Pick's disease, also known as dementia

It is one of the most complex brain pathologies. Most often associated with age-related changes caused by cell death that occurs due to age-related changes.

Age-related changes in the body provoke the onset of many diseases. One of which is Pick's disease. With this variant of senile dementia, disturbances occur in areas localized in the frontal and temporal lobes of the brain. This acquired senile dementia is characterized by behavioral disturbances. The patient's instincts are disinhibited, and cognitive functions collapse.

This type of senile dementia was first described at the end of the 19th century, in 1892, by psychiatrist Arnold Pick. At the initial stages of studying the disease, it was recognized as one of the manifestations of senile dementia. As the study progresses, Pick's disease is identified as a separate pathology. Until now, the pathology has been little described. It is diagnosed in 1-2% of older patients. The diagnosis is not always established immediately. For a long time, its manifestations were attributed to another variant of senile dementia, Alzheimer's disease. The difference is the localization of areas of death in the brain. If in Alzheimer's disease they are not strictly localized, the entire brain is affected; in Pick's disease the temporal and frontal lobes are affected.

A significant difference between the diseases is the absence of disturbances in the functioning of the cardiovascular system. Symptoms of the formation of plaques that occur during inflammatory processes do not appear. Due to death, thinning of the cerebral cortex occurs. The size of the cerebral ventricles increases. The distance between them practically disappears.

Manifestations start with speech disorders. Pick's disease causes behavioral changes in the patient. At the third stage, total dementia is noted.

Pick's disease is treatable, but age-related changes in the brain cannot be completely cured. The process of cell death is not completely stopped by medications.

Causes and risk factors for Pick's disease

Modern research shows that patients aged 50-60 years and older are susceptible to this type of senile dementia. Recently, the disease has been actively studied. But all the research so far does not allow us to accurately determine the reasons for the onset of age-related changes in the temporal and frontal lobes. Some common factors found in patients affected by pathology have been identified:

• Hereditary factor. In most cases, close relatives of the patient suffered from Pick's disease.
• The onset of degenerative processes is caused by a serious head injury, which causes the death of neurons, which leads to irreversible changes in the cerebral cortex.
• Neuronal damage caused by exposure to chemicals caused by exposure to heavy metals, their excessive concentration. The list of factors includes the constant impact of alcohol on the human body.
• Pick's disease is often a consequence of mental disorders. The risk group includes all patients under the supervision of a psychiatrist.
• A risk factor is the constant use of psychotropic drugs.
• A hypovitamin condition can lead to the onset of the disease.

A feature of the disease is the absence of a guaranteed start of Pick's disease, even with a combination of all these factors. Often, the death of neurons is caused by factors that doctors are currently unable to clearly identify.

Important: Treatment for Pick's disease is ineffective. Modern methods are not able to stop degenerative processes, which lead to complete dementia 5-6 years after the first episode.

The atrophic process continues continuously. It affects subcortical structures and cortex. Inflammation and vascular disorders are not detected.

During diagnosis, specialized studies are carried out to separate Pick's disease from other diseases with similar symptoms. Primarily for Alzheimer's disease. Senile dementia is also characterized by similar symptoms. Many symptoms are also present with intracerebral tumors.

Diagnosis in most cases is performed already at the second stage of a complex disease. In many cases, the appeal comes from the patient’s relatives who complain about his antisocial behavior.

In order to accurately determine the lesion, a personal examination of the patient by a specialist is carried out. In its course, the development of Pick's disease allows us to assume:

• aggressive behavior;
• failure of the patient to comply with hygiene skills;
• a penchant for crude humor appears;
• hypersexuality is noted.

Special tests are prescribed to identify concomitant diagnoses. An accurate diagnosis is established by analyzing the growing symptoms. Additionally, studies of the cerebral cortex are carried out using MRI or CT. Magnetic resonance therapy is preferable in this case. During this procedure, the brain is imaged layer by layer, helping to identify areas of damage. Such a thorough examination at the earliest stages allows specialists to determine the type of Pick's disease that the patient suffers from and to identify the exact location of the lesions.

Another study that helps determine the onset of the disease is performing an EEG (encephalography). The study determines the degree of brain activity. In many cases, EEG data is checked and confirmed by CT or MRI. Using all of the above research options provides the most complete picture.

It is important to note that if it is possible to conduct only one of the types of proposed studies, preference is given to MRI. It gives the most complete picture of the condition of the internal organs.

Conducting research ensures that errors in diagnosis are eliminated, allowing Pick's disease to be separated from other degenerative brain lesions at a very early stage. Primarily for Alzheimer's disease.

Often the classic form is also confused with Pick's disease, which is diagnosed in children. Despite the similarity of names, these are different diagnoses. They require different treatment methods.

