Several conditions constitute the group of motor neuron diseases, including amyotrophic lateral sclerosis, and cause progressive degeneration of upper and lower motor neurons, depending on the subtype. Their cause remains unknown and they are slightly more frequently encountered in males. Clinical presentation involves muscle weakness and atrophy in all forms. To make the diagnosis, numerous diseases have to be excluded, while treatment mainly rests on supportive measures.
In final stages of MNDs, respiratory failure eventually occurs and is the main cause of death across all subtypes.
To make the diagnosis of a MND, the following diagnostic criteria should be fulfilled :
Prior exclusion of various more common and possibly treatable conditions should be made. Infectious diseases, such as Lyme disease, hepatitis C and neurosyphilis should be excluded by appropriate serological testing, while myasthenia gravis, dermatomyositis, lead poisoning, multiple sclerosis, disorders of the thyroid and adrenal gland and spinal muscular atrophy are some of the conditions that may present with similar symptoms  . To exclude these conditions, a complete blood count, serum and urine protein immunofixation, levels of electrolytes and creatine kinase, while a lumbar puncture may be useful as well, especially if the presence of leukocytes is established. The cornerstone, however, is EMG studies together with MRI, which may reveal the presence of typical changes in nerve conduction and potential presence of tumors or other structures that may be responsible for the development of symptoms, respectively.
There is no cure for MNDs and the focus of treatment currently remains on supportive measures. A multidisciplinary approach is necessary to manage neurological, respiratory and psychiatric symptoms . Baclofen may be effectively used for management of spasticity, while anticholinergic drugs may be given to reduce excessive salivation. Antidepressants such as amitriptyline and other serotonin-selective reuptake inhibitors . Since the majority of patients die of respiratory failure, ensuring adequate ventilation is key in prolonging the patient's life for at least some time. Riluzole is a drug that has shown to prolong survival rate in patients with ALS due to its antagonistic effects to glutamate, but only for a few months.
The prognosis for virtually all forms of MNDs are very poor, as these conditions are universally fatal. In the case of ALS, 5-year survival rates are 20% and 10-year survival rates are 10% , while studies show a median survival rate of approximately 4 years . Progressive bulbar palsy is fatal within 1-3 years in the vast majority of patients, as dysphagia becomes intolerable and various respiratory complications occur, but progressive muscular atrophy has a somewhat better prognosis, since patients can reach up to 25 years . Primary lateral sclerosis results in total disability within several years, indicating that these conditions present as a significant burden to patients and their families.
It is hypothesized that a combination of genetic and environmental factors contribute to development of MNDs . The majority of cases are sporadic, meaning that mutations develop de novo, but approximately 10% of cases are familial. Familial MND is considered to be transmitted by autosomal dominant pattern of inheritance and in approximately 20% of patients, SOD mutations have been observed . Additionally, mutations of various genes and compounds, including TDP43, FUS, angiogenin, dynactin, vesicle-associated membrane-protein and several other have been documented . On the other hand, sporadic forms have shown a strong association with alterations in vascular endothelial growth factor and apolipoprotein A4 . The exact events that lead to progressive neuronal death, however, require further studies.
Incidence and prevalence rates currently rely on isolated studies that reflect the overall burden of the disease. In the United Kingdom, studies have established that prevalence rates of ALS, progressive muscular atrophy and primary lateral sclerosis combined are approximately 6 per 100,000 individuals, with an incidence rate of 1-2 per 100,000 . Similar reports are seen in Italy and Canada, where a crude incidence rate of 2.5 per 100 000 has been established  . When looking at ALS alone, studies report an annual incidence rate of 1.5-2.5 per 100,000 . MNDs are slightly more frequent among males and the onset is usually after 50 years . Risk factors are currently unknown, but smoking has shown to be one of the most prominent candidates for sporadic ALS .
Changes observed in MNDs invariably include pathological events in both UMNs and LMNs. Lower motor neurons include the cells in the anterior horn of the spinal cord and motor nuclei of certain cranial nerves, while upper motor neurons constitute the motor cortex and the corticospinal and corticobulbar tract. Although the exact pathophysiological mechanisms of disease are not understood, damage of nervous tissue occurs via several mechanisms. Oxidative stress, as a result of SOD mutations, excessive stimulation of NMDA receptors by glutamate in the CNS, mitochondrial injury, as well as intracellular protein and filament aggregation have all been observed in both human and animal models . The end-result is apoptosis and progressive, irreversible death of neuronal cells which significantly impairs normal signal conduction throughout the body. In the setting of LMN damage, hyporeflexia, atrophy, decreased muscle tone and fasciculations develop, while diseases that affect UMNs cause spasticity, increased muscle tone, hyperreflexia and atrophy in later stages of disease, but fasciculations are absent .
Current prevention strategies do no exist, as the exact pathophysiologic basis of these disease remain unknown. Having in the fact that these conditions are managed by supportive measures only, little can be done regarding prevention and treatment.
