NEUROLOGY AND NEUROSURGERY - Y. V. ALEKSEENKO - 2014

AMYOTROPHIC LATERAL SCLEROSIS

Chronic degenerative diseases of The Nervous system caused by the selective involvement of motor Neurons in the Spinal Cord, Brainstem, or Cerebral Cortex are currently grouped under motor neuron diseases. The most common among them are amyotrophic lateral sclerosis (ALS), spinal amyotrophies, and certain Other forms of pathology. These conditions manifest as Muscle weakness and atrophy, inevitably leading to severe motor impairments.

ALS accounts for over 80% of all motor neuron pathologies. As previously noted, ALS is a progressive degenerative disease of the nervous system characterized by primary damage to the motor neurons of the spinal cord, as well as the cortical and brainstem motor neurons. The clinical picture of ALS comprises progressive paresis and muscle hypotrophy combined with symptoms of corticospinal and corticonuclear tract involvement, ultimately leading to immobility and death from escalating respiratory failure or various comorbid conditions.

This disease occurs across various geographical regions with a frequency of 2–5 cases per 100,000 population. In the United States, for example, there are approximately 30,000 ALS patients. The cost of care per patient in the U.S. is around $200,000 per year. Men are affected slightly more often than women (a ratio of 3:2). The disease typically onset between the ages of 50 and 70.

Etiology AND Pathogenesis of Amyotrophic Lateral Sclerosis

Familial cases of ALS are known to occur (5–12%). The etiology of sporadic ALS remains unknown to this day. Currently, the prevailing view is that ALS has a multifactorial nature, wherein various exogenous pathological influences (infections, intoxications) play a significant role by triggering The process of motor neuron death against a Background of individual predisposition. The only certain fact is that the neurodegenerative process is initiated by a cascade of damaging reactions (activation of glutamate receptors, accumulation of free radicals, elevation of intracellular Ca²⁺ levels, and activation of Proteolytic Enzymes within The Cell).

The Glutamate Excitotoxicity Theory. The amino acid glutamate serves as an excitatory neurotransmitter in the Central Nervous System and is also involved in neuronal cellular METABOLISM. When its extracellular concentration rises above a certain threshold, it can exert neurotoxic effects. This may be caused by a deficiency in one of the glutamate transporter Proteins, EAAT2B, resulting from a mutation in the Gene encoding EAAT2B, which is found in 65% of patients with sporadic ALS. Taking these patterns into account, a specialized test system is currently under development for the early Diagnosis of ALS.

The Autoimmune Theory. The rationale behind The Theory of an autoimmune mechanism of motor neuron damage in ALS stems from the detection of Antibodies (IgG) in patient sera that induce Ca²⁺-dependent apoptosis (programmed cell death) involving oxidative stress mechanisms.

The Theory of Trophic Factor Deficiency or Absence. Neurotrophic Factors are protein compounds produced by various Cells of the nervous system. Their protective and reparative roles regarding various types of neurons are well established. Significant progress has been made in this area in recent years with the advent of Introduction/32.html">Genetic Engineering techniques that allow for The production of pure recombinant preparations. Neurotrophic factors exhibit neuroprotective properties across different groups of neurons. There is reason to believe that the selective degeneration of motor neurons characteristic of ALS may be caused by a genetically determined absence of some factor specific to motor neurons.

Genetically Determined Superoxide Dismutase Defect. Approximately 20% of patients with familial ALS exhibit a mutation in the gene encoding the Cu/Zn-dependent superoxide dismutase-I (SOD-1) protein. Mutations in the SOD-1 gene can cause neurodegeneration through the accumulation of cytotoxic free radicals in Tissues and the Toxic effects of interactions between the mutant enzyme and body proteins on motor neurons.

As is known, cell death in the body can occur via necrosis and apoptosis. Motor neuron death in ALS predominantly occurs through the engagement of apoptotic mechanisms. Thus, studying the Specifics of the apoptotic reaction cascade in ALS offers hope for clarifying the disease's pathogenesis. Conversely, blocking apoptotic mechanisms is one of the potential therapeutic directions for this condition.