The main difference is the age of the patients. Diagnosis is carried out with special care at the onset of pathology in patients in the age group of 30 to 40 years. Age-related changes begin in most situations after 50. But additional factors are taken into account. For example, lifestyle and type of work performed. Early senile changes may be associated with the death of neurons, which is provoked by frequent damage to the cerebral cortex by active chemicals, mechanical stress, alcohol and other factors. The specialist receives all this data during a personal conversation during a preliminary examination with the patient himself or his relatives. Pick's disease at an early age negatively affects the quality of life and requires complex therapy.

Treatment, Prognosis, Profplasia

No specific treatment has been developed. The use of hormonal drugs, vitamins, blood and plasma transfusions gives only a symptomatic effect.

The prognosis is unfavorable. The disease quickly leads to exhaustion and death due to intercurrent illnesses (usually pneumonia). Survival beyond age five is extremely rare.

Occupational plaster: when aggravated by N.—P. b. heredity, it is necessary to examine the amniotic fluid during each pregnancy for the purpose of prenatal diagnosis of P.—I. b. or abstain from childbearing.

Bibliography:

Andreev I. et al. Differential diagnosis of the most important symptoms of childhood diseases, trans. from Bulgarian, p. 202 and others, Plovdiv, 1977; Badalyan L. O., Tabolin V. A. and Veltishchev Yu. E. Hereditary diseases in children, p. 78, M., 1971; Kerpel-Fronius E. Pediatrics, trans. from Hungarian, p. 218, Budapest, 1975; Potter E. Pathological anatomy of fetuses, newborns and young children, trans. from English, p. 87, M., 1971; Yampolskaya O. A. Niemann-Pick disease (type B according to Crocker), Arch. pathol., t. 39, v. 6. p. 55, 1977; Van B o-gae g t L. La maladie de Niemann—Pick et ses rapports avec les idioties amauroti-ques, Rev. med. Liege, t. 17, p. 333, 1962; Niemann A. Ein unbekanntes KranJv kheitsbild, Jb. Kinderheilk., Bd 29, S. 1, 1914; Pick L. Zur pathologischen Anatomie des Morbus gaucher, Med. Klin., Bd 18, S. 1423, 1922.

L. A. Makhonova; G. M. Mogilevsky (pat. an.).

Stages of Pick's disease

A feature of this lesion of the cerebral cortex is a gradual increase in symptoms, which cannot be stopped. Development occurs from the degradation of social functions to physiological disorders, expressed in memory loss and the cessation of the ability to perform other tasks.

1. At the first stage, a change in behavior is observed. A person may suddenly leave his job. Damage to the basal frontal lobes provokes activation of selfishness, disinhibition of desires, loss of criticism, sexual disinhibition, physiological needs can be coped with in an environment not intended for this. It is easy to identify lesions affecting the right hemisphere by the appearance of euphoria. When the right lobes are affected, the patient becomes depressed. In case of damage to convexial surfaces, leading to atrophy, the patient experiences emotional dullness. The death of other areas can provoke indifference, spontaneity and other atypical forms of behavior.
2. At the second stage, focal symptoms increase, manifesting themselves in the form of agnosia. Patients have hearing and speech impairments, they lose tactile and visual perception. Due to moderate agnassia at this stage, complex motor acts begin to be disrupted. There is a gradual disintegration of speech from the use of stereotypical constructions when constructing phrases to the transition to echolalia. The patient can only repeat heard words and syllables. As symptoms increase in the second stage, the patient gradually ceases to clearly understand the purpose of using objects. For example, having received candy as a treat, the patient can unwrap it, throw away the sweet treat and start eating the wrapper.
3. The third stage is accompanied by a transition to total dementia. The patient loses the ability to perform any conscious activity, the possibility of recognition disappears. The patient feels severe weakness, practically losing the ability to move independently. However, Pick's disease is not accompanied by paralysis. At the thermal stage of the third stage, the patient develops a vegetative coma.

All stages of the disease, with an unfavorable course, develop within 3-4 years. The use of modern drugs and techniques, the patient’s health status and other factors can extend the duration of the disease to 7-10 years.

In medical practice, the disease differs depending on the location of the affected areas:

• in the case of a predominance of atrophy in the frontal part of the brain, most patients suffer primarily from disorders responsible for storing memory;
• atrophy in the temporal lobe causes speech disorders of aphasia;
• when the hypothalamus is affected, patients lose the ability to concentrate, they suffer from psycho-emotional disorders, depression or euphoria.

In medical practice, differences are observed only in the early stages of the lesion. The listed symptoms are combined in cases of simultaneous damage to both lobes of the brain.

Pick's disease in children

Irreversible damage to the cerebral cortex, characteristic of Pick's disease, in most cases affects older people. But in exceptional situations, this complex diagnosis is observed in representatives of other age groups, including children.

