Difficulty in diagnosing and treating anti-NMDA receptor encephalitis

4 (80%) Votes: 1

Delayed diagnosis and use of immunosuppressants in anti-NMDA receptor encephalitis (anti-receptor encephalitis) is associated with the development of a severe clinical syndrome, leading to the development of hypoventilation or status epilepticus. Such cases are often treated for a very long time in an intensive care unit.

These patients are usually considered to have a primary psychiatric disorder (eg, acute psychosis associated with schizophrenia or bipolar disorder) and are prescribed antipsychotics, which often cause motor disturbances such as muscle rigidity or akathisia. The latter can complicate the clinical picture, since pathological motor phenomena are also associated with catatonia, a characteristic manifestation of this type of encephalitis.

Another problem is the situation when the patient is given antipsychotics at a late stage of the disease. The combination of muscle rigidity, elevated serum muscle enzymes (particularly CPK), rhabdomyolysis, and autonomic failure are specific to this disorder even in the absence of antipsychotics. If the latter are prescribed, the clinical picture begins to resemble a malignant neuroleptic syndrome.

In addition, the presence of agitation, emotional lability, impulsivity, hallucinations, insomnia, and self-destructive behavior is grounds for psychiatric consultation. Because these patients are often unable to follow instructions and swallow, medications may be considered intravenously, intramuscularly, or via a nasogastric tube. Dopamine receptor antagonists have been prescribed to control aggression, arousal, and hallucinations without significant improvement; in fact, they may complicate an already severe clinical picture. Strong D 2 receptor antagonists (eg, haloperidol) should be used with extreme caution because these agents exacerbate movement disorders. Some psychiatrists prefer low-potency atypical antipsychotics (eg, quetiapine) to evening low doses to control insomnia and agitation. In these patients, several different classes of drugs were empirically used - mood stabilizers for emotional lability, benzodiazepines and other hypnotics, as well as antihistamine intermediaries (for example, diphenhydramine) for insomnia, and psychostimulants for hyperactivity and impulsivity.

If catatonia develops, intravenous benzodiazepines are given at regular intervals (eg, lorazepam 2 mg every 6 hours). To achieve clinical improvement, the daily dose of this drug should reach 20-30 mg. Some child psychiatrists have successfully used amantadine to treat the catatonic symptoms of this encephalitis. The therapeutic team pays special attention to malignant catatonia, in which patients become unresponsive to benzodiazepines. This condition is characterized by sudden onset of unresponsiveness, lack of speech, psychomotor changes, fever, and dysautonomia. The latter often ends in death. Malignant catatonia is sometimes difficult to differentiate from neuroleptic malignant syndrome because both disorders are accompanied by hyperthermia and muscle rigidity. However, muscle rigidity in catatonia is more characterized by dystonic posture, waxy flexibility, and stereotypical serial movements. Electroconvulsive therapy (ECT) remains the gold standard for the treatment of this complication, as supported by several studies. Previous reports suggest that 7-8 ECT sessions over 2-4 weeks induce remission of the catatonic symptoms of encephalitis. In a small number of patients with progressive movement disorders and impaired levels of consciousness who do not respond to first-line treatment, ECT remains adjuvant therapy. In animal models, it has been shown to upregulate NMDA receptors, explaining the therapeutic efficacy in patients with both this encephalitis and schizophrenia. However, only a direct effect on the autoimmune process is important for the optimal treatment of the clinical manifestations of the disease, including psychiatric ones.

The rapid development of psychiatric symptoms, seizures, cognitive impairment and movement disorders in female patients without fever alerts the physician to a possible encephalitic process. Anti-NMDA receptor encephalitis is the second most common form of autoimmune encephalitis and is now considered in the differential diagnosis of any patient with an altered mental state. After the diagnosis is established, they try to quickly perform a screening for a possible tumor process and start immunosuppressive therapy. Against the background of rapid, aggressive and long-term use of the latter, most patients report a long-term remission and achieve a level of daily functioning close to premorbid.

In the medical literature, encephalitis is understood as a whole group of diseases manifested by inflammatory processes in the brain. The disease is characterized by severe symptoms and can have a variety of causes, such as an autoimmune process that causes anti-receptor encephalitis, or the presence of certain bacteria and viruses. of the brain require immediate qualified treatment, otherwise the risk of irreversible consequences or death is too high. In this article, we will consider anti-receptor encephalitis.

What is encephalitis?

Encephalitis causes various pathological disorders in the body and leads to the formation of dementia (dementia). The disease can affect not only the brain, but also part of the internal organs and joints.

