Amyotrophic lateral sclerosis syndrome.

Amyotrophic lateral sclerosis (Charcot's disease (Gehrig's disease)) is a serious diagnosis, equivalent to a medical "sentence".

This diagnosis is not always simple, since in recent years the range of diseases has significantly expanded, in the clinical manifestations of which not a disease but amyotrophic lateral sclerosis syndrome may be observed. Consequently, the most important task is to differentiate Charcot's disease from amyotrophic lateral sclerosis syndrome and to clarify the etiology of the latter.

Amyotrophic lateral sclerosis is a severe organic disease of unknown etiology, characterized by damage to the upper and lower motor neurons, a progressive course and inevitably ending in death.

Symptoms of amyotrophic lateral sclerosis

The symptoms of amyotrophic lateral sclerosis, according to this definition, are those of lower motor neuron involvement, including weakness, atrophy, cramps, and fasciculations, and those of the corticospinal tract—spasticity and increased tendon reflexes with abnormal reflexes in the absence of sensory impairment. The corticobulbar tracts may be involved, exacerbating disease already present at the brainstem level. Amyotrophic lateral sclerosis is a disease of adults and does not begin in individuals under 16 years of age.

The most important clinical marker of the initial stages of amyotrophic lateral sclerosis is asymmetric progressive muscular atrophy with hyperreflexia (as well as fasciculations and cramps). The disease can begin with any striated muscles. There are high (progressive pseudobulbar palsy), bulbar (progressive bulbar palsy), cervicothoracic and lumbosacral forms. Death is usually associated with the involvement of the respiratory muscles after about 3-5 years.

The most common symptom of amyotrophic lateral sclerosis, occurring in about 40% of cases, is progressive weakness of the muscles of one upper limb, usually beginning in the hand (onset in proximally located muscles reflects a more favorable variant of the disease). If the onset of the disease is associated with the appearance of weakness in the muscles of the hand, then the thenar muscles are usually involved in the form of weakness of adduction (adduction) and opposition of the thumb. This makes it difficult to grasp with the thumb and index finger and leads to a violation of fine motor control. The patient experiences difficulties in picking up small objects and in dressing (buttons). If the dominant hand is affected, then progressive difficulties in writing are noted, as well as in everyday household activities.

In the typical course of the disease, there is a steadily progressing involvement of other muscles of the same limb and then spread to the other arm before the lower limbs or bulbar muscles are affected. The disease can also begin with the muscles of the face or mouth and tongue, with the muscles of the trunk (the extensors suffer more than the flexors) or the lower limbs. In this case, the involvement of new muscles never "catches up" with those muscles from which the disease began. Therefore, the shortest life expectancy is observed in the bulbar form: patients die from bulbar disorders, remaining on their feet (patients do not have time to live to the point of paralysis in the legs). A relatively favorable form is the lumbosacral.

In the bulbar form, there are some variants of a combination of symptoms of bulbar and pseudobulbar paralysis, which manifests itself mainly as dysarthria and dysphagia, and then - respiratory disorders. A characteristic symptom of almost all forms of amyotrophic lateral sclerosis is an early increase in the mandibular reflex. Dysphagia when swallowing liquid food is observed more often than solid food, although swallowing solid food becomes difficult as the disease progresses. Weakness of the masticatory muscles develops, the soft palate hangs down, the tongue in the oral cavity is immobile and atrophic. Anarthria, continuous salivation, and inability to swallow are observed. The risk of aspiration pneumonia increases. It is also useful to remember that cramps (often generalized) are observed in all patients with ALS and are often the first symptom of the disease.

It is characteristic that atrophy throughout the disease has a clearly selective character. In the arms, the thenar, hypothenar, interosseous and deltoid muscles are affected; in the legs, the muscles that perform dorsiflexion of the foot; in the bulbar muscles, the muscles of the tongue and soft palate.

The most resistant to damage in amyotrophic lateral sclerosis are the extraocular muscles. Sphincter disorders are considered rare in this disease. Another intriguing feature of amyotrophic lateral sclerosis is the absence of bedsores even in patients who are paralyzed and bedridden (immobilized) for a long time. It is also known that dementia is rare in amyotrophic lateral sclerosis (with the exception of some subgroups: the familial form and the Parkinsonism-ALS-dementia complex on the island of Guam).