The danger lies in family history. In the case of the presence of dementia caused by this diagnosis in relatives, in rare cases, Pick's disease can develop in children. Inheritance occurs according to an autosomal recessive principle. If the disease is diagnosed in one of the parents, the hereditary lesion can occur in a child of either sex. An unfavorable prognosis is given if the pathological gene is present in both parents.

The progression of the pathology occurs in the first weeks of life. At birth, the baby is considered completely healthy.

Manifestations of pathology include:

• the presence of constant nausea, which often leads to vomiting;
• the child has no appetite;
• liver size is increased;
• body weight is rapidly decreasing, the baby is significantly behind in growth compared to peers;
• lymph nodes enlarge;
• pigmentation is observed on the skin;
• The cornea of ​​the eye becomes cloudy.

As a result of a significant increase in the size of the internal organs, the abdomen of a small patient appears disproportionately large.

Pick's disease is incurable regardless of the patient's age. As the child’s symptoms develop, the central nervous system becomes disrupted. This manifests itself in the absence of speech, “humming” in infants, and visual and hearing impairment is diagnosed. The baby may develop seizures, similar to manifestations of epilepsy. Reflex activity in patients increases significantly. In the most difficult cases, when the disease starts in the first months, children rarely survive to one year.

In addition to the classic form of Pick's disease, children may develop:

• visceral type, most often beginning in children aged 6-7 years;
• in adolescence, the juvenile type of Pick's disease begins;
• A special form of Novo Scottia, also most often beginning in the first 20 years.

These types may not be accompanied by neurological disorders. In the juvenile type, children and adolescents experience severe muscle weakness, which can lead to loss of motor activity.

The choice of treatment option for pathology directly depends on the type of disease. The classic type develops rapidly and is fatal within a maximum of five years. Patients with other types can live up to 30 years.

Prevention includes testing with a geneticist for families planning to conceive a child.

Niemann–Pick disease type C: diagnosis, follow-up and treatment of patients in Russia

Niemann–Pick disease belongs to the group of lysosomal storage diseases and is characterized by autosomal recessive inheritance. For pediatric neurologists, Niemann-Pick disease type C is of particular interest due to the polymorphism of clinical symptoms unusual for childhood, which depends on the age of manifestation of the disease (muscle hypotonia, delayed psychomotor development, cataplexy, dysphagia, intellectual disability, ataxia, etc.). The only method of pathogenetic treatment of Niemann-Pick disease type C is substrate-reducing therapy with miglustat (Zaveska®). The effectiveness of the drug in improving neurological symptoms (spontaneous eye movement in the vertical plane, impaired swallowing function, impaired coordination of movements, etc.), stabilizing the disease or slowing its progression has been proven. Miglustat has a favorable safety profile. Early diagnosis of this orphan disease is fundamental to the effectiveness of therapeutic interventions.

Table 1. Prevalence of rare (orphan) lysosomal storage diseases [3]

Table 2. Molecular genetics of Niemann–Pick disease, type C

Table 3. Frequency of clinical manifestations of Niemann–Pick disease, type C [7]

Table 4. Recommended dose of Zavesca® for Niemann-Pick disease, type C, depending on body surface area

Table 5. Safety profile of Zavesca® [21]

Table 6. Symptomatic treatment of patients with Niemann–Pick disease, type C [11]

In recent years, attention to rare (orphan) diseases, and in particular to lysosomal diseases, has increased significantly. First of all, this is due to the revelation of the essence of many lysosomal diseases. An equally important stimulus to the study of lysosomal diseases was the discovery of the possibility of their pathogenetic treatment using enzyme replacement agents. An extensive group of lysosomal storage diseases, including 45 nosological forms, includes Niemann–Pick disease type C [1].

Definition, frequency and etiology of Niemann–Pick disease type C

Lysosomal storage diseases are characterized, as a rule, by early manifestation of the disease, progression of the course, severe damage to vital organs and systems of the body, leading to early disability and premature death, often starting from the neonatal period. Niemann-Pick disease type C is clearly distinguished from other forms of lysosomal diseases, including Niemann-Pick disease type A and type B, is an independent disease and belongs to the category of rare (orphan) diseases.

The incidence (incidence) of Niemann–Pick disease type C is 1:100,000–1:120,000 live births [2]. The estimated prevalence of Niemann–Pick disease type C is 0.85 per 100,000 population [3]. In reality, the prevalence is obviously higher, which may be due to the presence of unregistered cases, incorrect diagnosis, incomplete diagnosis, etc. The disease is pan-ethnic in nature and widespread everywhere. A high incidence of Niemann-Pick disease type C1 has been noted among some genetic isolates: the French colony of Acadia (Nova Scotia), Bedouin groups in Israel, Spanish settlements in Colorado and New Mexico, which is associated with the founder effect.

