Amyotrophic Lateral Sclerosis

Introduction

Amyotrophic lateral sclerosis (ALS) (also known as a disease of motor neurons, Lou Gehrig’s disease) is a slowly progressive, incurable degenerative disease of the central nervous system, which is characterized by the defeat of both upper (motor cerebral cortex) and bottom (anterior horns of the spinal cord and nuclei of the cranial nerves) motor neurons, which leads to paralysis and subsequent muscle atrophy. It is also characterized by a progressive defeat of the motor neurons, followed by paralysis (paresis) of limbs and muscle atrophy.¹ Death occurs from respiratory tract infections or respiratory failure due to muscle weakness. Amyotrophic lateral sclerosis is to be distinguished from the syndrome of ALS that can accompany diseases such as tick-borne encephalitis.⁵ The disease was first described in 1869 by Jean-Martin Charcot.² ALS accounts for about 3% of all organic lesions of the nervous system.⁴ The disease usually develops when people are between 30-50 years old. Amyotrophic lateral sclerosis is a disease of adults and does not start in people younger than 16 years.⁵ ALS is a neurodegenerative disease that is accompanied by destruction of central and peripheral motor neurons, characterized by a steady progression, leading to death.

Causes

Being a rare disease, ALS occurs in 2-6 cases per 100 000 people. Currently, causes of ALS are unknown. Most scientists consider ALS a degenerative disease. 5-10% of the patients are carriers of the hereditary form of ALS.⁶ According to modern concepts, ALS is a disease, which can not be caused by one single reason. The vast majority of cases (90-95%) is not related to inheritance and cannot be positively attributed to any external factors (transferred diseases, injuries, environmental situation, and so on.). Convincing evidence that ALS can be caused by some environmental factors is not received, although research is ongoing.⁶ For example, some scientists believe that a mechanical injury or contact with lead can have a certain attitude to the development of ALS. Moreover, at present, about 15 genes with mutations (or damage) are already identified in patients with ALS.⁶ Several scientific studies have found a statistical correlation between ALS and some agricultural pesticides.⁶ Thus, it is suggested that ALS is caused by various combinations of hereditary factors and environmental factors. Since the disease is relatively uncommon, the number of patients and the possibilities of modern statistical methods do not allow revealing certain regularities.

The Incidence Rate

Nowadays, there are more than 350,000 cases of ALS in the world.³ The incidence rate (number of new cases) of ALS is 100,000 people per year.³ It is 15 new cases of ALS per day. ALS can affect anyone. The disease can strike both men and women and it affects all ethnic and socio-economic groups. ALS can affect young or elderly adults; however, it is most commonly diagnosed in middle and late adulthood. Every year more than 5,600 Americans are diagnosed with ALS.³ In the US and Europe, men are affected more often than women. The vast majority of cases have a sporadic nature; familial cases make up 5-10%. Less than 10% of ALS cases are hereditary.³

Risk Factors

Risk factors are the following:

• Heredity. Up to 10 percent of patients inherit the disease from their parents. If parents have the disease, the risk among children is 50%.⁴
• Age. ALS is most common in people aged 40 to 60.⁴
• Sex. At the age of 65 years, the probability of the disease is higher in men. The gender difference disappears after the age of 70 years.⁴ It is possible that ALS, like other diseases, is caused by some combination of environmental factors in people who already have a genetic predisposition to this disease. For example, some studies of the human genome have identified numerous genetic variations that are typical for patients with ALS that may make a person more susceptible to the disease.

Environmental factors that increase the risk of this disease include:

• Smoking. The statistics indicate that amyotrophic lateral sclerosis occurs 2 times more frequently in smokers than non-smokers. The longer the experience of smoking, the greater the risk.⁴
• Lead intoxication. Some data suggest that the effect of lead on the body during the work at harmful manufacturing plants may be related to the development of ALS.⁴
• Military service. Recent studies show that people, who have served in the army, are at increased risk for the development of amyotrophic lateral sclerosis.⁴ The exact precipitating factor in people who served in the army (injury, exercise, infection or exposure to harmful substances) is unknown.