Forms with uniform involvement of the upper and lower motor neurons have been described, with a predominance of damage to the upper (pyramidal syndrome in “primary lateral sclerosis”) or lower (anterior horn syndrome) motor neuron.

Among paraclinical studies, electroneuromyography has the most significant diagnostic value. It reveals widespread damage to the cells of the anterior horns (even in clinically intact muscles) with fibrillations, fasciculations, positive waves, changes in the potentials of motor units (their amplitude and duration increase) with a normal speed of excitation conduction along the fibers of sensory nerves. The content of CPK in the plasma may be slightly increased.

Diagnosis of amyotrophic lateral sclerosis

Diagnostic criteria for amyotrophic lateral sclerosis (according to Swash M., Leigh P 1992)

To diagnose amyotrophic lateral sclerosis, the following must be present:

• symptoms of lower motor neuron damage (including EMG confirmation in clinically intact muscles)
• symptoms of upper motor neuron damage progressive course.

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Exclusion criteria for amyotrophic lateral sclerosis (negative diagnostic criteria)

To diagnose amyotrophic lateral sclerosis, the following must be absent:

• sensory disorders
• sphincter disorders
• visual impairment
• vegetative disorders
• Parkinson's disease
• Alzheimer's type dementia
• ALS-mimicking syndromes.

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Criteria for confirmation of amyotrophic lateral sclerosis

The diagnosis of amyotrophic lateral sclerosis is confirmed by:

Fasciculations in one or more areas; EMG signs of neuronopathy; normal conduction velocity in motor and sensory fibers (distal motor latencies may be increased); absence of conduction block.

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Diagnostic categories of amyotrophic lateral sclerosis

Definite amyotrophic lateral sclerosis: presence of lower motor neuron symptoms plus upper motor neuron symptoms in 3 body regions.

Probable amyotrophic lateral sclerosis: lower motor neuron symptoms plus upper motor neuron symptoms in 2 body regions with upper motor neuron symptoms rostral to the lower motor neuron symptoms.

Possible amyotrophic lateral sclerosis: lower motor neuron symptoms plus upper motor neuron symptoms in 1 body region or upper motor neuron symptoms in 2 or 3 body regions, such as monomelic amyotrophic lateral sclerosis (amyotrophic lateral sclerosis manifestations in one limb), progressive bulbar palsy, and primary lateral sclerosis.

Suspected amyotrophic lateral sclerosis: lower motor neuron symptoms in 2 or 3 regions such as progressive muscular atrophy or other motor symptoms.

To clarify the diagnosis and conduct a differential diagnosis for amyotrophic lateral sclerosis, the following examination of the patient is recommended:

• Blood test (ESR, hematological and biochemical blood tests);
• Chest X-ray;
• ECG;
• Thyroid function test;
• Determination of vitamin B12 and folic acid levels in the blood;
• Serum creatine kinase;
• EMG;
• MRI of the brain and, if necessary, the spinal cord;
• Lumbar puncture.

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Syndromes mimicking or resembling amyotrophic lateral sclerosis

1. Spinal cord lesions:
   1. Cervical myelopathy.
   2. Other myelopathies (radiation, vacuolar in AIDS, electrical trauma).
   3. Ventral spinal cord tumor.
   4. Syringomyelia (anterior corneal form).
   5. Subacute combined degeneration of the spinal cord (vitamin B12 deficiency).
   6. Familial spastic paraparesis.
   7. Progressive spinal amyotrophy (bulbospinal and other forms).
   8. Post-polio syndrome.
2. Lymphogranulomatosis and malignant lymphomas.
3. GM2 gangliosidosis.
4. Heavy metal intoxication (lead and mercury).
5. ALS syndrome in paraproteinemia.
6. Creutzfeldt-Jakob disease.
7. Multifocal motor neuropathy.
8. Axonal neuropathy in Lyme disease.
9. Endocrinopathies.
10. Malabsorption syndrome.
11. Benign fasciculations.
12. Neuroinfections.
13. Primary lateral sclerosis.

Spinal cord lesions

Cervical myelopathy, among other neurological manifestations, often reveals typical symptoms of amyotrophic lateral sclerosis with hypotrophy (usually in the arms), fasciculations, tendon hyperreflexia and spasticity (usually in the legs). The syndrome of amyotrophic lateral sclerosis in the picture of spondylogenic cervical myelopathy is distinguished by a relatively favorable course and prognosis.