Among other lysosomal storage diseases, Niemann–Pick disease type C occupies a middle position in terms of prevalence. Comparative data on the prevalence of individual forms of lysosomal diseases are presented in table. 13].

In the Russian Federation, diagnosis of Niemann–Pick disease type C began in 2008. At the beginning of 2013, 11 patients were diagnosed, of which 2 were foreign citizens. Among the diagnosed patients there are 10 children from 3 to 18 years old and 1 adult (26 years old). Treatment has begun for 7 people. The predicted number of patients is more than 170 people.

Niemann-Pick disease type C is a progressive autosomal recessive hereditary neurodegenerative disease with hepatosplenomegaly associated with dysregulation of intracellular lipid trafficking [4]. It is characterized by an unfavorable prognosis in the absence of timely and adequate specific treatment (substrate-reducing therapy). The etiology of the disease is associated with mutations in the NPC1 gene (in 95% of cases) or in the NPC2 gene (about 5% of cases) - Niemann-Pick disease, types C1 and C2, respectively [5], which leads to disruption of intracellular lipid transport and accumulation of cholesterol and glycosphingolipids in the brain and other tissues (Table 2).

Both types of the disease are inherited in an autosomal recessive manner. The NPC1 gene is mapped on the long arm of chromosome 18, in the q11-q12 locus – 18q11-q12. The Niemann–Pick disease gene NPC2 is localized on chromosome 14, in the region of its long arm – q24.3 – 14q24.3 [5].

Pathogenesis

Niemann-Pick disease type C develops as a result of hereditary failure of intracellular (lysosomal) transport of lipids (cholesterol) and their esterification (impaired fat metabolism), which leads to the accumulation of free non-esterified cholesterol in the cells of various tissues, secondary accumulation of sphingomyelin and glycosphingolipids (sphingomyelin lipidosis) mainly in the brain with profound functional and structural changes in neurons, as well as Gm2- and Gm3-gangliosides [6]. In this disease, other organs (particularly the liver and spleen) are almost always involved.

Niemann–Pick disease type C is characterized by normal levels of the lysosomal enzyme sphingomyelinase.

Clinical picture and diagnosis

Most often (in 70% of all cases) the disease manifests itself between the ages of three and eight years. Less commonly, the onset of pathology can be observed between 10 and 15 years of life. Along with this, isolated cases of the onset of the disease in the neonatal period with jaundice and splenomegaly and in adults (55 years or more) have been described. As a rule, until the manifestation of the main clinical symptoms of the disease, the psychomotor development of patients remains normal.

Early typical signs of Niemann-Pick disease type C in preschool children are impaired coordination of movements, ataxia, tremor, dysarthria, and choreoathetosis. The onset of the disease at school age and in adults is usually manifested by disorders of cognitive activity with the subsequent formation of mental retardation. A decrease in intelligence is characteristic of all cases of the disease, but the degree of its severity may vary. The pathognomonic symptom of the disease is gaze paralysis when looking up and down. Quite often (about one third of patients) convulsive paroxysms develop, which are focal or generalized. Seizures are usually resistant to anticonvulsant therapy. A characteristic feature of types C1 and C2 is hepatosplenomegaly, which can manifest itself both at the onset of the disease and after the development of neurological symptoms. The frequency of clinical manifestations of the disease is shown in table. 3 [7].

The disease progresses steadily, ending in death, usually between 5 and 15 years of life. Variants with a later onset of the disease (during school years and in adults) are characterized by a significantly slower progressive course [8, 9, 10].

Types C1 and C2 are similar in their clinical manifestations.

The following clinical forms of the disease are distinguished [11, 12].

Neonatal form

manifests up to three months of age; often debuts with intrauterine fetal hydrops. In the newborn period, the main symptoms may be prolonged jaundice, hepatosplenomegaly, ascites, and muscle hypotension.

Early infantile form

manifests itself between the ages of 3 months and 2 years; characterized by hepatosplenomegaly, delayed psychomotor development, muscle hypotonia, and progressive cerebellar disorders (ataxia).

Late infantile form

manifests at 2–6 years of age. The main clinical manifestations are progressive ataxia, dysarthria, behavioral disorder, hepatosplenomegaly, intellectual disability, vertical gaze paresis, epilepsy, spasticity, cataplexy, dysphagia, dystonia. Fatal outcome – at the age of 7–12 years.

Youth (juvenile) form

manifests from 6 to 15 years; characterized by delayed psycho-speech development, behavioral disturbances, cerebellar (ataxia, intention tremor, dysarthria, changes in gait) and extrapyramidal (muscle hypotonia, various types of hyperkinesis) disorders, various types of epileptic seizures, and sometimes polyneuropathy. A specific symptom is vertical ophthalmoparesis.