Pathological conditions can be caused by a number of reasons. According to the factors provoking the disease, there are the following types encephalitis:

• inflammation caused by infection;
• bacterial or fungal encephalitis;
• a disease caused by exposure to a toxic substance;
• autoimmune encephalitis.

The disease affects different parts of the brain. Inflammation can be localized in its cortex, subcortex or cerebellum. Each type is distinguished by its own signs, symptoms, and treatments.

What is anti-receptor encephalitis? More on this later.

Infectious and bacterial inflammation

The factors that cause infectious encephalitis are viruses and bacteria. For example, the herpes virus, HIV infection, tuberculosis bacteria, streptococcus and staphylococcus aureus, toxoplasma. In addition, tick-borne encephalitis is a serious problem. This is a viral disease, the carrier of which are some types of ticks. The virus enters the body after an insect bite.

However, with tick-borne encephalitis, the brain is not always affected, in 50% of cases the patient experiences only fever. The disease also belongs to viral species. The disease is very dangerous and in most cases ends in death. This type of encephalitis is characterized by a rapid course, a few days after infection, the patient falls into a coma. Herpes encephalitis is fatal in nine out of ten cases, it is almost impossible to treat.

How does anti-receptor encephalitis manifest itself? Let's tell in more detail.

Autoimmune diseases

There is also a group of encephalitis that are caused in the body. In this case, the patient's own immune cells begin to attack the brain. Diseases of this nature are extremely difficult to treat, cause dementia, lead to impaired brain activity and the work of the peripheral nervous system. In addition to dementia, the disease is accompanied by paralysis and epileptic-like seizures. Such diseases include, for example, limbic encephalitis. The disease causes an autoimmune response of the body to the presence of cancer cells or a disease that is infectious or viral in nature. The rate of development of limbic encephalitis divides the disease into acute and subacute forms. The causes of anti-receptor encephalitis are discussed below.

Acute Syndrome

In acute syndrome, the development of the disease occurs rapidly over three to five days. If you do not take urgent measures, then death occurs very quickly. In the subacute course of the disease, the first signs become noticeable after a few weeks from the initial moment of the development of the pathology. These conditions are characterized by the following symptoms:

• memory impairment;
• cognitive disorders;
• epileptic seizures;
• (high level of anxiety, depression, agitation);
• behavioral disorders.

In addition, clear signs are: progressive dementia, sleep disturbances, epileptic seizures with hallucinations. It is not uncommon for autoimmune brain damage to be correlated with the presence of cancer. As a rule, such encephalitis is caused by lung cancer.

Anti-NMDA receptor encephalitis

This is an autoimmune disease that affects young women more. In males, the pathology is extremely rare. The features of this type of encephalitis include the presence of severe symptoms, which are expressed in serious psychoneurotic changes. That is why these patients are often diagnosed with schizophrenia instead of encephalitis. Women who were diagnosed with this pathology suffered from mental disorders (lack of coherent speech, impaired consciousness).

In addition, a characteristic symptom of anti-receptor encephalitis is impaired short-term memory and muscle function. For example, many patients noted causeless contraction of the abdominal muscles, as well as convulsive movements of the legs or arms.

Approximately half of the examined patients had ovarian cancer. However, there are cases when the patient does not have oncology. Moreover, there have been cases of diagnosis of anti-receptor encephalitis in children who do not suffer from such diseases. They spontaneously appear and begin to actively develop antibodies associated with certain brain structures, which are called NMDA receptors. Antibodies are fixed and block receptors, which in turn causes mental disorders, movement disorders and epileptic seizures. All this indicates that in many cases doctors cannot determine the exact cause of the disease. It should be noted that this disease, in principle, was able to identify and learned to diagnose no more than ten years ago. The symptoms and treatment of anti-receptor encephalitis are interrelated.

Diagnostics

An experienced doctor, who is not the first time faced with such pathologies, will have suspicions even at the stage of examining the patient. Additional studies are needed to make an accurate diagnosis. As a rule, the appointment of magnetic resonance imaging is completely justified here. MRI will confirm or refute suspicions of inflammatory processes in the brain, but it will not help to identify the cause of the disease.

In autoimmune diseases, including suspected anti-receptor encephalitis (we examined the causes of the disease), an analysis is made of the presence of antibodies to the NMDA receptor. In some situations, an analysis of cerebrospinal fluid and a biopsy of the brain are prescribed. A biopsy is prescribed only as a last resort, when other methods for identifying the cause of the disease are not informative. In this case, you can not do without consulting an oncologist.