The Symptoms

The symptoms of amyotrophic lateral sclerosis are considered the symptoms of damage of lower motor neuron, including weakness, atrophy, fasciculations and cramps, and symptoms of damage of the corticospinal tract – spasticity and increase of tendon reflexes, pathological reflexes in the absence of sensory impairments. They may involve the corticobulbar tract, increasing the already developed disease at the level of the brainstem.¹ The most important clinical marker of early stages of amyotrophic lateral sclerosis is a progressive asymmetrical muscular atrophy with hyperreflexia (as well as the fasciculations and cramps).⁷ The disease can start with any of the striated muscles. Since early symptoms of the disease such as twitching, cramps, numbness, muscle weakness in the limbs, difficulty in speech are peculiar to many more common diseases, the diagnosis of ALS is difficult as long as the disease develops to the stage of muscular atrophy.⁷

Depending on what part of the body the disease affected primarily high (progressive “laughing sickness”), bulbar (“progressive bulbar palsy”), cervicothoracic and lumbosacral forms are distinguished. ²

“Limb-onset” ALS (up to three quarters of patients) usually starts with the destruction of one or both legs. Patients feel uncomfortable when walking, and suffer from rigidity in the ankle and stumbling. Lesion of the upper extremities is less common. In this case, it is difficult for the patients to implement common actions that require flexibility of fingers or hands.²

“Bulbar-onset” ALS manifests itself in speech difficulties (a patient’s speech has a nasal, snuffling character, s/he is not able to control the volume of the speech, further has difficulty with swallowing).²

In all cases, muscle weakness gradually covers more parts of the body. The patients with “bulbar-onset” ALS may not live to complete paresis of the limbs. The symptoms of ALS include signs of lesion of both lower and upper motor neurons:

• upper motor neurons damage involves muscle hypertonicity, hyperreflexia, abnormal reflexes (Babinski sign)
• lower motor neurons damage involves weakness and muscle atrophy, convulsions, involuntary fasciculations (twitching) of muscles.²

Eventually, the patient loses the ability to move independently. The disease does not affect mental abilities, taste or touch sensing processes; however, it leads to severe depression due to anticipation of slow death. In the later stages of the disease, it affects the respiratory muscles, thus, patients experience interruptions of breathing. Involvement of respiratory muscles after about 3-5 years usually leads to death. Ultimately, their lives can only be maintained by the use of mechanical ventilation and artificial feeding. Typically, nearly three to five years pass from identifying the first signs of ALS to death. ² However, Stephen Hawking (b. 1942), a well-known theoretical physicist and Jason Becker (b. 1969), a guitarist, are the only known patients with clearly diagnosed ALS, whose state stabilized over time.⁶

Diagnosis of ALS

Unfortunately, the exact etiology of ALS has not been established yet. In most cases, the disease occurs completely spontaneously, without any apparent reason. Therefore, a method that would allow curing a patient with such a diagnosis once and for all does not exist nowadays. After the initial detection of ALS an average person does not live more than six years. Correct interpretation of the existing clinical presentation of an individual patient plays an important role in the diagnosis of this disease, because this pathology must be differentiated from a plurality of processes with similar symptoms, including ALS syndrome, which sometimes accompany such pathology as tick-borne encephalitis.⁴ Also, there is a variety of diseases that cause the same symptoms as the early stages of ALS. Diagnosis of the disease is only possible by exclusion of more common diseases. The two key features of ALS (lesions of upper and lower motor neurons) are shown at a sufficiently advanced stage of the disease.⁵

Since the test which allows diagnosing ALS has not been developed yet, the disease is detected on the basis of clinical symptoms of upper and lower motor neuron damage on the one level of the central nervous system, further distributing them to other levels.