Adult form

– onset of the disease over the age of 15 years, manifested by ataxia, dystonia, psychiatric symptoms, hepatosplenomegaly, dementia.

The disease is characterized by a wide range of clinical manifestations. The average age at diagnosis is 10.4 years, life expectancy is 16.2 years, and life expectancy is 38 years.

Therapeutic prospects increase the importance of timely diagnosis of Niemann-Pick disease type C, which should be based on the clinical alertness of neurologists, pediatricians, psychiatrists, therapists, geneticists and other specialists who may include patients with the disease in question [13].

For diagnosis, biochemical methods are used (accumulation of non-esterified cholesterol in lysosomes, Philipin staining to detect lipid accumulation), histological methods (foam cells in bone marrow and spleen biopsies, azure histiocytes in bone marrow biopsies, polymorphic bodies in the cytoplasm of skin, liver or brain cells ). Genetic methods (DNA diagnostics) are used to confirm the diagnosis, prenatal diagnosis, and identify homozygotes in proband families. To identify atrophic changes in brain structures, magnetic resonance imaging (MRI), computed tomography, and proton magnetic resonance spectroscopy are used.

Data from laboratory, functional and pathomorphological studies are also used. MRI of the brain diagnoses symmetrical atrophy of the cortex, cerebellum and hypoplasia of the corpus callosum. In biopsy samples of the liver, spleen, lymph nodes, bone marrow, tonsils, kidneys, lungs and smooth muscles, “foamy” cells with lipid PAS-positive inclusions are detected. Light microscopy reveals the deepest damage to the neurons of the globus pallidus, caudate nucleus and cranial nerves with the accumulation of PAS-positive lipids in them. Glia cells also record deposits of fats, cholesterol and lipids. Electron microscopy reveals concentric lamellar bodies in neurons, similar in structure to inclusions in Gm2 gangliosidoses.

Differential diagnosis, treatment and prevention

Niemann-Pick disease type C should be differentiated from other storage diseases: Gm1- and Gm2-gangliosidoses, mucopolysaccharidoses and Gaucher disease.

Obviously, for Niemann-Pick disease type C, etiotropic treatment (gene therapy) would have the greatest effect, but it has not yet been developed.

Pathogenetic therapy

Due to little knowledge of the pathogenesis of the disease, pathogenetic methods of therapy for Niemann–Pick disease type C began to be developed relatively recently. Knowledge of the mechanisms of damage to the nervous system, in particular the assessment of the number of viable neurons in the central nervous system (CNS), is extremely important for the success of therapeutic interventions. This is the basis of targeted therapy used in the treatment of hereditary neurodegenerative diseases, one of the representatives of which is Niemann-Pick disease type C.

Clinical studies have examined the effectiveness of using cholesterol-lowering agents (lowering intracellular cholesterol levels) or restricting cholesterol intake. Despite the fact that such therapy caused a decrease in cholesterol levels in the liver and plasma, no improvement in neurological manifestations was noted [14, 15]. Attempts were made to transplant bone marrow or liver, which partially normalized the accumulation of cholesterol and sphingomyelin in tissues. However, these methods were ineffective in treating neurological symptoms in patients with mutations in the NPC1 gene [16].

Because Niemann–Pick disease type C is usually diagnosed late, patients have already damaged or lost a significant portion of their central nervous system neurons. In this case, the goal of therapy is to preserve viable neurons, stabilize the disease and reduce the rate of progression of the pathological process. The severity of damage to the nervous system varies among patients, so the choice of therapy should be individualized [17].

Difficulties in treating Niemann–Pick disease type C still persist. This is primarily due to the lack of knowledge of the pathogenetic mechanisms of the disease, late diagnosis and the paucity of scientific research in this direction. The situation began to change after the creation of a new generation drug - miglustat (Zaveska®) and the development of a new direction in the treatment of lysosomal diseases - substrate-reducing therapy.

Establishment of the molecular genetic nature of Niemann-Pick disease type C, the nature of biochemical disorders, identification of mutant genes and their chromosomal localization made it possible to develop new approaches to the treatment of this lysosomal disease associated with the use of agents that prevent the formation of initial products (substances) that are precursors accumulated substrates. In Niemann–Pick disease type C, it was possible to reduce the formation of glycosphingolipids as initial accumulation products by suppressing the enzyme glycosylceramide synthase (the first enzyme in the synthesis of most glycolipids) using a specific drug, miglustat. Accordingly, a decrease in the synthesis of the initial biochemical metabolic products (glycosphingolipids) leads to a decrease in their accumulation in the organs and tissues of the body. Substrate-reducing therapy can be called a new direction of pathogenetic treatment, since it is aimed at interrupting the initial pathogenetic link of the disease.

