Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease (MND), characterized by progressive degeneration of motor neurons in the cortex, the brainstem, and the spinal cord [1]. According to recent global burden of disease studies, MND has emerged in the last decade as the fourth most common cause of death among neurological disorders in the U.S.A., and among the diseases with the largest increase in absolute numbers in Western countries [2]. The typical clinical phenotype of ALS involves simultaneous upper (UMN) and lower motor neurons (LMN) and is usually fatal within 4 years of onset. Muscle weakness begins in a discrete body region (usually the face, arm or leg) and advances steadily over time and space. Less typical forms of the disease are characterized by much longer survival, or pure UMN or LMN involvement [1]. Clinical phenotypes of ALS can also involve other motor and non-motor regions. The most frequent is the presence of cognitive and/or behavioral impairment, which can be observed in up to 50% of patients; and in about 15%, it leads to the fulfilment of the diagnostic criteria for frontotemporal dementia (FTD) ^[1][3][1,3]. In addition to cognitive dysfunction, other systems can be involved, including extrapyramidal motor systems, sleep, and the autonomic nervous system [4]. Finally, other regions such as the hypothalamus may be implicated as defects in energy metabolism including weight loss, hypermetabolism, and hyperlipidemia have been associated with ALS [5]. Based on these observations, ALS can no longer be considered a disease limited to the motor system but rather a multisystem neurodegenerative disorder that involves other motor and non-motor domains [6].

2. Extrapyramidal Motor Features

Table 1 includes population-based studies exploring the prevalence and association of extra-pyramidal and non-motor features in patients with ALS. The concurrence of frank levodopa-responsive parkinsonism and ALS has been observed endemically in Guam and the Kii Peninsula, and has been named Guam ALS/Parkinsonism Dementia Complex [7]. Furthermore, the presence of clinical ALS and Parkinson’s disease (PD), outside the known Guam and Kii Peninsula foci, has been described as a distinct and rare pathological entity, named Brait–Fahn–Schwartz disease, in which basal ganglia, corticospinal and anterior horn cell degeneration are merely part of a more encompassing disease [8]. However, mild parkinsonian features have been reported in patients with ALS [9]. Several studies have shown imaging ^[9][10][9,10] and pathologic ^[11][12][11,12] evidence of degeneration of substantia nigra and striatum in ALS. The EURALS population-based study, which investigated the presence of parkinsonism features in 146 patients with newly diagnosed ALS, showed that patients with ALS have a higher than expected chance to report parkinsonian features [13]. The odds are almost five-fold for bradykinesia and six-fold for rigidity. In another prospective population-based study, about one-third of patients with ALS showed parkinsonism features meeting the diagnostic criteria for parkinsonism [14]. In the majority of cases, parkinsonism features were detected at the time of ALS diagnosis or during the follow-up, but also in the advanced stages. Patients with ALS and parkinsonism were more frequently male, but they did not show any other clinical or demographic difference compared with patients with ALS without parkinsonism signs. The neuropsychological profile did not differ between ALS with and without parkinsonism. Interestingly, a 123I-FP-CIT SPECT scan demonstrated that the dopaminergic nigrostriatal pathway was preserved, indicating that parkinsonian features in patients with ALS are likely to be related to extra-striatal brain pathways dysfunction [14].

3. Non-Motor Features

A growing body of evidence from recent years suggests that ALS results in a wide range of non-motor symptoms, which can have a significant impact on patients’ quality of life [4]. The presence of non-motor symptoms in ALS is the clinical demonstration that ALS is a multisystem disorder. As for other neurodegenerative diseases, non-motor symptoms in ALS can arise from pathological disease spread of motor areas into neighboring non-motor regions of the brain [4]. However, unlike PD [15], non-motor symptoms in ALS have been poorly defined and their biological substrates have been scarcely investigated so far. Non-motor symptoms are not strictly correlated to an underlying motor pathology and can be largely categorized into neuropsychiatric, gastrointestinal, and autonomic disturbances. [4]. Among the non-motor features, depression, pain, weight changes, fatigue and cognitive impairment are common in ALS and can contribute to diminished health outcomes and reduced quality of life [16]. Remarkably, due to a lack of awareness by both clinicians and patients, some of the non-motor symptoms result to be underreported and underdiagnosed [15]. Although several case–control studies have investigated non-motor symptoms in ALS, there have been few population-based clinical studies of the prevalence of non-motor symptoms [4] (Table 2). Depression is one of the major cognitive and psychiatric disorders reported by people with ALS, affecting between 6% and 29% of patients [4]. Roos and colleagues examined the relative risk of depression among patients with ALS, before and after diagnosis [17], in a nested case–control study based on Swedish national health and population registers. They found that patients with ALS had a highly increased risk of depression, even before diagnosis. Antidepressant use was more common in patients with ALS than in controls, especially during the year before and the year after diagnosis. Similarly, a population study in Sweden found a near sixfold increased risk for suicide among ALS patients over a 40-year period. The highest relative risk for suicide was observed within the first year after the patient’s first period of hospitalization [18]. Population-based studies have also long corroborated the relationship between psychotic events and ALS. This close association may underlie the prodromal nature of the extra-motor symptoms in the framework of ALS pathogenesis. It has been demonstrated, in fact, an increased risk of hospitalization due to schizophrenic symptoms in the 5 years preceding ALS diagnosis ^[19][20][19,20]. The risk of hospitalization due to a psychiatric disorder is higher 1 year prior to the onset of motor symptoms ^[19][20][19,20]. Furthermore, a register-based nested case–control study showed that family members of ALS patients, especially children, had an increased risk for manifesting psychiatric disturbances both before and after their relative’s diagnosis [20]. Similarly, aggregation studies suggested neuropsychiatric illnesses and ALS clusters in families. Two population-based cohort studies showed that the relative risk of developing a neuropsychiatric condition, such as schizophrenia, psychosis, obsessive-compulsive disorder, autism, and alcoholism, was significantly higher in first- or second-degree relatives of ALS patients ^[21][22][21,22]. Whether this can be explained by a shared polygenic risk between psychiatric diseases and ALS or by genetic pleiotropy of a few variants into several kindreds spectrum remains to be elucidated. Weight loss is another non-motor feature of ALS and has been investigated in a population-based setting by Marin and colleagues [23]. At the time of diagnosis, 50.6% of ALS patients reported a weight loss of more than 5%, and 36.0% of patients reported a weight loss of more than 10%. Furthermore, weight loss was independently associated with survival. Several observational studies have demonstrated that sleep disorders are frequent in ALS ^[24][25][24,25]. A recent systematic review showed that between 50–63% of patients with ALS reported poor sleep quality which was assessed by the Pittsburgh Sleep Quality Index (PSQI) [24]. To date, population-based studies of the prevalence of sleep problems in ALS are unavailable. Such studies are required to shed light on theour understanding of sleep disorders in ALS. Chiò and colleagues investigated the prevalence and characteristics of pain in an epidemiological series of patients with ALS compared with a population-based control [26]. Patients with ALS reported pain more frequently than controls (56.9% vs. 33.1%), with pain frequency and intensity correlated with a worse functional score and a longer disease duration [26]. Pain in patients with ALS was more frequently located at the extremities and interfered with all areas of daily function, but patients reported a greater interference than controls in the domains of enjoyment of life and relation with other people. Patients with ALS were also more frequently prescribed non-opioid analgesics and opioids than controls. These population-based studies indicated that pain is an under-recognized and undertreated non-motor symptom in ALS. Population-based studies are lacking regarding other non-motor features in ALS.