recent population-based study in a series of ALS patients investigated several hematological markers evaluated at diagnosis . Authors found that only serum albumin, creatinine, and lymphocytes were significantly associated with ALS outcome with a dose–response effect (better survival with increasing levels) in both genders, even after correction for known prognostic factors. Serum creatinine was correlated with fat-free mass and reflects the state of muscle mass. Serum albumin was correlated with indices of inflammatory state and not with nutritional parameters, and represents a marker of chronic inflammatory state rather than of nutritional status. Sensitivity and specificity values in predicting 1-year mortality indicated that serum albumin and creatinine have properties similar to the well-established prognostic factors of ALS such as ALSFRS-R score and age. None of the other hematological factors examined – in particular lipid status and uric acid, previously reported to influence survival – were predictive of ALS outcome.
EMG signs include the presence of fibrillation potentials and positive sharp waves and enlarged motor units. However, these abnormalities do not predict disease progression.
Motor Unit Number Estimation (MUNE) is a group of techniques to estimate the number of intact motor units. It has been proposed for longitudinal assessments of motor unit death and changes in single motor unit size. However, this technique needs extensive training of health-care staff and has a rather high test–retest variability; at present, there is no consensus about its use to follow disease progression in clinical trials.