Miglustat (international nonproprietary name (INN) - miglustat; trade name - Zaveska) was developed and introduced for the treatment of patients with Niemann-Pick disease type C by Actelion (Switzerland). According to the chemical structure, miglustat is N-butyldeoxynojirimycin (NB-DNJ) and belongs to iminosugars. The most important property of miglustat, which is an inhibitor of glycososphingolipid synthesis, is its ability to penetrate the blood-brain barrier [18]. Miglustat, along with inhibiting glycosylceramide synthase, the initial enzyme in the formation of glycosphingolipids, also inhibits sucrose-isomaltase and other disaccharidases in the small intestine, which underlies the gastrointestinal side effects of miglustat. Under the influence of miglustat, the accumulation of toxic metabolites (gangliosides GM2 and GM3, lactosylceramide and glycosylceramide) and their neurotoxic effect are prevented. However, miglustat does not inhibit the synthesis of sphingomyelin and galactosylceramide (the main component of myelin), nor does it cause ceramide accumulation [11].

Zavesca® (miglustat) was approved by the US Food and Drug Administration (FDA) as the first drug treatment for Niemann-Pick disease type C and was subsequently approved in Europe (January 2009). .). For use in the Russian Federation, Zaveska® was registered in November 2009 (registration number: LSR-008892/09). The drug is available in capsule form (1 capsule contains 100 mg) for oral administration.

In the United States, miglustat was given orphan drug status in 2008.

To date, Zavesca® is the first and only drug registered for the treatment of Niemann-Pick disease type C. Given the mechanisms of action of miglustat, it is also used in Gaucher disease as a substrate-reducing therapy.

In connection with the advent of a drug for the pathogenetic treatment of Niemann-Pick disease type C, two acute problems have arisen: 1) the need for early diagnosis of the disease, 2) the prescription of treatment as early as possible. So far, unfortunately, the developed drug is recommended for use in children with Niemann-Pick disease type C starting from the age of four. It is clear that a positive decision on the use of miglustat in young children is not only a matter of time, but also of early diagnosis of the disease, as well as the recruitment of the necessary cohort of patients and the conduct of appropriate clinical trials.

Indications for use of the drug Zaveska® are:

• treatment of progressive neurological symptoms in adults and children with Niemann–Pick disease type C, which may slow progression of the disease;
• oral therapy for mild to moderate Gaucher disease type I, including those who are intolerant or unable to use enzyme replacement therapy in adults [19].

For Niemann-Pick disease type C, the recommended dose of Zaveska® for adults and children over 12 years of age is 200 mg 3 times a day; for children from 4 to 11 years of age, the dose is prescribed based on body surface area (see instructions for the drug, Table 4 ).

The effectiveness and safety of miglustat (Zavesca®) have been demonstrated in a number of studies. An evaluation of the results of a multicenter study involving 66 patients with Niemann–Pick disease type C showed that the majority of patients experienced stabilization or improvement of their condition after treatment with miglustat [19]. At the same time, the rate of decrease in the total index on the modified disability scale decreased significantly, and in 75% of patients the effect of the therapy was rated as “good.” It is important to emphasize that in patients with Niemann–Pick disease type C, miglustat therapy has a positive effect on neurological disorders. In addition, when using the drug Zaveska®, there is a slowdown in the progression of the disease. In a study by MC Patterson et al. During therapy with Zavesca®, in the majority of patients of all age groups, the condition either improved or stabilized in at least 3 of 4 parameters (ataxia, dystonia, dysarthria, dysphagia) [20].

The drug is characterized by a favorable safety profile and good tolerability in both children and adults (Table 5) [21]. As shown in the study by M. Pineda et al., in which the average time of use of Zavesca® in 67 patients was 533 days, 45% of patients experienced at least one adverse reaction [21].

There are data on the effectiveness of treatment with miglustat in patients aged from 7 months to 44 years (mean age 14.68 ± 10.84 years) with Niemann-Pick disease types C1 and C2 [14]. During therapy with Zaveska®, patients with mutations in the NPC1 gene showed an improvement in swallowing function (water, puree, paste, biscuit) (according to video monitoring using videofluoroscopy (videofluoroscopic swallowing study, VFSS) - in 85% of patients; stabilization - in 81 %; improvement in the parameter “dystonia” – in 80%, “dysmetria” – in 74%, “dysarthria” – in 63%; increase in DQ from 45 to 65 units (after 24 months of treatment with miglustat). After 36 months of treatment with miglustat improvement or stabilization of symptoms was observed in 22 patients with mutations in the NPC2 gene. Thus, improvement in the parameter “spontaneous eye movements in the vertical plane" was noted in 7 patients during Zaveska therapy and in 1 patient who did not receive miglustat; no change was recorded in 8 and in 1 patient; deterioration in 2 and 3, respectively. Improvement in the oculomotor sphere was also noted in the study by M. Pineda et al.: after 12 months of using the drug Zaveska®, an improvement or stabilization of the symptom “spontaneous vertical eye movements” was shown in patients 12 years and older [21].