Possible Complications

Autoimmune diseases are difficult to diagnose, therefore, in the absence of proper experience from a doctor, a patient may end up in a psychiatric clinic due to an incorrect diagnosis. The lack of necessary treatment leads to psychiatric abnormalities, which are often irreversible. In addition, there is a high probability that the patient may fall into a coma. If the patient does not take the medicines necessary for treatment, a vegetative state develops very quickly, and in a third of patients

Treatment of anti-receptor encephalitis

To make a correct diagnosis, first of all, the patient is referred for examination and consultation with a neurologist. The disease is diagnosed when certain antibodies are present in the blood. An examination by an oncologist is also required to rule out a misdiagnosis. With timely treatment and properly built oncological treatment, in most cases it is possible to achieve stable and long-term remission. Also, good results are achieved in the treatment of immunomodulators. But this type of treatment is available only if the suspicions of oncology turned out to be groundless.

To reduce psychiatric symptoms, patients are prescribed drugs with a sedative effect. They calm and normalize sleep. With the appearance and repeated repetition of seizures, antispasmodic drugs are prescribed. Removal of acute inflammation is achieved with the help of corticosteroids. They are administered intramuscularly, and the duration of the course of treatment is prescribed by the doctor.

Anti-prescription encephalitis is almost impossible to cure completely. Treatment helps stop further progression of the disease and eliminates the development of neurological disorders. If the disease was caused by oncology, then the elimination of the tumor gives a completely stable result, and 70% of patients recover completely. How can anti-receptor encephalitis of the brain be prevented?

Prevention

From childhood, we know that you need to go to the forest in closed clothing, which prevents ticks from getting on exposed skin. Such measures help in the prevention of viral and bacterial encephalitis. It is also important to contact medical institutions in a timely manner and follow the instructions of doctors. As for brain diseases of an autoimmune nature, including anti-prescription encephalitis, the development of such pathologies cannot be prevented.

Conclusion

According to available data, almost half of patients suffering from anti-receptor encephalitis recover completely. A third of patients have mild residual effects, and a small proportion of patients suffer from serious complications. About 10% of patients died.

Therefore, it must be emphasized once again that if a tumor is detected at an early stage and removed, the functions of the body are restored in full, that is, recovery occurs. All this allows us to conclude that it is necessary to consult a doctor at the first symptoms of the disease in order to increase the chance of a successful outcome.

The famous German philosopher Arthur Schopenhauer claimed that nine-tenths of our happiness depends on health. Without health, there is no happiness! Only complete physical and mental well-being determines human health, helps us successfully cope with illnesses, adversities, lead an active social life, reproduce offspring, and achieve our goals. Human health is the key to a happy and fulfilling life. Only a person who is healthy in all respects can be truly happy and capable ofto fully experience the fullness and diversity of life, to experience the joy of communicating with the world.

They talk about cholesterol so unflatteringly that it is just right for them to scare children. Do not think that this is a poison that only does what destroys the body. Of course, it can be harmful, and even dangerous to health. However, in some cases, cholesterol is extremely necessary for our body.

The legendary asterisk balm appeared in Soviet pharmacies in the 70s of the last century. It was in many ways an indispensable, effective and affordable drug. "Asterisk" They tried to treat everything in the world: both acute respiratory infections, and insect bites, and pains of various origins.

Language is an important human organ that can not only chat incessantly, but without saying anything, can tell a lot. And there is something to tell him, especially about health.Despite its small size, the tongue performs a number of vital functions.

Over the past few decades, the prevalence of allergic diseases (AD) has received the status of an epidemic. According to the latest data, more than 600 million people worldwide suffer from allergic rhinitis (AR), approximately 25% of them in Europe.

For many people, there is an equal sign between a bath and a sauna. And a very small number of those who are aware that there is a difference can clearly explain what this difference is. Having considered this issue in more detail, we can say that there is a significant difference between these pairs.

Late autumn, early spring, periods of thaw in the winter - this is a period of frequent colds, both adults and children. From year to year the situation repeats itself: one member of the family falls ill and after him, as in a chain, everyone suffers a respiratory viral infection.

Salu odes can be read in some popular medical weeklies. It turns out that it has the same properties as olive oil, and therefore you can use it without any reservations. At the same time, many argue that it is possible to help the body "purify itself" only by fasting.

In the 21st century, thanks to vaccination, the prevalence infectious diseases. According to the WHO, vaccination prevents two to three million deaths a year! But, despite the obvious benefits, immunization is shrouded in many myths that are actively discussed in the media, and in general in society.

