Anti-NMDA receptor encephalitis: causes, symptoms and treatment.

Difficulty in diagnosing and treating anti-NMDA receptor encephalitis

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

It is generally believed that these patients have a primary psychiatric disorder (for example, acute psychosis due to schizophrenia or bipolar disorder), and they are prescribed antipsychotics, which often cause motor disorders - 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 in the late stage of the disease. The combination of muscle rigidity, increased muscle enzymes in the blood serum (in particular, CPK), rhabdomyolysis and autonomic failure are specific for this disorder even in the absence of antipsychotics. If the latter are prescribed, the clinical picture begins to resemble a malignant antipsychotic syndrome.

In addition, the presence of arousal, emotional lability, impulsivity, hallucinations, insomnia and self-destructive behavior is the basis for a psychiatric consultation. Since these patients are often unable to follow instructions and swallow, they are considering using medication intravenously, intramuscularly, or through a nasogastric tube. Dopamine receptor antagonists have been prescribed to control aggression, agitation and hallucinations without significant improvement; they can actually complicate an already difficult clinical picture. Strong antagonists of D 2 receptors (for example, haloperidol) are prescribed with extreme caution, because these agents increase motor disorders. Some psychiatrists prefer low-potent atypical antipsychotics (such as quetiapine) in the evening for low doses to control insomnia and agitation. Several different classes of drugs were empirically used in these patients - normotimics for emotional lability, benzodiazepines and other hypnotics, as well as antihistamines (for example, diphenhydramine) for insomnia, and psychostimulants for hyperactivity and impulsivity.

With the development of catatonia, benzodiazepines are used intravenously at regular intervals (for example, 2 mg of lorazepam every 6:00). To achieve clinical improvement, the daily dose of this drug should reach 20-30 mg. Some pediatric psychiatrists have successfully used amantadine to treat the symptoms of catatonia with this encephalitis. The therapeutic team pays special attention to malignant catatonia, in which patients become reactive to benzodiazepines. This condition is characterized by the sudden development of areactivity, lack of speech, psychomotor changes, fever and dysautonomia. The latter often ends fatally. Malignant catatonia is sometimes difficult to differentiate from malignant antipsychotic syndrome, since both disorders are accompanied by hyperthermia and muscle rigidity. However, muscle rigidity in catatonia is more characterized by dystonic position, waxy flexibility and stereotyped serial movements. Electroconvulsive therapy (ECT) remains the gold standard for treating this complication, as confirmed by several studies. Previous reports suggest that 7-8 ECT sessions for 2-4 weeks cause a remission of the catatonic symptoms of encephalitis. In a small number of patients with progressive motor disorders and worsening levels of consciousness who do not respond to first-line treatment, ECT remains adjuvant therapy. In animal models, it has been shown that it enhances the regulation of NMDA receptors, explains the therapeutic efficacy in patients with 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, convulsive seizures, cognitive impairment and motor disorders in female patients without fever warns the doctor about a possible encephalitis process. Anti-NMDA receptor encephalitis is the second most common form of autoimmune encephalitis, now it is considered in the differential diagnosis of any patient with an altered mental state. After the diagnosis is established, they try to quickly screen for a possible tumor process and begin immunosuppressive therapy. Against the background of rapid, aggressive and prolonged use of the latter, most patients note prolonged remission and reach a level of daily functioning close to premorbid.

Anti NMDA Receptor Encephalitis , also known as encephalitis antibody NMDA receptor , is an acute form of inflammation of the brain that is potentially fatal, but has a high probability of recovery after treatment.

This is caused by an attack on the immune system, primarily targeting the NR1 subunit of the NMDA receptor (N-methyl-D-aspartate). The condition is associated with tumors, mainly teratomas of these ovaries. However, many cases are not related to malignant tumors.

The disease was officially classified and named by Josep Dalmau and his colleagues in 2007.

Before developing a complex of symptoms that are specific for anti-NMDA receptor encephalitis, people may experience prodromal manifestations, including headaches, flu-like illness, or notice upper respiratory infections. They become noticeable within weeks or months before the onset of the development of pathology. In addition to prodromal symptoms, the disease progresses with various indicators, and patients may exhibit neurological dysfunctions. At the initial stage of development, the symptoms are different between children and adults.

However, behavioral changes are a common first sign in both groups. They often are paranoia, psychosis. Other common manifestations include cramps and bizarre movements, mainly of the lips and mouth, but also strange pedal movements with legs or arms resembling a piano. Some other symptoms characteristic of the onset of the disease include cognitive impairment, memory deficits, and speech problems (aphasia, persistence, or mutism).

Symptoms usually manifest themselves in psychiatric practice, which can lead to a differential diagnosis. In many cases, this makes diagnosis impossible. As the disease progresses, the symptoms become medically urgent and often include autonomic dysfunction, hypoventilation, cerebral ataxia, hemiparesis, loss of consciousness, or catatonia.

During this acute phase, most patients require treatment in the intensive care unit to stabilize breathing, heart rate and blood pressure. Loss of feeling on one side of the body can be a symptom. A distinctive feature of anti-NMDA receptor encephalitis is the simultaneous presence of many of the manifestations listed above. Most patients experience at least four symptoms, others six or seven during the course of the illness.