According to D. Bruschini et al., the use of miglustat for 2 years in 4 patients aged 11 months, 9, 10 and 12 years (3 with a mutation in the NPC1 gene and 1 with a mutation in the NPC2 gene) contributed to the normalization of swallowing function in all patients [18].

Symptomatic therapy

Along with pathogenetic treatment, symptomatic therapy is also of great importance for Niemann-Pick disease type C. Its main directions are shown in table. 6. [11].

Symptomatic drugs, although they have wide variability in their action, can be very useful in improving the condition of patients and improving their quality of life.

Particular attention should be paid to the nutrition of patients and systematically assess the ability to swallow food (there are special scales for assessing swallowing - swallowing liquid food, semi-liquid, thick, etc.). During treatment, a diet low in cholesterol and the use of drugs that reduce its level in the blood serum are recommended. If the swallowing function is significantly impaired, patients are recommended to have tube feeding or a gastrostomy tube, which makes it possible to provide patients with the necessary amount of nutrients, sufficient fluid and calories.

To correct the function of salivation in patients, atropine drops in small doses can be used.

Dysphagia is often complicated by secondary lung damage. In these situations, antibiotics may be prescribed to prevent pneumonia.

If gastrointestinal disorders develop, most often diarrhea, antidiarrheal drugs and a special diet are recommended. However, diarrhea may be a consequence of miglustat use. In these cases, to eliminate side effects during miglustat therapy and the development of diarrhea syndrome, it is recommended to review the diet and reduce the intake of lactose-containing products or intake of other carbohydrates. Separating miglustat intake from food may have a positive effect. In some cases, it is possible to prescribe antidiarrheal drugs such as loperamide or discontinue the drug Zaveska® for a short time.

To resolve emerging issues, consultations with relevant specialists (gastroenterologist, neurologist, psychiatrist, etc.) may be required.

In general, increasing the effectiveness of treatment for patients with Niemann–Pick disease type C is possible by following a number of fundamental principles:

• accurate diagnostics (institutions, methods, regional and federal registers, etc.);
• qualified medical opinions (consultant, regional council, federal council, etc.);
• developed and approved treatment standards (financial and economic calculations, financing, etc.);
• developed and approved clinical guidelines (international, federal, etc.);
• effective interaction in the provision of medical care (children - adults, institutions, doctors, approved documentation);
• advisory assistance during the treatment process (institutions, experts);
• timely replenishment of the list of vital and essential drugs (inclusion of drugs, orphan drugs, etc.).

The prognosis of the disease is significantly improved with the use of miglustat (Zaveska®).

Prevention

Prevention is based on data from medical genetic counseling. The medical genetic risk for the proband's siblings is 25%. If the genotype of the proband and the types of mutations in carriers are established, prenatal diagnosis of Niemann-Pick disease types C1 and C2 is possible. The diagnosis can be established at 10–12 weeks of pregnancy with a molecular genetic study of chorionic villus biopsy. In some cases, the study of sphingomyelinase activity in amniocytes and chorionic villus biopsies using biochemical methods can provide some assistance, but such an analysis requires a cell culture.

Treatment of Pick's disease

There is currently no specific therapy for Pick's disease. Its development is being carried out by leading medical centers, but has not yet led to guaranteed success. In order to alleviate the health condition of patients, supportive therapy is used.

The basis of the course are:

• galantamine, donepezil, choline alfoscerate and other anticholinesterase pharmaceuticals;
• in case of aggressive behavior of the patient, antipsychotics are prescribed
• nootropics, such as piracetam, gamma-aminobutyric acids, memantine.

Psychotherapy can play a major role in the early stages of the disease. Classes with a psychologist allow the patient to accept the fact of the onset of an incurable pathology. Understanding the problem can help a patient with initial brain damage to control his behavior.

Sessions with a psychologist are also recommended for the patient’s relatives. They allow you to adjust your behavior towards a sick close relative. At the third stage, constant supervision by a specialist is recommended. This allows timely changes to be made to the course of maintenance therapy. The use of effective techniques even during the transition to a vegetative state makes the patient’s situation easier.

In the early stages of the disease, physiotherapy and walking are recommended. Such measures help maintain the patient’s motor activity and reduce the rate of muscle atrophy. Presence training, sensory room, and art therapy are used.