Interest in paraneoplastic neurological syndromes in the late 80s. the last century entered the Renaissance. This was largely due to the work of J. Dalmau et al., who improved the technology for detecting antineuronal antibodies and subsequently applied them to study a number of neurological syndromes of unclear etiology. In the middle of this decade, this group of researchers isolated a disease called encephalitis with antibodies to N-methyl-D-aspartate (NMDA) receptors, the development of which is associated with the production of antibodies to NR1 / NR2 heteromers of NMDA receptors. For the first time the disease was diagnosed in young women suffering from ovarian teratoma. Prior to the discovery of the etiological role of antibodies to NMDA receptors, it was called paraneoplastic encephalitis associated with ovarian teratoma. According to Japanese researchers T. Iizuka et al. (2005, 2008), the clinical picture of encephalitis with antibodies to NMDA receptors has a complete phenotypic correspondence with previously described encephalitis of unknown etiology, which was given various names: acute diffuse lymphocytic meningoencephalitis, acute reversible limbic encephalitis, acute juvenile nonherpetic encephalitis affecting women, acute juvenile encephalitis.

NMDA receptors are ligand-gated cation channels. Activation of NMDA receptors plays a key role in synaptic plasticity, which are composed of NMDAR1 (NR1) and NMDAR2 (NR2) subunits. Glycine binds NR1 subunits, and glutamate binds NR2 (A, B, C or D), they combine with each other to form various receptor subtypes with distinctive pharmacological properties, localization and the ability to interact with intracellular messengers. It is assumed that the hyperactivity of NMDA receptors, which causes excitotoxicity, is essential in the mechanisms of development of epilepsy, dementia, the pathogenesis of stroke, and other conditions, while their low activity is associated with the formation of schizophrenia.

Clinical picture

The description of the clinical manifestations of encephalitis with antibodies to NMDA receptors, given below, is based on studies of patients with a well-established etiology of the disease. The average age of onset of the disease is 23-25 ​​years. The disease occurs frequently in women, in men only isolated cases have been described. T. Iizuka et al. (2008) identified several phases (stages) in the development of this encephalitis: prodromal, psychotic, areactive, hyperkinetic, and a phase of gradual regression of symptoms.

Patients in the prodromal phase of the disease suffer from non-specific SARS-like symptoms (fever, fatigue, headache). This phase of the development of the disease lasts an average of about five days.

The transition to the next, psychotic, phase marks the appearance of psychopathological symptoms. Obligate emotional disturbances (apathy, insufficiency of emotions, depression, withdrawal into oneself, fear), cognitive decline (disorders of short-term memory, difficulties in using the telephone, other electronic means), severe schizophrenia-like symptoms, including disorganization of thinking, compulsive ideas, delirium, visual and auditory hallucinations, reduced criticism of one's condition.

Amnestic disorders in the initial stage of the disease are not expressed and occur in less than a quarter of patients. Behavioral disorders are often a reason for relatives to seek psychiatric help, which leads to the establishment of a "psychiatric" diagnosis at the initial stages of observation.

Two weeks after psychotic symptoms, the areactive phase of the disease occurs. Most patients (more than 70%) have seizures before this. According to J. Dalmau et al. (2008), generalized tonic-clonic seizures predominate, less often - complex partial and other types of seizures. The areactive phase is characterized by a disturbance of consciousness resembling a catatonic state, mutism, akinesia, lack of response to verbal commands with open eyes. In several patients, a violent grimace resembling a smile was noted. Often develop athetoid movements and dystonic postures, echopractical phenomena, cataleptic symptoms.

Stem reflexes are not affected in this phase of the disease, however, spontaneous eye movement is impaired in patients, including in response to a visual threat. Some paradoxical phenomena (lack of response to painful stimuli in the presence of resistance to passive opening of the eyes) resemble a psychogenic reaction or simulation. At the same time, slow d-wave activity on the electroencephalogram (EEG) does not correspond to the changes observed in them.

The hyperkinetic phase is accompanied by gradually developing hyperkinesis. So, its most characteristic manifestations (Fig. 1) include orolingual dyskinesias (lip licking, chewing), athetoid dyskinetic postures of the fingers, these hyperkinesias are not associated with the use of antipsychotics. With the aggravation of the hyperkinetic syndrome, fanciful orofacial and limb dyskinesias appear, such as prolonged movements of the lower jaw, strong clenching of the teeth, dystonia of opening the mouth, intermittent forced abduction or reduction of the eyeballs, hand movements resembling dance. These dyskinesias vary in patients in terms of speed, localization, motor pattern, often resembling psychogenic motor disorders. At this stage of the disease, symptoms of autonomic instability develop, including arterial pressure lability, bradycardia or tachycardia, hyperthermia, and sweating. Hypoventilation is a particular danger.