To confirm the diagnosis international criteria El Escorial, updated in 1997, was designed by the World Federation of Neurology.¹ According to it, to make a correct diagnosis it is necessary to observe the following:

• signs of upper motor neuron damage (clinical data)
• signs of peripheral motor neuron damage (clinical, electrophysiological and pathologic data)
• progressive spread of symptoms within one or more areas of innervation that can be detected by monitoring of patients¹

It should be noted that there are a number of syndromes imitating ALS, hence it is necessary to conduct a thorough examination, including structural neuroimaging, neurophysiological and laboratory tests in order to make the diagnosis. In the case of electoral upper motor neuron damage, genetic diseases should be excluded. A muscle biopsy is recommended to exclude atypical myopathies.⁷

Electromyography (EMG)

The standard neurophysiological investigations of patients with ALS include electromyography (EMG) and, in some cases, transcranial magnetic stimulation. Study of nerve conduction is necessary to exclude a number of syndromes imitating ALS, including demyelinating motor neuropathies.⁶ In the early stages of ALS normal conductivity of the motor nerve fibers is noted, however, denervation of muscle fibers occurs as the disease progresses, what is evidenced by the decrease in the amplitude of the action potential. The speed of impulse conduction along the fibers of the sensory nerves remains normal that distinguishes ALS from demyelinating neuropathies.⁶ Severe conduction disturbances along sensory fibers is a reason to doubt the correctness of the diagnosis. It is important to exclude multifocal motor neuropathy in patients with the signs of prevailing lower motor neuron damage.⁶

EMG may aid in detection of electrical activity in the muscles. Certain EMG results may indicate the presence of ALS. Using EMG denervation changes, reducing the number of action potentials of motor units (including the giant units) and polyphase action potentials, and fasciculations are detected.⁶ EMG method is also used to confirm lower motor neuron damage. Fibrillation potentials, positive sharp waves, and chronic neurogenic changes are recorded using this method. The pathological changes detected by EMG were added to the previously described clinical signs of damage in the revised criteria El Escorial.¹ Fibrillation potentials and positive sharp waves are subclinical signs of lower motor neuron damage and may be registered before the onset of clinical symptoms, allowing diagnosis of ALS at an earlier stage. ⁶

A distinctive feature of ALS is involuntary muscle twitching due to the emergence of fasciculation potentials – spontaneous action potentials of intact motor units. A specific sign of ALS is fasciculations of the tongue muscles. The presence of fasciculations while other pathological changes in EMG are absent should be interpreted very carefully, as they may be a sign of less serious disorders.⁴ On the other hand, according to the criteria of diagnosis of ALS, created by clinicians from around the world, in patients with suspected ALS fasciculations should equate to fibrillation potentials. Moreover, fasciculations in ALS are complex (“malignant”), and may be a sign of reinnervation, and their comparison with chronic neurogenic changes has a high diagnostic value.⁶

Magnetic Resonance Imaging (MRI)

Today the main advantage of the use of MRI is the possibility to rule out other diseases manifesting in a similar way on the basis of the obtained data. The method develops rapidly and it helped to explore that ALS belonged to multisystem neurodegenerative diseases. Further, the key points obtained from the application of neuroimaging techniques, which in some cases apply for the role of biomarkers are considered.

1. The hyperintense foci of the corticospinal tract, detected by MRI. A significant expression of hyperintense areas in the corticospinal tract is indicated using MRI. However, it is not specific to ALS.⁵
2. Identification of cerebral atrophy using MRI. Voxel morphometry method allows to quantitatively determine the degree of atrophy of the brain by evaluating the local structure of the gray and white matter. Using this method in patients with ALS an association of severity of cerebral atrophy with cognitive impairment is found and regional differences in patients with the sporadic form and hereditary form of ALS, characterized by a longer life expectancy are established. The method also allows determining the focal pathological changes of the brain by constructing 3-dimensional MR reconstruction.⁶
3. Magnetic resonance spectroscopy. Change in the ratio between the N-acetylaspartate and creatinine and / or phosphocreatine and choline is a marker of neuronal cell death. The sensitivity of MR spectroscopy can detect violations of an upper motor neuron and, thus, a differential diagnosis between ALS and progressive muscular atrophy.⁵
4. Diffusion Weighted MRI. The method allows studying the changes in the corticospinal tract of patients with ALS. In addition, tractography allows studying the structural relationship of various pathways.⁶
5. Identification of preclinical markers of the disease. The absence of high-risk factors of a sporadic form of ALS significantly complicates the detection of early preclinical markers of the disease. As a result of the diffusion weighted MRI changes that are absent in healthy people were revealed in patients with a mutation in SOD1-gene.⁶
6. Functional studies. For the evaluation of patients with ALS such techniques as positron emission tomography and functional MRI may be applied. They allow assessing the functional features of different areas of the brain. ⁵

