Amyotrophic Lateral Sclerosis

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Classification according to ICD-10
G12.2
Motor neuron disease - lateral sclerosis, myatrophic (amyotrophic)
ICD-10 online (WHO version 2019)

The amyotrophic lateral sclerosis ( ALS ) belongs to the group of diseases motor neuron and is an incurable degenerative disease of the motor nervous system . The degeneration of the first motor neurons leads to increased muscle tone (spastic paralysis). Damage to the second motor neurons leads to increasing muscle weakness ( paresis to plegia ), which is accompanied by muscle wasting . This leads to a progressive restriction in the activities of daily living.

Further names of the disease are amyotrophic lateral sclerosis , myatrophic lateral sclerosis , Lou Gehrig syndrome or, after Jean-Martin Charcot, Charcot's disease . The English name is Motor Neurone Disease .

Symptoms

ALS results in progressive and irreversible damage or degeneration of the nerve cells (neurons) that are responsible for muscle movements. These are also called motor neurons , or motor neurons , respectively. Both the so-called first motor neurons, motor nerve cells located in the motor cortex (motor cortex) , and the anterior horn cells of the spinal cord called second motor neurons or the motor cells of the brain stem in the cranial nerve nuclei can be affected . The axons of the first motor neurons pull to the second motor neurons , which in turn pull with their appendages to the skeletal muscles and innervate them.

The two forms lead to slightly different symptoms . The degeneration of the first motor neurons leads to increased muscle tone ( spastic paralysis ). Damage to the second motor neurons leads to increasing muscle weakness ( paresis to plegia ), which is associated with muscle wasting (amyotrophy). The paralysis of the muscles leads to gait , speech and swallowing disorders , impaired coordination and weakness of the arm and hand muscles and thus to a progressive limitation in the activities of daily life.

Amyotrophic lateral sclerosis cannot be cured. The focus of therapy is on symptom relief and psychological support. The average survival time is around three to five years. Death often occurs as a result of pneumonia , the development of which is promoted by the loss of the ability to swallow and the paralysis of the respiratory muscles .

Frequency and occurrence

Amyotrophic lateral sclerosis is a worldwide but rare disease . Around one to three out of 100,000 people develop ALS ( incidence ). The prevalence - that is, the number of people sick at a certain point in time - is given as 3 to 8 per 100,000.

ALS is more common in men than in women (the gender ratio is around 1.5: 1). Most diseases occur between the ages of 50 and 70, with the mean age of onset being 56 to 58 years. ALS rarely affects younger patients between the ages of 25 and 35.

Although ALS occurs around the world with about the same frequency, there are some exceptions that are important for research. A variant of the disease, which in addition to the symptoms of ALS also includes symptoms of Parkinson's syndrome and dementia , is particularly common on individual islands in the Pacific region. Among the Chamorro in Guam , the Auyu and Jakai in Western New Guinea and on the Kii Peninsula in Japan, the incidence of this so-called ALS-Parkinson's-dementia complex is up to 100 (up to 1,000 in New Guinea) per 100,000 people. The incidence in these areas has continued to decline over the past few decades. Since the affected populations are genetically independent of one another, not only genetic factors but also environmental factors are discussed as the cause of the disease in the respective populations.

The increased relative frequency among soccer players is also noteworthy. A study by the University of Pavia found in a study of Italian football professionals an increased risk of developing ALS before the age of 49.