The regression of symptoms is primarily concerned with the improvement of hyperkinetic disturbances. Their regression usually occurs within two months of the disease, however, cases are described when hyperkinesis persists for more than six months and is resistant to many therapeutic effects. Usually, in parallel with extrapyramidal disorders, the neuropsychiatric status also improves. The recovery period is characterized by the presence of a persistent amnestic syndrome.

Examination methods

According to reports with a small number of patient observations, the prevailing number of patients did not observe changes during magnetic resonance imaging (MRI) in standard modes, diffusely weighted and FLAIR mode. There were also no changes in image enhancement with gadolinium injection. In single observations, foci of increased signal intensity were detected in the medial areas of the temporal lobes during MRI in the FLAIR mode (Fig. 2). Some patients at the stage of convalescence developed frontotemporal atrophy.

Sequential development of orolingual dyskinesia and athetoid dystonic posture (A), followed by violent movements, including clenching of the jaws (B), unfriendly deviation of the eyeballs (hidden by a black stripe), rhythmic contractions of the upper limbs, synchronized with orofacial dyskinesia (B), non-rhythmic fidgeting of the hands ( C) and strong opening of the mouth (D).
Rice. 1. Video monitoring of hyperkinesis in a patient with anti-NMDA receptor encephalitis (according to T. Iizuka et al.)

In a study of 100 patients with encephalitis and anti-NMDA receptor antibodies, 55 of them showed foci of signal changes in the FLAIR and T2 modes, weak or transient signal enhancement from the cerebral cortex, the surrounding meningeal membrane, or the basal ganglia. These changes were limited to single foci, most often (n = 16) they were localized in the medial parts of the temporal lobe, less often in the corpus callosum (n = 2) and brainstem (n = 1). Follow-up studies, including 70 patients with complete regression of symptoms or minimal symptoms, demonstrated a significant improvement and normalization of the MRI picture.

In a number of observations, individuals with encephalitis with antibodies to NMDA receptors underwent positron emission tomography with fluorodeoxyglucose (SPECT and FDG-PET) of the brain. During SPECT, most patients in the acute stage of the disease did not reveal significant focal changes. In one patient, hypoperfusion was recorded in the frontotemporal region in the early recovery stage and prefrontal hypoperfusion in the recovery stage. In another observation, hypoperfusion of the right lower frontal and temporal cortex was observed at the convalescence stage. In one patient, according to FDG-PET data, symmetrical accumulation of the tracer in the primary motor, premotor, and additional motor areas was noted in the absence of its accumulation in the basal ganglia. The study was performed at the time of maximum severity of orofacial dyskinesia in a patient. During the re-examination of the same patient in the recovery stage, the accumulation of the tracer in these areas did not occur.

EEG monitoring studies during the areactive and hyperkinetic phases of the disease revealed diffuse or predominantly frontotemporal d- and q-activity without paroxysmal changes. In one of the patients, slow-wave activity was replaced by drug-induced fast-wave activity after an increase in the dose of anesthetic.

In the traditional study of cerebrospinal fluid (CSF), nonspecific changes were found in almost all (95%) patients, the most characteristic of which are minor lymphocytic pleocytosis (up to 480 cells per 1 ml), an increase in protein concentration (49-213 mg / dl) and increased content of immunoglobulins G.

A specific test for establishing the diagnosis of the disease is the determination of the titer of antibodies to NMDA receptors in CSF and serum. The study was carried out by ELISA using a lysate of human embryonic kidney cells (HEK293) expressing NR1 or NR1/NR2B NMDA receptor heteromers. It was shown that the level of antibodies in the cerebrospinal fluid (CSF) is higher than their content in serum, which indicates intrathecal antibody synthesis. It should also be noted that patients who died from neurological complications of encephalitis had the highest concentration of antibodies to NMDA receptors in the CSF. Patients with mild neurological disorders, in contrast to the deceased, had low antibody titers. In individuals with regression of clinical symptoms, serum antibody titers decreased in parallel, while those without clinical improvement showed high concentrations of antibodies in the CSF and serum.

Dalmau et al. (2008) present the results of brain biopsy of 14 patients with anti-NMDA receptor encephalitis: in 2 patients, no changes in the substance of the brain were detected, in 12, perivascular lymphocytic infiltrates were detected, and in 10, activation of microglia. In all cases, screening for the presence of viruses led to negative results.