Depending on the localization of the lesion, several Variants of the disease are distinguished. There may be limited involvement of the brainstem, the motor neurons of the spinal anterior horns, or the corticospinal tracts. Macroscopic Changes in the Brain AND SPINAL cord in this disease are minimal. Microscopically, degeneration of the anterior horn cells is observed—most pronounced at the level of the cervical enlargement of the spinal cord—along with secondary gliosis. The motor neurons of the sacral region remain relatively spared, which explains the absence of pelvic organ dysfunction as the motor deficit progresses. Degeneration of corticospinal and other pathways in the anterior and lateral columns of the spinal cord is observed. Peripheral nerves exhibit phenomena of axonal degeneration and secondary demyelination.

Clinical Features and Diagnosis of Amyotrophic Lateral Sclerosis

Motor disorders in ALS have a mixed (spastic-atrophic) character, which is explained by the involvement of both upper and lower motor neurons in this disease. The primary clinical phenomenon in such cases is a motor deficit—muscle weakness and restricted range of voluntary movement. As is known, upper motor neuron damage manifests as increased muscle tone and tendon Reflexes, along with the appearance of pathological plantar and grasp reflexes. Lower motor neuron damage manifests as muscle hypotonia and atrophy, decreased tendon reflexes, and fasciculations.

The initial signs of the disease may include weakness in the distal upper extremities, clumsiness in performing fine finger movements, wasting of the hands and forearms, and fasciculations. Somewhat less frequently, the disease presents with weakness in the proximal upper extremities or shoulder girdle, signs of lower spastic paraparesis, or lower extremity muscle atrophy. The bulbar form of the disease begins with dysarthria or dysphagia. In approximately 30% of ALS patients, painful muscle cramps or spasms occur before overt motor impairments appear. Muscle weakness and atrophy tend to gradually generalize. Impairments of chest wall and diaphragmatic Muscle Function can lead to respiratory disorders. A hallmark sign of ALS is the hyperreflexia of tendon reflexes and the presence of pathological plantar or grasp reflexes against a background of pronounced muscle atrophy and fasciculations. The individual clinical picture of the disease is determined by the localization of the pathological process and The ratio of upper and lower motor neuron signs.

A distinctive feature of this disease is that extraocular motility disorders are extremely rare at all stages of its development. Sensory disturbances are not characteristic. Pelvic organ Functions are typically unaffected in ALS. Furthermore, in the vast majority of cases, bedridden cachectic patients do not develop pressure ulcers, which is likely due to changes in the Structure OF THE Skin's Collagen fibers.

Due to the wide Variability of clinical manifestations in ALS, experts from the World Federation of Neurology have proposed diagnostic Criteria for the disease:

  ∞ the presence of lower motor neuron degeneration signs detected through clinical examination (muscle weakness, atrophy, fasciculations), electrophysiological, or neuromorphological studies;

  ∞ the presence of upper motor neuron degeneration signs detected clinically (hyperreflexia, spasticity, pathological pyramidal signs);

  ∞ the progressive spread of motor neuron involvement signs to adjacent (longitudinally oriented) Regions of the spinal cord;

  ∞ the absence of electrophysiological and neuroimaging evidence indicating any other nervous system disease affecting lower and/or upper motor neurons.

Four main forms of ALS are distinguished: high, bulbar, cervicothoracic, and lumbosacral. Patients with the high form of ALS predominantly exhibit signs of corticospinal and corticonuclear tract involvement, manifested by The Development of spastic tetraparesis and pseudobulbar syndrome. In the bulbar form, bulbar and pseudobulbar disorders (dysphagia, dysarthria, oral primitive reflexes, forced laughter and crying) dominate the clinical picture. The cervicothoracic form of ALS is characterized by a spastic-atrophic paresis of the arms and spastic paresis of the legs. In the lumbosacral form, atrophic paresis of the legs predominates in the clinical picture.

ALS is characterized by the gradual spread and progressive escalation of motor impairments. The disease leads to death within 3–5 years due to respiratory failure or other somatic complications. The prognosis is significantly worse when the pathological process has a bulbar localization. However, in some cases, the progression of motor disorders slows down, and patient survival may reach 10–15 years.

Unfortunately, to date, no laboratory or instrumental tests have been developed that are sufficiently specific for ALS. Therefore, diagnosis relies primarily on the characteristic clinical manifestations of the disease. Electroneuromyography can detect rhythmic fasciculation potentials in the absence of changes in nerve conduction velocity along nerve trunks. This method allows

confirming the lesion of the anterior horns of the spinal cord. MRI reveals no significant abnormalities, except for signal intensity changes in the area of the pyramidal structures. CEREBROSPINAL FLUID in ALS remains normal or shows a slight increase in protein levels.