Positron Emission Tomography (PET Scan)

Positron emission tomography is imaging using gamma-rays, but not X-rays. The method is connected to the use of short-lived isotopes, using which substances introduced into the body (glucose, ATP, etc.), which are involved in the metabolic processes of the brain, are labeled.² Thus, this method allows to obtain important information. PET scan can help to detect amyotrophic lateral sclerosis, exploring the blood flow in the brain and metabolic activity. Several researchers observed a decrease of metabolism, including glucose in ALS patients using positron emission tomography.² PET scan makes it possible to detect abnormalities in the precentral gyrus of the brain (reduction of glucose metabolism). However, in itself it is not sufficient to form diagnostic conclusions.²

Muscle Nerve Biopsy

A biopsy of skeletal muscle, peripheral nerves, and other tissues is not required for diagnosis of the disease, except for those cases where there are clinical, neuropsychological and neuroimaging data not characteristic for the disease.² Also, a muscle biopsy is recommended to exclude atypical myopathy, in particular, a form of glycogen storage disease of Type IV – APBD (adult polyglucosan body disease). ¹When biopsy of skeletal muscle is carried piece of muscle tissue is removed; the procedure is conducted under local anesthesia. Further analysis shows signs of its denervation.

Lumbar Puncture

Lumbar puncture with subsequent laboratory analysis of received cerebrospinal fluid can be used in order to rule out multiple sclerosis and infectious diseases that may be accompanied by similar symptoms. Lumbar puncture is a method of diagnosis during which a needle is placed into the subarachnoid space of the spinal cord at the lumbar level. In patients with ALS, this procedure will reveal a moderate increase in protein content. In one-third of patients, the level of protein in the cerebrospinal fluid increased up to 45- 95 mg%.⁶

Myelogram

Currently, there are no specific biochemical and pathological markers of ALS. Only myelogram makes it possible to confirm the defeat of the anterior horn of the spinal cord, which can not be explained by any other local process.⁷ Myelogram reveals posterior osteophytes at several levels and the narrowing of the spinal canal. Liquor and liquorodynamic tests do not show deviations from the norm, except rare cases when a partial block of the spinal subarachnoid space and moderate hyperalbuminemia in the cerebrospinal fluid are detected.⁷

Treatment

Patients with ALS require a special therapy to relieve symptoms. Gradually, a patient’s respiratory muscles begin to weaken, respiratory failure develops, and it becomes necessary to use special equipment to facilitate breathing during sleep (IPPV or BIPAP). Then, after a complete failure of the respiratory muscle activity, it is necessary to use medical ventilator around the clock. The tube which passes from the mouth or nose through the trachea is used in this case. Also, tracheotomy may be needed; it is an operation during which a plastic tube is inserted directly into a patient’s trachea through a hole in his/her neck.

Gastrostomy is the only way to prevent the exhaustion which inevitably occurs with the progression of swallowing disorders in the majority of patients with ALS. Gastrostomy should be performed when the patient swallows relatively well, breathes and can take care of him/herself. During gastrostomy, a specialist sets a device with the endoscope through the abdominal wall of the stomach. The probe is held by passing inside holding plate, and studs by a silicon wafer.

Food and Drug Administration has approved only one drug to treat ALS – Rilutek. It is designed to reduce the effect of glutamic acid on the activity of motor neurons by activating a glutamine transporter. Furthermore, it is believed that it performs other neuroprotective effects by blocking sodium and calcium channels.

Experimental treatment is widely studied now. Some authors recommend repeated blood transfusions. The effect is associated with the removal of toxic substances and circulation of immune complexes. Also, the protective effect of ultra-high doses of vitamin B12 and its analog, methylcobalamin, and vitamin D, administered by injection, on neurons of the cerebral cortex is studied now. Ultra-high doses of methylcobalamin slow down a progressive decrease in muscle tone and, therefore, the progression of ALS.