Most studies have identified tumors in patients with anti-NMDA receptor encephalitis. In the vast majority of cases, neurological symptoms developed before the diagnosis of neoplasm was established. In some patients, the tumor was discovered after recovery from encephalitis. The most common type of tumor is ovarian teratoma, in some cases bilateral. All teratomas in the study by Dalmau et al. (2008) had nervous tissue in their structure, tumors tested for the presence of NMDA receptors gave a positive result. Isolated cases of a combination of anti-NMDA receptor encephalitis and immature testicular teratoma, small cell lung cancer are described, descriptions of metastasis are also few.

Treatment

The issues of adequate treatment of anti-NMDA receptor encephalitis are controversial. This applies both to the impact on the pathogenesis of the disease, and the treatment of its individual syndromes. Only the conditions for providing care to such patients are not in doubt - intensive care units (blocks), given the possibility of developing life-threatening respiratory and hemodynamic disorders in patients. Thus, according to these studies, a significant number of patients required ventilation support.

Immunotherapy is obviously the main pathogenic effect. In most cases, patients received glucocorticoids (methylprednisolone) and intravenous immunoglobulins, rarely used plasmapheresis, monoclonal antibodies (rituximab), in isolated cases, cytostatics (cyclophosphamide, azathiaprine) were prescribed. However, it is difficult to assess the effectiveness of such treatments in general and comparative effectiveness, given the design of ongoing studies.

Proven pathogenetic effects include early removal of the tumor as a source that triggers the production of antibodies that cross-damage the nervous tissue. As will be shown below, early removal of the tumor process contributes to the shortening of the encephalitis treatment time.

In the treatment of convulsive syndrome, drugs with anticonvulsant activity (phenytoin, phenobarbital, clobazam, clonazepam) were used, and typical and atypical antipsychotics were used to control dyskinesias. With regard to dyskinesias, none of the traditional approaches was effective, their control was achieved with propofol and midazolam.

Given the similarity of some of the manifestations of anti-NMDA receptor and herpetic encephalitis, many patients received acyclovir before establishing the final diagnosis. This approach seems quite logical.

Disease outcomes

In the largest follow-up study of 100 patients with anti-NMDA receptor encephalitis lasting up to 194 months, 47 participants fully recovered, 28 had mild stable residual deficiency, 18 had severe deficiency, and 7 died as a result of neurological violations. Patients in whom the tumor was detected and removed in the first 4 months from the development of encephalitis had a better outcome than the rest. The median time to first sign of improvement was recorded at about 8 weeks (range 2 to 24) for those with early tumor treatment, 11 (4 to 40 weeks) for those with late or untreated onset, and 10 (2 to 50 weeks) for those without. tumor process.

The median length of hospitalization for patients with anti-NMDA receptor encephalitis was 2.5 months (range 1 to 14). After discharge, the majority (85%) of patients either had a mild neuropsychiatric deficit in the form of symptoms of frontal dysfunction (weakening of attention, impaired planning, impulsiveness, incontinence), or, in the end, achieved a complete recovery. About 20% of individuals had severe sleep disorders: hypersomnia and inversion of the sleep-wake pattern.

In a study with a large sample during the follow-up period, there were from one to three relapses of encephalitis (up to 15% of cases). In a small number of cases, no patient has reported recurrence of encephalitis symptoms during 4 to 7 years of follow-up. The median time from disease onset to last exacerbation was 18 months (1-84 months). Relapses were less common in patients with earlier tumor treatment: in 1 out of 36 compared with other patients (14 out of 64; p = 0.009), including also those who started tumor treatment late (8 out of 42; p = 0.03).

Pathogenesis

The pathogenetic role of anti-NMDA receptor antibodies in the development of this disease is supported by a number of evidence. There is a correlation between the titer of antibodies to NMDA receptors and neurological outcomes of the disease. The observed decrease in postsynaptic receptors in cell culture is also caused by the presence of antibodies to them. The decrease in the number of antibodies in the recovery stage of the disease explains the potential reversibility of symptoms. A number of NMDA receptor antagonists (MK801, ketamine, pheneclidine) cause symptoms similar to those of anti-NMDA receptor encephalitis, including psychotic, signs of dopaminergic involvement (rigidity, dystonia, orofacial movements, tremor) and autonomic dysfunction (cardiac arrhythmias, hypertension, hypersalivation).