Motor neuron disease (MND) is a term that comprises several neurodegenerative disorders - amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PCS), progressive bulbar palsy, progressive pseudobulbar palsy and progressive muscular atrophy, although ALS is most extensively studied . ALS (also known as Lou Gehrig's disease) is the most common MND, with an approximate incidence of 1.5 per 100 000 individuals. The sixth and seventh decade of life is the period of most frequent onset . The hallmark of all MNDs is progressive degeneration of upper and lower motor neurons (UMN and LMN, respectively), depending on the subtype. The cause remains unknown. The majority of MNDs develop sporadically, but up to 10% of cases are classified into familial forms and their clinical presentation is identical . Several mutations have been described, such as genes encoding superoxide dismutase (SOD), one of the main enzymes involved in suppressing free-radical injury, certain RNA-binding proteins such as FUS/TLS and TDP43, whereas alterations in promoter genes, angiogenin, apolipoprotein E4 and several other have been established as well  . Although the etiology of MNDs are not known, nerve damage is thought to be a result of several pathophysiological changes. In addition to oxidative stress, excessive glutamate stimulation that leads to neuronal death and aggregation of proteins and neurofilaments that are supposedly toxic to cells leads to apoptosis and cell death . As a result of these changes, progressive degeneration of neuronal tissue is observed in patients suffering from MNDs and gives rise to the appearance of symptoms that may involve both lower and upper motor neurons. The clinical presentation somewhat varies depending on the subtype of MND, but weakness and muscle atrophy are usually seen in all disorders. A progressive deterioration of nervous system occurs, as weakness and atrophy eventually affect all limbs, together with the onset of fasciculations, dysphagia, dysarthria, hoarseness and excessive salivation . Pseudobulbar affects are commonly observed and are characterized by excessive laughter, yawning and crying . In the setting of ALS, a distinguishing feature from other disorders is the fact that the senses, urinary sphincters, oculomotor nerve functions and cognition are almost always spared, for unknown reasons. Making the diagnosis of MND is difficult, as there are no specific diagnostic tests, but also because numerous conditions may present with similar symptoms. Myasthenia gravis, polymyositis, Lyme disease and many other have to be excluded in the workup . Electromyography, magnetic resonance imaging, serum and urine protein electrophoresis and genetic testing, as well as numerous other tests to exclude other conditions, should be included in the diagnostic protocol. Treatment rests on supportive measures, as there is no cure for neither of MNDs and is primarily aimed at ensuring adequate respiratory function and acceptable everyday life. The overall prognosis of patients with MND is quite poor, as these disorders are universally fatal. 3-year survival rate for ALS is 50% after onset, progressive bulbar palsy is universally fatal within 1-3 years, while patients suffering from progressive muscular atrophy may live up to 25 years .
Motor neuron disease (MND) is a term that encompasses several neurodegenerative disorders that affect the nerves that are responsible for innervation of muscles and various other structures in the central nervous system. Amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease) is the most common MND, occurring in approximately 2 per 100,000 individuals, while progressive bulbar palsy, progressive pseudobulbar palsy, primary lateral sclerosis and progressive muscular atrophy are other subtypes. Their cause remains unknown, but it is hypothesized that a combination of various genetic factors is responsible for the development of these diseases. Namely, mutations in enzymes that are responsible for fighting free radicals, superoxide dismutase (SOD), have been identified in a significant number of patients, while alterations in several other genes have been documented. Moreover, approximately 10% of all MNDs are familial, meaning that some inherited factors may also play a role. Risk factors are currently not established, but some studies have associated smoking and MNDs. These disease are slightly more commonly encountered in males and their onset is usually between 50-70 years. Patients may present with diverse symptoms, the most prominent being muscle weakness and atrophy. Because these diseases are progressive in nature, gradual worsening of symptoms and appearance of various other complaints is the usual clinical course. Main neurological symptoms include either diminished or increased reflexes and abnormal muscle tone, while difficulties chewing, eating, talking, as well as voice changes and clumsiness are all frequently observed in patients. In some MNDs, such as progressive bulbar palsy, significant emotional reactions may be observed, such as intense involuntary crying or laughing. To make the diagnosis, it is necessary to perform electromyography, a procedure that evaluates nerve conduction signaling, but various other conditions that may present with similar symptoms have to be excluded. Myasthenia gravis, syphilis, hepatitis C, Lyme disease, lead poisoning, diseases of the thyroid gland and many other may mimic MNDs, which is why a thorough diagnostic workup is necessary, often including various laboratory studies and magnetic resonance imaging (MRI) of the head. Treatment, unfortunately, is focused on supportive measures, as there is no cure for these universally fatal diseases. The prognosis of MNDs are very poor and all subtypes eventually lead to fatal outcomes. Approximately 50% of patients suffering from ALS die within 3 years, whereas the majority of patients with progressive bulbar palsy die within 1-3 years after the onset of symptoms. A somewhat better prognosis is seen in progressive muscular atrophy, where patients live up to 25 years. Overall, MNDs cause a rapidly progressive deterioration of the nervous system that always leads to fatal outcomes.