ALS must be differentiated from A number of diseases manifested by atrophic motor disorders and bulbar symptoms. Most commonly, these include spinal cord tumors, syringomyelia, vertebrogenic myelopathy, Chronic lead poisoning, and paraneoplastic lesions of the spinal cord and peripheral nerves.

Treatment of Amyotrophic Lateral Sclerosis

Only one drug is known to slow disease progression—riluzole, which acts as a presynaptic glutamate release inhibitor. The Use of this medication extends the life of ALS patients by an average of 3 months. Currently, no other effective treatments for ALS exist. Comprehensive symptomatic therapy is applied. Patients are advised to avoid excessive physical exertion and maintain their usual active lifestyle whenever possible. Therapeutic exercise (physical therapy) somewhat slows the development of disuse muscle atrophy and prevents contracture formation. Various orthopedic AIDS are used to facilitate movement: special collars for neck fixation and HEAD support, grasping devices, wheelchairs, functional beds, etc. Swallowing disorders pose a serious problem. Salivation can be reduced with atropine preparations. Patients and their relatives are trained to clear the Oral Cavity and prevent saliva aspiration into the respiratory tract by changing body position or tilting the patient forward. If necessary, some patients are fed via a nasogastric tube or gastrostomy. Experience shows that artificial pulmonary ventilation in ALS is inexpedient.

To reduce muscle spasticity, muscle relaxants (mydocalm, diazepam, etc.), thermal Procedures, and massage are used. However, certain medications (especially baclofen) at effective dosages cause increased muscle weakness and worsen the patients' well-being. Carbamazepine (finlepsin) and diazepam are used for painful muscle cramps. Pronounced pain requires nonsteroidal anti-inflammatory drugs. In the terminal stage, narcotic analgesics are used.

Depressive disorders and Sleep disturbances are corrected by prescribing tranquilizers and tricyclic antidepressants (amitriptyline, imipramine, zoloft).

Psychological support is extremely important for the patient and their relatives at all Stages of the disease. Since cognitive functions remain intact in ALS, patients often acutely realize the progressive deterioration of their condition and the inevitability of an unfavorable outcome. The patient is recommended to maintain a familiar and, if possible, active lifestyle. However, the physician should not completely conceal the seriousness of the disease or give false hope regarding any special treatments. Many international specialists believe that patients have the right to know the true prognosis. The question of whether a patient should be fully informed about The Nature of their illness must be considered individually, taking into account the opinion of close relatives. At the same time, predicting the exact Life expectancy and the time of death is impossible, and discussions on this topic should be avoided. It is not enough to answer a patient's direct question about how much time they have left by saying it is unknown. One should redirect the question and listen to how the patient assesses their own condition.

As the patients' condition deteriorates, they become concerned with issues related to work, family, specific manifestations of the disease, and increasing dependence on others. These should be addressed with the mandatory participation of the patient. In such situations, a physician must always be ready to discuss these problems. Some specialists, feeling helpless regarding such patients, reduce their contact with them and their families to a minimum. Meanwhile, communication with the physician, feeling their attention and support, is of great importance to the patient. This allows them to clearly formulate their thoughts, questions, or doubts and speak out, which in itself brings significant relief.

Clinical Problems

Option 1

A 38-year-old patient has developed weakness in the upper limbs and slight muscle Atrophy of the shoulder girdle over the past 8 months. They began to notice difficulty swallowing. Neurological examination revealed decreased strength in the arms, atrophy and fasciculations in the Muscles of the face, Tongue, and shoulder girdle. Brisk tendon reflexes in the upper and lower extremities, along with pathological hand and FOOT reflexes. Impaired articulation of tongue-twisting words and sentences.

   • List the main neurological disorders.

   • Determine the Nature of the motor impairments.

   • Explain The Nature and Water/144.html">Origin of the swallowing and speech disorders.

   • Formulate the topographic diagnosis.

   • Formulate the preliminary clinical diagnosis.

   • List other diseases that can cause similar symptoms.

   • Indicate the necessary instrumental examination Methods and the goals of their application.

   • Describe the necessary somatic examination.

   • What is the specific feature of motor disorders in this disease?

   • Name other possible causes of speech impairment.

   • Determine the prognosis of the disease.