The diagnosis is confirmed by identifying other neurological manifestations of cervical myelopathy (including posterior column sensory disturbances and sometimes bladder dysfunction) and by neuroimaging of the cervical spine and spinal cord.

Some other myelopathies (radiation, vacuolar myelopathy in HIV infection, consequences of electrical trauma) can also manifest as a similar or identical syndrome of amyotrophic lateral sclerosis.

A ventral spinal cord tumor at the cervicothoracic level may manifest itself at certain stages with purely motor symptoms resembling the cervicothoracic form of amyotrophic lateral sclerosis. Therefore, patients with spastic-paretic atrophy in the arms and spastic paraparesis in the legs always require a thorough examination to exclude compression damage to the spinal cord at the cervical and cervicothoracic level.

Syringomyelia (especially its anterior horn form) at this level of the spinal cord can present with a similar clinical picture. The detection of sensory disturbances and neuroimaging examination are crucial in its recognition.

Subacute combined degeneration of the spinal cord with vitamin B12 or folic acid deficiency (funicular myelosis) usually develops against the background of somatogenic malabsorption syndromes and is typically manifested by symptoms of damage to the posterior and lateral columns of the spinal cord at the cervical and thoracic levels. The presence of lower spastic paraparesis with pathological reflexes in the absence of tendon reflexes sometimes forces us to differentiate this disease from amyotrophic lateral sclerosis. The diagnosis is aided by the presence of sensory disorders (deep and superficial sensitivity disorders), ataxia, sometimes pelvic disorders, as well as the detection of a somatic disease (anemia, gastritis, tongue condition, etc.). Of decisive importance in diagnostics is the study of the level of vitamin B12 and folic acid in the blood.

Familial spastic paraparesis (paraplegia) of Strumpell is a hereditary disease of the upper motor neuron. Since there are forms of amyotrophic lateral sclerosis with predominant damage to the upper motor neuron, differential diagnosis between them sometimes becomes very important. In addition, there is a rare variant of this disease ("hereditary spastic paraparesis with distal amyotrophy"), in which lateral amyotrophic sclerosis must be ruled out first. The diagnosis is aided by a family history of Strumpell's disease and its more favorable course.

Progressive spinal muscular atrophy

1. Bulbospinal, X-linked, Kennedy-Stephanie-Choukagosi amyotrophy is observed almost exclusively in men with the onset of the disease most often in the 2-3 decades of life and is manifested by fasciculations in the face (in the lower part), amyotrophic and paretic syndrome in the limbs (starting with the arm) and mild bulbar syndrome. Family history, transient episodes of weakness and endocrine disorder syndrome are characteristic (gynecomastia occurs in 50% of cases). Sometimes there is tremor, cramps. The course is benign (compared to amyotrophic lateral sclerosis).
2. The bulbar form of progressive spinal amyotrophy in children (Fazio-Londe disease) is inherited in an autosomal recessive manner, begins at the age of 1-12 years and is manifested by progressive bulbar paralysis with the development of dysphagia, intense salivation, repeated respiratory infections and respiratory failure. General weight loss, decreased tendon reflexes, weakness of the facial muscles, ophthalmoparesis may develop.
3. Differential diagnosis with amyotrophic lateral sclerosis may also be required for other forms of progressive spinal amyotrophy (proximal, distal, scapuloperoneal, oculopharyngeal, etc.). Unlike amyotrophic lateral sclerosis, all forms of progressive spinal amyotrophy (PSA) are characterized by damage to the lower motor neuron only. All of them are manifested by progressive muscle atrophy and weakness. Fasciculations are not always present. Sensory impairments are absent. Sphincter functions are normal. Unlike amyotrophic lateral sclerosis, PSA already at the onset are manifested by fairly symmetrical muscle atrophy and have a significantly better prognosis. Symptoms of upper motor neuron damage (pyramidal signs) are never observed. EMG examination is of decisive importance for the diagnosis.

Post-polio syndrome

Approximately a quarter of patients with residual paresis after poliomyelitis develop progressive weakness and atrophy of previously affected and previously unaffected muscles (postpoliomyelitis syndrome) 20-30 years later. Weakness usually develops very slowly and does not reach a significant degree. The nature of this syndrome remains unclear. In these cases, differential diagnosis with amyotrophic lateral sclerosis may be necessary. The above criteria for diagnosing amyotrophic lateral syndrome are used.