Thus, the recently appeared hypothesis of NMDA receptor hypofunction in schizophrenia is based on the facts of worsening of the symptoms of this disease under the influence of NMDA antagonists. It has been proven that these drugs can induce schizophrenic disorders in healthy individuals, while drugs that increase the activity of NMDA receptors reduce these symptoms. The psychomimetic effect of NMDA antagonists is due to the functional blockade of NMDA receptors of presynaptic GABAergic interneurons of the thalamus and frontal cortex, causing a decrease in GABA release. In turn, this leads to impaired suppression of glutamate transmission in the prefrontal cortex and glutamate-dopamine dysregulation.

The main targets of the autoimmune response are NR1/NR2B heteromers of NMDA receptors. They are predominantly expressed in the forebrain of adults, including the prefrontal cortex, hippocampus, amygdala and hypothalamus, that is, precisely those structures that, according to T. Iizuka et al. (2008), are most commonly involved in anti-NMDA receptor encephalitis. The development of schizophrenia-like symptoms in this suffering is obviously associated with their defeat.

Central hypoventilation is an important symptom in the majority of cases of anti-NMDA receptor encephalitis. It has been proven that animals after turning off NR1 die from hypoventilation. Thus, the production of antibodies to the NR1 subunit of NMDA receptors may explain the development of respiratory disorders at the height of the disease.

Prolonged severe dyskinesia is a serious problem for patients with this form of encephalitis. Conducting long-term EEG monitoring allowed us to conclude that hyperkinesias are non-epileptic in nature. They are resistant to antiepileptic and sedative drugs and respond to propofol and midazolam therapy. The mechanism of dyskinesia remains unclear.

Persistent amnesia observed during the recovery period of the disease is associated with impaired synaptic plasticity processes, in which NMDA receptors play a key role.

This disorder is characterized by slow recovery. Symptoms of the disease may recur, especially in individuals with an undetected tumor or its recurrence. A possible explanation for the slow recovery may be the inability of the traditionally used treatment (corticosteroids, plasmapheresis, intravenous immunoglobulins) to rapidly and significantly control the immune response in the CNS. Thus, it has been shown that in patients at the stage of improvement of neurological symptoms, the rate of decrease in titers of antibodies to NMDA receptors in the CSF was much less than the decrease in their titers in plasma. Moreover, the majority of patients who did not respond to glucocorticoid therapy in the study by J. Dalmau et al. (2008) were susceptible to cyclophosphamide, rituximab, or a combination. These drugs are more effective against immune diseases of the CNS.

A number of works discuss the issue of the frequent development of virus-like symptoms in the prodrome of the disease. The direct viral pathogenesis of the disease can be excluded with certainty, given the negative studies of viral agents in CSF, brain biopsy specimens during autopsies. Whether the prodromal symptoms are part of an early immune activation or a non-specific infection that activates the permeability of the blood-brain barrier to an immune response is currently unclear.

conclusions

Thus, anti-NMDA receptor encephalitis is a specific form of paraneoplastic encephalitis. Its development is associated with the production of antibodies to NR1 and NR2 subunits of NMDA receptors. Manifesting vivid psychopathological disorders, the disease is considered the basis for referring patients to a psychiatric service. It is extremely difficult to suspect an organic brain lesion at this stage. Further aggravation of the severity of the disease by the development of seizures, impaired consciousness, catatonic symptoms, dyskinesias is the moment when such an assumption should be made, since the patient at this stage of the disease requires multidisciplinary approaches during observation and treatment. With hypoventilation and hemodynamic disorders that develop in almost all patients, intensive therapy is necessary. Despite the severity of the disease, about 75% of individuals recover completely or with little residual deficiency.

It is important to understand that anti-NMDA receptor encephalitis is often the first manifestation indicating the presence of a possible neoplastic process. Oncological screening should be the most important component of the diagnostic algorithm. At the same time, even with an in-depth examination, as data from well-organized observations show, tumors (mainly ovarian teratomas) cannot be detected in more than 40% of patients.

Unfortunately, traditional methods of paraclinical diagnostics (EEG, MRI, CSF studies) are also not very specific in relation to the diagnosis. Lymphocytic pleocytosis in the absence of positive tests for viral agents may help to some extent in the diagnosis of the disease. To some extent, MRI in the FLAIR mode is effective, revealing foci of signal changes mainly in the deep parts of the temporal lobes. At the same time, visualization changes in the brain are found only in half of the patients, and they do not always correlate with the clinical picture. Therefore, the detection of antibodies to NMDA receptors is the basis for establishing a diagnosis in this group of patients. Moreover, G. Davies et al. (2010) recommend that this study be performed in all individuals who develop neuropsychiatric disorders in combination with severe motor symptoms.