The name Lou Gehrig Syndrome is derived from the fact that the popular New York Yankees baseball player Lou Gehrig , who is still one of the most successful representatives of his sport, fell ill with ALS during his active career. The illness forced him to abandon a streak of 2,130 consecutive games in 14 years. After being diagnosed with ALS shortly afterwards on his 36th birthday, he ended his career in 1939. Gehrig died two years later at the age of 37. The sympathy for Gehrig's fate made the rare disease known to a large public for the first time. The name Lou Gehrig's disease (Lou Gehrig syndrome) quickly established itself as a simpler name .

root cause

The cause (etiology) of the disease is unclear. Genetic factors are found in most people with ALS; whether they are the sole triggers is unknown. Most cases occur sporadically, i.e. without familial accumulation (sporadic ALS, sALS). In a small proportion of cases (5–10%), however, there is a familial accumulation (familial ALS, fALS). Three groups of mutations in different genes (TARDBP, C9ORF72, VAPB, FUS, SOD1) are found in the majority of cases. They lead to the pathological accumulation or the premature degradation of a wrongly folded protein (TDP-43, FUS or SOD1), which ultimately (like the tau protein in tauopathies ) triggers neurodegeneration.

In a hypothesis from 2015 it was suggested that in ALS patients misfolded variants of the enzyme SOD1 in the cell space (interstitium) of the brain and spinal cord ( CNS ) were not sufficiently flushed out through the glyphatic system , a special microcircuit for waste disposal in the CNS discovered in 2012.

In about 20% of the families an expansion of a repetitive gene segment of C9ORF72 can be detected, in another 10% of the affected families mutations of the SOD1 gene coding for a superoxide dismutase can be detected. Often there is an autosomal dominant inheritance. A number of other genes have also been linked to familial occurrence. For example, mutations in the TAR DNA binding protein gene (TDP-43) have been described that were degraded more rapidly in vitro and triggered increased apoptosis in neural cells.

Mutations in the UBQLN2 gene were detected in a familial form with an X-linked inheritance . This gene codes for ubiquilin 2 - a protein that is involved in regulating the breakdown of ubiquitinated proteins - and may also play a role in sporadic ALS. Another factor in the disease could be excitotoxic events (overexcitation) at the NMDA receptor . The transmitter D -serine is a co-agonist on this receptor and increases the receptor affinity of the agonist glutamate. Overexcitation of the NMDA receptor can have neurotoxic consequences. A slowed degradation of serine caused by a pathological mutation of the enzyme D -amino acid oxidase could cause the physiological concentration of this D -amino acid to rise too sharply.

In the Lou Gehrig case, it was speculated that head injuries could play a role in sports (protective helmets were still uncommon in baseball at the time). This speculation would also explain the incidence of the disease (mentioned above) among professional footballers, who also suffer more head trauma than the normal population.

The results of a study at the University of Michigan in Ann Arbor (May 2016) reinforced the longstanding suspicion that exposure to chlorinated hydrocarbons (including in pesticides), polychlorinated biphenyls as used in insulating oil and polybrominated biphenyls (flame retardants in plastics and textiles) can increase the risk of ALS developing.

Clinical picture

Usual clinical picture and course

Amyotrophic lateral sclerosis has a very variable clinical picture - especially in the initial stage - which is characterized by degeneration and the associated dysfunction of the first and second motor neurons. This results in muscular deficits. The clinical symptoms are accordingly characterized by a combination of spastic and flaccid paralysis of the muscles. Depending on the location of the damage to the motor pathways, the muscles of the upper and lower extremities , the bulbar muscles and the trunk muscles are impaired.

Spastic paralysis results from the degeneration of the first motor neuron and leads to functional impairment due to an increase in muscle tone. Depending on the location of the damage, this can be seen, among other things, in a spastic and slow gait pattern , limited dexterity of the hands and bulbar symptoms, such as speech and swallowing disorders , difficulty opening the mouth, up to the jaw clamp (trismus). Spastic speech disorder is characterized by strained and slow speech.

The damage to the second motor neuron leads to flaccid paralysis. The increasingly restricted innervation causes the muscles to break down ( atrophy ), and muscle weakness occurs. In addition, fasciculations and painful muscle cramps (crampi) are typical. If the bulbar muscles are affected, the muscle weakness also leads to speech and swallowing disorders. Uncontrolled twitching ( fibrillation ) of the tongue is also typical .

Special forms

Chronic juvenile ALS is a variation of the disease that progresses extremely slowly. The best-known patient was the British astrophysicist Stephen Hawking , who was diagnosed with ALS at the age of 21, but who only died of the consequences of this disease at the age of 76.