Lymphogranulomatosis, as well as malignant lymphoma

These diseases may be complicated by a paraneoplastic syndrome in the form of lower motor neuronopathy, which is difficult to differentiate from amyotrophic lateral sclerosis (but still its course here is more benign with improvement in some patients). Symptoms of predominant lower motor neuron involvement with subacute progressive weakness, atrophy and fasciculations in the absence of pain predominate. Weakness is usually asymmetric; the lower limbs are predominantly affected. When studying the conduction of excitation along the nerves, demyelination is noted in the form of a conduction block along the motor nerves. Weakness precedes lymphoma or vice versa.

GM2 gangliosidosis

Hexosaminidase A deficiency in adults, which is phenomenologically distinct from the well-known Tay-Sachs disease in infants, may present with symptoms resembling motor neuron disease. The manifestations of hexosaminidase A deficiency in adults are highly polymorphic and may resemble both amyotrophic lateral sclerosis and progressive spinal amyotrophy. Another closely related genotype, which is based on hexosaminidase A and B deficiency (Sandhoff disease), may also present with symptoms resembling motor neuron disease. Although amyotrophic lateral sclerosis syndrome is probably the main manifestation of hexosaminidase A deficiency in adults, the clinical spectrum of its manifestations still allows us to assume that it is based on multisystem degeneration.

Heavy metal intoxication (lead and mercury)

These intoxications (especially mercury) are now rare, but they can cause the development of amyotrophic lateral sclerosis syndrome with predominant damage to the lower motor neuron.

Amyotrophic lateral sclerosis syndrome in paraproteinemia

Paraproteinemia is a type of dysproteinemia characterized by the presence of a pathological protein (paraprotein) from the immunoglobulin group in the blood. Paraproteinemia includes multiple myeloma, Waldenstrom's macroglobulinemia, osteosclerotic myeloma (more common), primary amyloidosis, plasmacytoma, and paraproteinemia of unknown genesis. Some neurological complications in these diseases are based on the formation of antibodies to myelin or axon components. Polyneuropathy is most often observed (including in the POEMS syndrome), cerebellar ataxia and Raynaud's phenomenon are less common, but since 1968 amyotrophic lateral sclerosis syndrome (motor neuronopathy) with weakness and fasciculations has also been periodically mentioned. Paraproteinemia has been described both in classical ALS and in the slow-progressing variant of amyotrophic lateral sclerosis syndrome (in rare cases, immunosuppressive therapy and plasmapheresis have led to some improvement in the condition).

Creutzfeldt-Jakob disease

Creutzfeldt-Jakob disease is a prion disease and typically begins at the age of 50-60 years; it has a subchronic course (usually 1-2 years) with a fatal outcome. Creutzfeldt-Jakob disease is characterized by a combination of dementia, extrapyramidal syndromes (akinetic-rigid, myoclonus, dystonia, tremor), as well as cerebellar, anterior corneal and pyramidal signs. Epileptic seizures occur quite often. For the diagnosis, an important role is played by the combination of dementia and myoclonus with typical changes in the EEG (triphasic and polyphasic activity of acute form with an amplitude of up to 200 μV, occurring with a frequency of 1.5-2 per sec) against the background of normal cerebrospinal fluid composition.

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Multifocal motor neuropathy

Multifocal motor neuropathy with conduction blocks occurs mainly in men and is clinically characterized by progressive asymmetric weakness in the limbs without (or with minimal) sensory impairment. Weakness is usually (90%) expressed distally and to a greater extent in the arms than in the legs. Muscle weakness is often asymmetrically distributed and "tied" to individual nerves: radial ("drooping wrist"), ulnar and median. Atrophies are often detected, but may be absent in the early stages. Fasciculations and cramps are observed in almost 75% of cases; sometimes - myokymia. In about 50% of cases, tendon reflexes are reduced. But occasionally reflexes remain normal and even accentuated, which gives reason to differentiate multifocal motor neuropathy from ALS. The electrophysiological marker is the presence of multifocal partial blocks of excitation conduction (demyelination).