Treatment of Niemann-Pick pathology

There is no specific treatment for Niemann-Pick pathology. Therapy is aimed at stopping the progression of the pathology and improving the patient’s quality of life.

Niemann-Pick disease is incurable and symptomatic therapy is carried out with such groups of drugs.

• A group of anticonvulsant medications - the drug Depakine;
• To correct salivation - the drug Atropine (drops in the mouth);
• Antidepressants for mental disorders - Prozac, Zoloft;
• The drug Valproate for psychosis;
• Anti-diarrhea drugs - Loperamide;
• For infections in the respiratory tract - antibacterial drugs;
• Bronchodilator medications - Berodual;
• Anticholinergic medications for hand tremors - the drug Cyclodol, the drug Parkopan.

In modern medical practice, to prevent the accumulation of sphingomyelin fat, the drug Miglustat is used.

This medication blocks the synthesis of glycosphingolipid molecules, which are precursors to sphingomyelin fat molecules.

This medication is used for treatment 1 - 2 times a day and the dosage depends on the patient’s age and the degree of damage - from 100.0 milligrams to 200.0 milligrams.

The medication Miglustat prevents nerve cells from destruction and protects a person from neurological pathologies.

Positive dynamics in the treatment of Niemann-Pick disease with the drug Miglustat, after taking from 6 months to 12 months. Also, during drug treatment, a diet is prescribed for the patient.

Positive dynamics in the treatment of Niemann-Pick disease with Miglustat

Possible complications and consequences

Pick's disease is an incurable disease. With the best care and the right type of therapy, it will not be possible to stop its development. You can only correct the patient’s well-being.

In the early stages, patients primarily experience moral complications. The problem becomes the inevitability of awareness of the onset of a vegetative state. Against this background, a significant proportion of patients experience depression.

As Pick's disease progresses, patients lose contact with the outside world. The state of health gradually deteriorates due to the appearance of stagnation in muscle tissue. To eliminate unpleasant manifestations, massages are recommended. Blood flow to the skin reduces the risk of bedsores. Without proper care, patients with Pick's disease rapidly develop congestive pneumonia and ascending pyelonephritis.

To eliminate the risk of further deterioration in health, patients require constant medical supervision. Prescription of additional medications to relieve manifestations of concomitant diseases.

The list of complications of this serious disease:

• the patient’s transition to the stage of deep insanity, excluding the manifestation of cognitive functions;
• complete immobility sets in, caused by the patient's inability to understand that he simply must do something.

An incurable disease leads to death in a short time. The task of relatives and friends is to alleviate the condition of an incurable patient.

Diagnostics

No special methods have yet been developed to combat this disease.

When the first signs of the disease appear or the child lags behind in physical and mental development, it is necessary to urgently consult a doctor. If a genetic pathology is suspected, the geneticist will prescribe the following tests:

• genetic testing,
• biopsy of the lymph node, liver and spleen,
• fundus analysis,
• skin biopsy
• bone marrow puncture,
• laboratory blood diagnostics.

Prognosis and prevention

From the moment of the onset of the disease in an adult patient, the period of development of the disease to a thermal state and death lasts from 2 to 10 years. The speed of development has not been precisely determined by doctors. Improvements in the condition are observed in patients receiving constant supportive medication, physiotherapeutic and psychological care.

There are currently no specific measures to prevent the occurrence of complex brain pathology leading to profound dementia and death. Maintaining a healthy lifestyle becomes an important condition for maintaining health. The development of any form of dementia is additionally provoked by the use of alcohol and psychotropic drugs. People whose family has been diagnosed with senile dementia, specifically Pick's disease, are recommended to undergo preventive examinations. To identify disorders in the cerebral cortex, CT and MRI are recommended. These early studies will allow us to determine the risk of disease onset and develop the appropriate type of effective therapy.

When a case of illness is identified, it is recommended to consider the procedure for future care of a sick relative. In this situation, it is not advisable to spend money on inviting doctors who are ready to recommend experimental courses and techniques. Pick's disease today continues to be included in the list of incurable diagnoses. For the purpose of prevention in the early stages, the patient or his relatives can take care of creating comfortable conditions for the patient, which will be required at the moment when he has already lost the ability to move independently. First of all, this relates to preliminary consideration of types of care.

Causes and pathogenesis

In the pathogenesis of Niemann-Pick disease, the leading role belongs to mutations in genes that are passed on to subsequent generations. The type of inheritance of Niemann-Pick disease is autosomal recessive. Due to dysfunction of lipid transport, lipid metabolism is disrupted. As a result, free cholesterol accumulates in tissues. Secondary accumulation of sphingomyelin in the brain substance provokes irreversible damage to neurons, which leads to structural and functional changes in nerve cells.