Progressive muscular atrophy (PMA) is viewed as a further variant .

diagnosis

Increasing muscle weakness, muscle atrophy ( muscle atrophy ) or muscle twitching that does not affect movement ( fasciculations ) usually lead patients to the doctor for the first time. Muscle twitches alone almost always represent so-called benign fasciculations . The eye muscles are excluded from the failure ; otherwise the disease can appear first anywhere on the body. Upon examination, the simultaneous appearance of signs of flaccid and spastic paralysis reinforces the suspicion of a diagnosis of amyotrophic lateral sclerosis.

Look for muscle wasting, especially in the hand muscles. Malignant muscle twitches (fasciculations), for example when sticking out the tongue (here it is fibrillation), are also typical . Malignant muscle twitches differ from the much more common benign muscle twitches in their irregularity and lower frequency. The reflexes can be triggered for a long time even on paralyzed parts of the body; they are even significantly increased at the beginning as a sign of a lesion of the first motor neuron, which is also used to make a diagnosis , for example in the form of an increased masseter reflex . The sick sometimes show a loss of control when laughing, crying or yawning ( affect lability ).

An electromyographic and electroneurographic examination is essential for making a diagnosis. Internationally standardized criteria have been developed for diagnosis (El Escorial criteria).

The loss of substance is visible during the autopsy : It affects the precentral cortex in the cerebrum , in which the cell bodies of the first motor neuron are located, the anterior horns of the spinal cord, in which the cell bodies of the second motor neuron lie, and the nerve tracts running between them (so-called pyramidal tract from Precentral gyrus to the spinal cord).

It is important to distinguish it from tropical spastic paraparesis because this disease caused by HTLV-1 is contagious. However, other neurological diseases that can have symptoms similar to ALS (“ ALS mimics ”) must also be clarified using differential diagnosis.

treatment

The treatment of patients with amyotrophic lateral sclerosis is ideally carried out in an interdisciplinary team of health and nursing staff, occupational therapists , physiotherapists , speech therapists , orthopedists , pulmonologists and neurologists, palliative care specialists , psychologists and the general practitioner . It includes, on the one hand, drug therapy with riluzole, which is based on the disease mechanism, and, on the other hand, symptomatic therapy. Symptomatic therapy should help avoid complications of muscular weakness and improve the patient's quality of life.

Neuroprotective Therapy

The therapy with riluzole, which is based on the suspected disease mechanism, is also known as neuroprotective therapy, as the active ingredient used inhibits the destruction of motor nerve cells. Riluzole is a so-called glutamate antagonist that influences the effect of the neurotransmitter glutamate on the nerve cells. Studies have shown that the administration of riluzole causes an increase in survival time (on average by about three months). In addition, it is believed that patients will remain in earlier stages of the disease longer.

However, riluzole cannot stop the disease from progressing. In Japan, Edaravon is approved against ALS, although no conclusive statement can be made about its effectiveness. The US Food and Drug Administration has now also granted its approval.

Symptomatic therapy

The symptoms and complications that typically arise in the course of the disease can be treated with a variety of therapeutic measures. Important areas of application for symptomatic therapy are swallowing disorders (and the associated flow of saliva from the mouth), speech disorders, cramps or increased tone of the muscles, weakness of the respiratory muscles and psychological changes such as depression or anxiety.

Muscle cramps (crampi)

Cramps in individual muscles (for example calf cramps) are a common, but also unspecific, early symptom of ALS. The cramps can affect several muscles at the same time. They can occur spontaneously - for no apparent immediate reason - or after physical activity, cold stimulation, sleep deprivation, alcohol or nicotine consumption. Passive stretching of the muscle is recommended for acute therapy. Regular physical training, physiotherapy exercises and massages are recommended for prevention. Quinine sulfate , magnesium or carbamazepine can be used if the level of suffering is appropriate .