Axonal neuropathy in Lyme disease

Lyme disease (Lyme borreliosis) is caused by a spirochete that enters the human body through a tick bite and is a multisystem infectious disease that most often affects the skin (erythema migrans annulare), nervous system (aseptic meningitis; facial nerve neuropathy, often bilateral; polyneuropathy), joints (recurrent mono- and polyarthritis) and heart (myocarditis, atrioventricular block and other cardiac arrhythmias). Subacute polyneuropathy in Lyme disease sometimes has to be differentiated from Guillain-Barré syndrome (especially in the presence of diplegia facialis). However, patients with polyneuropathy in Lyme disease almost always have pleocytosis in the cerebrospinal fluid. Some patients with borreliosis develop primarily motor polyradiculitis, which may resemble motor neuronopathy with symptoms similar to ALS. A study of cerebrospinal fluid can again help in the differential diagnosis.

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Endocrinopathies

Hypoglycemia associated with hyperinsulinism is one of the known endocrinopathies described in foreign and domestic literature that can lead to the development of amyotrophic lateral sclerosis syndrome. Another form of endocrinopathy - thyrotoxicosis - can resemble amyotrophic lateral sclerosis with pronounced general weight loss and the presence of symmetrically high tendon reflexes (sometimes there is also a Babinski symptom and fasciculations), which is often observed in untreated thyrotoxicosis. Hyperparathyroidism is most often caused by adenoma of the parathyroid gland and leads to calcium metabolism disorders (hypercalcemia) and phosphorus. Complications from the nervous system concern either mental functions (memory loss, depression, less often - psychotic disorders), or (less often) motor functions. In the latter case, muscle atrophy and weakness sometimes develop, usually more noticeable in the proximal parts of the legs and often accompanied by pain, hyperreflexia and fasciculations in the tongue; dysbasia develops, sometimes resembling a duck gait. Preserved or increased reflexes against the background of muscle atrophy sometimes serve as a basis for suspecting amyotrophic lateral sclerosis. Finally, in practical work, cases of diabetic "amyotrophy" are sometimes encountered, requiring differential diagnosis with ALS. In the diagnosis of motor disorders in endocrinopathies, it is important to recognize endocrine disorders and apply the diagnostic criteria (and exclusion) of amyotrophic lateral sclerosis.

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Malabsorption syndrome

Gross malabsorption is accompanied by a disturbance of vitamin and electrolyte metabolism, anemia, various endocrine and metabolic disorders, which sometimes leads to pronounced neurological disorders in the form of encephalopathy (usually with stem, cerebellar and other manifestations) and damage to the peripheral nervous system. Among the neurological manifestations of severe malabsorption, a symptom complex resembling amyotrophic lateral sclerosis is encountered as a rare syndrome.

Benign fasciculations

The presence of fasciculations alone without EMG signs of denervation is insufficient for the diagnosis of ALS. Benign fasciculations continue for years without any signs of involvement of the motor system (no weakness, atrophy, no change in relaxation time, no change in reflexes, no change in the speed of excitation conduction along the nerves; no sensory disturbances; muscle enzymes remain normal). If for some reason the patient loses weight, then sometimes in such cases a reasonable suspicion of ALS arises.

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Neuroinfections

Some infectious lesions of the nervous system (poliomyelitis (rare), brucellosis, epidemic encephalitis, tick-borne encephalitis, neurosyphilis, HIV infection, the above-mentioned Lyme disease, "Chinese paralytic syndrome") can be accompanied by various neurological syndromes, including pyramidal and anterior corneal symptoms, which at certain stages of the disease may raise suspicion of ALS syndrome.

Primary lateral sclerosis

Primary lateral sclerosis is an extremely rare disease in adulthood and old age, characterized by progressive spastic tetraparesis preceding or following pseudobulbar dysarthria and dysphagia, reflecting combined involvement of the corticospinal and corticobulbar tracts. Fasciculations, atrophy, and sensory disturbances are absent. EMG and muscle biopsy show no signs of denervation. Although long-term survival has been described among patients with primary lateral sclerosis, there are patients with the same rapid course that is characteristic of ALS. The final nosological affiliation of this disease has not been established. The prevailing view is that primary lateral sclerosis is an extreme variant of ALS, when the disease is limited to damage of the upper motor neuron only.

In the literature, one can find isolated descriptions of syndromes resembling amyotrophic lateral sclerosis in diseases such as radiation damage to the nervous system (motor neuronopathy), myositis with inclusion bodies, paraneoplastic encephalomyelitis with the involvement of anterior horn cells, juvenile spinal muscular atrophy with distal atrophy in the arms, Machado-Joseph disease, multiple system atrophy, Hallervorden-Spatz disease, some tunnel neuropathies, and craniovertebral junction anomalies.