Future studies of anti-NMDA receptor encephalitis should establish the most effective types of immune therapies, the role of prodromal events in provoking the immune response, and the molecular mechanisms involved in reducing the number of NMDA receptors.

The bibliography is under revision.

1 One of the most famous books by O. Sachs, a professor of neurology and psychiatry at Columbia University Medical Center (along with his memoir Awakening), based on which the Oscar-nominated film of the same name was made.
2 J. Dalmau is a neurologist and oncologist who first described encephalitis with the production of antibodies to NMDA receptors.

I recently compared Roskomnadzor’s actions to block Telegram to an autoimmune disease: “Recognizing an imaginary terrorist threat, he went to fight all the healthy tissues of the Internet.” Many wrote in the comments: “Lupus!” But no, it's not lupus. It is time to make a differential diagnosis and expand the biological metaphor of what is happening.

Lupus, so beloved by Dr. House's team, manifests itself as a rash on the face, but in general it is a disease of the connective tissue and its derivatives. If we imagine that people living in a country are cells of a single organism, collectively working for its prosperity, then lupus is more likely when the rights of truckers are infringed upon, people are covered with garbage and roads are not repaired.

The Internet is the fiber of the country's nervous system. Therefore, massive blocking of sites should be considered autoimmune encephalitis. The disease is characterized by inflammation of the brain and the appearance of antibodies to molecules located on the surface of nerve cells. First of all, these are various neurotransmitter receptors. They are blocked by antibodies, like sites by IP addresses: our titer of such antibodies has already exceeded 18 million.

Since many nerve cells have the same type of receptor (you can't block just one), the latter fail in groups. Please note that this is exactly how Roskompozor operates!

Depending on which molecules fall prey to a malfunctioning immune system, different types of autoimmune encephalitis are observed. Everyone has their own set of symptoms, including psychiatric ones.

For example, we do not see the stiffness syndrome that is characteristic of autoimmune encephalitis, with damage to GABA-A or glycine receptors, or movement disorders associated with damage to dopamine receptors. But one diagnosis fits perfectly.

The most common variant of autoimmune encephalitis is anti-NMDA receptor encephalitis (we will come back to what NMDA stands for later). Psychiatric syndromes in NMDA receptor encephalitis include (I'm not imagining anything, everything is taken in the order of the scientific publication):

1. Delusions of grandiosity;
2. Paranoid delusions;
3. Hallucinations - sound and visual;
4. Unusual behavior;
5. Anxiety;
6. Fear;
7. Insomnia;
8. Confusion;
9. Loss of memory.

What, if not paranoid delusions with hallucinations, is a round-the-clock search for fictional terrorists in Telegram? What, if not memory loss, blocking of sites that store scientific and other valuable information, growing censorship of the Internet? What, if not a delusion of grandiosity, ignoring the interests of millions of Telegram users and numerous organizations whose websites went down due to carpet locks? What if not confusion, denial of the absurdity of what is happening?

Coincidence? I don't think!

The symptoms of anti-NMDA receptor encephalitis are treated with immunosuppressants. That is, it is worth suppressing the activity of Roskomnadzor, recognizing that it is hyperactive. But, alas, everything is not so simple.

In the human body, everything is well provided. Our brain is protected from the immune system - including the blood-brain barrier (in the metaphor with the Internet, anonymizers, Tor, VPN try to perform its function). For survival is very important that nothing interfere with the transmission of information.

Therefore, autoimmune encephalitis is very rare. And, as a rule, they occur not just like that, but against the background of a tumor. In the case of anti-NMDA receptor encephalitis, it is usually ovarian teratoma (which makes sense, because Russia is feminine). Immature teratomas can grow into nearby tissues and metastasize.

The key characteristics of cancer cells are:

1. Violations of programmed cell death. In other words, the absence of cell turnover;
2. Violations of the control of the cell cycle;
3. Unjustified consumption of glucose and other nutrients. Something like intercellular corruption. Together with proposals to all other cells, tighten their belts.

And again, all the signs are there. It is because of a corrupt tumor that the immune system does not solve real problems (for example, fire safety in shopping centers), but deals with inflammation of the brain. By the way, the NMDA receptor is a glutamate receptor. Therefore, it is not surprising that deputies are actively fighting this substance.

So the final diagnosis is: anti-NMDA receptor encephalitis secondary to immature metastatic ovarian teratoma. The tumor needs to be removed. Steroids to suppress the immune system. intravenous immunoglobulin. Plasmaphoresis to eliminate autoreactive antibodies. The main thing is that they do not have time to ban the import of medicines.

It remains to be said that each of us can throw steroids