Swallowing disorder

A weakness of the throat muscles leads to swallowing disorders (dysphagia) in ALS patients . The normal swallowing process ensures that no part of the ingested food or liquids (saliva) gets into the airways. An impaired swallowing mechanism increases the risk of what is known as aspiration pneumonia - pneumonia that occurs as a result of fluids spilling into the lungs. Furthermore, due to the difficult food intake with frequent swallowing, weight loss and insufficient fluid intake with the risk of dehydration can occur. If the symptoms occur, a change in diet to pureed foods and thickened liquids is recommended. Energy-rich food supplements can be used to meet the energy needs of the organism. With the help of speech therapy measures, swallowing techniques can be learned that make it easier for the patient to swallow. Since, as the disease progresses, these measures are often no longer sufficient to ensure the necessary food and fluid intake, the installation of a feeding tube (PEG tube) is recommended. This should be applied at an early stage, as the complication rate is increased in patients with advanced respiratory muscle weakness. Oral feeding is still possible after inserting a feeding tube.

salivation

Salivation from the mouth ( sialorrhea ) occurs as a result of the difficulty swallowing and weakness of the mouth and neck muscles. There is no increased saliva production in ALS patients. Sialorrhea is socially stigmatizing and is often experienced as stressful by affected patients. It can be treated with the help of drugs that inhibit saliva production (for example amitriptyline , scopolamine or glycopyrronium bromide ) as well as physiotherapy, orthopedic and speech therapy measures (such as training to close the lips and support the neck muscles).

Speech disorder and communication

The impairment of the tongue, mouth and palate muscles as well as speech-dependent shortness of breath lead in ALS patients to a progressive speech disorder ( dysarthria ) . The restriction of communication with the environment is experienced by patients and relatives as very stressful. One therefore is at an early stage speech therapy treatment appears to be facilitated with the help of exercises for breathing and speaking and coordinated. In addition, early provision of communication aids is also recommended.

Alphabet and picture boards are used here, for example. Above all, computer-aided communication aids enable communication with the environment as the disease progresses. Special systems can be controlled with the fingers, for example, or with advanced paralysis with the help of eye movements. With the help of so-called brain-computer interfaces , brain waves can be transmitted to a computer and made legible.

Pathological laughter and crying

As pathological laughing and crying (Pseudobulbäraffekt, pseudobulbar emotional lability) is a sudden, inappropriate laughing or crying the situation referred to the patient. The symptom occurs in up to 50 percent of ALS patients and is organic. If the patient requests therapy, amitriptyline or so-called serotonin reuptake inhibitors such as fluvoxamine or citalopram can be used.

Breathing disorder

With advanced ALS, the respiratory muscles are regularly weak and this leads to insufficient ventilation of the lungs (hypoventilation) . This restriction of lung function ( respiratory insufficiency ) leads to a reduced oxygen content in the blood ( hypoxemia ) and - due to a reduced exhalation - to an increased carbon dioxide content in the blood ( hypercapnia ) . Symptoms of impaired respiratory function are sleep disorders, morning headaches, tiredness during the day, concentration disorders, restlessness and, in advanced cases, shortness of breath ( dyspnoea ) . Infections of the respiratory tract (such as aspiration pneumonia) can worsen the function of the lungs even further. Respiratory failure is the most important cause of the limited life expectancy in ALS patients.

If symptoms of respiratory insufficiency occur, there is the option of adapting mechanical ventilation ( home ventilation ) that can also be carried out in the home environment . A distinction is made between so-called non-invasive and invasive ventilation. Non-invasive ventilation is machine-assisted ventilation that takes place through a breathing mask and is used primarily every night for 6 to 8 hours. Non-invasive ventilation can relieve symptoms of pulmonary dysfunction and improve quality of life. In the case of advanced respiratory insufficiency, mechanical ventilation via a tracheostoma (after a surgical tracheal incision) is possible (invasive ventilation). Both the adaptation of non-invasive ventilation and the creation of a tracheostoma and subsequent mechanical ventilation are therapy options that should be discussed with the patient at an early stage. Around 15 percent of patients opt for nightly non-invasive ventilation and less than 10 percent for mechanical ventilation via a tracheostoma. The proportion of patients who make use of mechanical ventilation support differs between cultures, countries and ethnic groups.

Depression, insomnia, and anxiety

A depressive syndrome with depression, joylessness and reduced drive can significantly reduce the patient's quality of life. Depressive episodes can be treated with medication with antidepressants such as amitriptyline , sertraline , fluoxetine or paroxetine as well as psychotherapy . Sleep hygiene measures as well as zolpidem and diphenhydramine are used to treat sleep disorders . For sleep disorders that occur as part of a depressive episode, an additional antidepressant therapy is used. Anxiety can occur, for example, with shortness of breath. In addition to treating underlying causes, diazepam , lorazepam or bupropion can be used as medication if the level of suffering is appropriate .

Public attention

A prominent ALS patient was astrophysicist Stephen Hawking , who suffered from the disease from 1963 until his death in March 2018. The American playwright and actor Sam Shepard, who died in 2017, also suffered from ALS; he processed his physical decline in the posthumously published book Spy of the First Person .

Sociology professor Morrie Schwartz was also diagnosed with ALS in 1994. The progression of his disease was noted by the writer Mitch Albom in the book Tuesdays at Morrie , which quickly became a modern and inspiring classic.

The American psychologist and computer scientist Catherine G. Wolf was diagnosed with ALS in 1997 and worked with a computer system for communication until 2012 at the Thomas J. Watson Research Center, the IBM research center. She got involved with PatientsLikeMe, an online community that provides a forum for people with ALS and other diseases to share their experiences and catch up on the latest medical developments. She is known for her research in the field of human-computer interaction.

The painter Jörg Immendorff moved more into the public eye due to his ALS disease, the consequences of which he died. In 2004 he donated a scholarship to the ALS outpatient clinic of the Charité to promote ALS therapy research.

Krzysztof Nowak , professional footballer for the first division club VfL Wolfsburg and Polish national player, suffered from the incurable disease from the end of 2000. In the beginning, the treating doctors had problems diagnosing Nowak for a long time. In March 2001 the diagnosis was made. Nowak had to end his football career at the age of 25. For years, already exhausted in a wheelchair, he and his family attended his club's games until he died in 2005 at the age of 29. It went down in VfL Wolfsburg's collective fan memory as number 10 of the hearts . The Krzysztof Nowak Foundation he founded in Wolfsburg in May 2002 supports ALS patients and research projects.

In the triathlon in Ironman races, some athletes perform a so-called Blazeman roll when crossing the finish line and cross the finish line while lying on the floor while rolling - in memory of Jon Blais (known as “Blazeman”): He suffered from ALS, but finished the Ironman in 2005 Hawaii and rolled over the finish line.

Guitarist Jason Becker , who was diagnosed with ALS in 1989, but was still active as a composer even in the most advanced stages of the disease, is also known to a large audience .

The disease received increased attention from the global public with the Ice Bucket Challenge launched by the ALS Association (ALSA) on July 15, 2014 . People challenged to do so on the Internet should pour a bucket of ice-cold water over themselves and donate money to research and combat ALS. In Germany, the ALS ambulance of the Charité and the German Society for Muscular Diseases e. V. supported by donations.

Also in 2014, with the US feature film Das Glück by my side (Original title: You're Not You ), the ALS theme was dramatically worked on for the cinema. Hilary Swank portrays the fictional concert pianist Kate, who - affected by the diagnosis - not only has to give up her job.

In February 2017, South African ex-rugby world champion Joost van der Westhuizen died of the disease six years after the diagnosis.

In November 2018, the American comic artist Stephen Hillenburg , the inventor of the comic figure SpongeBob SquarePants , died as a result of this nervous disease.

literature

Web links

Individual evidence

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  14. ↑ Lou Gehrig and CTE
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