Pathophysiology

The condition is mediated by antibodies that target the NMDA receptors in the brain. They can be obtained by cross-reactivity with NMDA receptors in teratomas that contain many types of cells, including brain cells, and thus represent a window in which the breakdown of immunological tolerance can occur. Other autoimmune mechanisms are suspected in patients who have no tumors. While the exact pathophysiology of the disease is still under discussion. An empirical assessment of the origin of anti-NMDA antibodies in serum and cerebrospinal fluid leads to consideration of two possible mechanisms.

Some of them can be determined by simple observations. Serum NMDA receptor antibodies are sequentially detected at higher concentrations than antibodies to cerebrospinal fluid, an average of ten times higher. This strongly indicates that antibody production is a systemic and not a brain or cerebrospinal fluid. When concentrations normalize for total IgG, intrathecal synthesis is detected. This means that there are more NMDA receptor antibodies in the cerebrospinal fluid than would be predicted based on the expected amounts of total IgG.

Passive access involves the diffusion of antibodies from the blood through a pathologically impaired blood-brain barrier (GBS). This cell filter, which separates the central nervous system from the circulatory system, usually prevents large molecules from entering the brain. Various causes have been proposed for such a collapse of integrity, with the most likely response being acute inflammation of the nervous system. Similarly, it was shown that the participation of the hormone-releasing corticotropin in mast cells during acute stress contributes to the penetration of OGB. However, it is also possible that autonomic dysfunction, which manifests itself in many patients in the late stages of the disease, contributes to the introduction of antibodies. For example, an increase in blood pressure will cause large proteins to be extravasated into the cerebrospinal fluid.
A possible mechanism is also intrathecal production. Pharmaceutical company Dalmau et al. showed that 53 out of 58 patients with the condition had at least partially retained GBS, with a high concentration of antibodies in the cerebrospinal fluid. In addition, cyclophosphamide and rituximab, drugs used to eliminate dysfunctional immune cells, were a successful treatment in the second line of patients where therapy failed. They destroy excess antibody-producing cells, thus alleviating the symptoms.

A complex analysis of the processes associated with the presence of antibodies in the cerebrospinal fluid hints at the combination of these two mechanisms in tandem.

NMDA Receptor Antibodies

As soon as antibodies enter the CSF, they bind to the NR1 subunit of the NMDA receptor. There are three possible methods in which neuron damage occurs.

Decreased density of NMDA receptors on the postsynaptic handle due to receptor internalization after antibody binding.
Direct antagonism of the NMDA receptor, similar to the action of typical pharmacological receptor blockers, such as phencyclidine and ketamine.
Recruitment of the complement cascade through the classical pathway (antibody-antigen interaction). The membrane attack complex is one of the end products of this cascade and can be inserted into neurons as a molecular cylinder, allowing water to penetrate. Then the cell is lysed. It is noteworthy that this mechanism is unlikely, since it causes the neuron to die, which is incompatible with existing evidence.

Diagnostics

First of all, this is a high level of clinical suspicion, especially in young people who exhibit abnormal behavior, as well as autonomic instability. A change in the level of sensom and seizures in the early stages of the disease. Clinical examination may additionally reveal delusions and hallucinations

Treatment

If people have a tumor, a long-term prognosis is usually better, and the likelihood of relapse is much lower. This is due to the fact that the tumor can be removed surgically, thereby eradicating the source of autoantibodies. In general, early diagnosis and aggressive treatment are believed to improve patient outcomes, but this cannot be known without data from randomized controlled trials. Given that most patients are initially accepted by psychiatrists, it is imperative that all doctors consider NMDA receptor encephalitis as a possible cause of acute psychosis in young patients who have no past neuropsychiatric history.

If a tumor is detected, its removal should occur in combination with first-line immunotherapy. Includes steroids, intravenous immunoglobulin and plasmapheresis for the physical removal of autoantibodies. A study of 577 patients showed that over four weeks, about half of them felt better after taking the drugs.
Second-line immunotherapy includes rituximab, a monoclonal antibody that targets the CD20 receptor on the surface of B cells, thereby destroying self-reactive ones. Cyclophosphamide, an alkylating agent that cross-links DNA, is used to treat both cancer and autoimmune diseases.
Other medicines, such as alemtuzumab, remain experimental.

Forecast

The recovery process from encephalitis against NMDA can take many months. Symptoms appear in the reverse order and the condition of the patients is gradually improving.

Epidemiology

The number of new diseases per year is unknown. According to the California encephalitis project, the largest series of cases to date characterizes 577 patients with antimesodiagnostic encephalitis. The study provides the best approximation of the distribution of diseases. It was found that women are disproportionately affected - 81%. Pathology begins in children under the age of 21 g. Only 5% of cases were older than 45 years. The same survey showed that 394 out of 501 people (79%) had good results, 30 patients (6%) died by 24 months, and the rest remained with mild and severe deficiency. The study also confirmed that patients are more often of Asian or African descent.

Society and Culture

Symptoms of pathology are the main cause of historical tales of demonic possession of patients.

Reporter from New york city Suzanne Kahalan wrote a book called " Brain on Fire: My Month of Madness about her illness experience.

Dallas Cowboys protective lineman Amobi Okoye spent 17 months. anti-NMDA encephalitis receptor. In addition to three months in a coma caused by medicine, he experienced a 145-day memory gap and lost 78 pounds. He returned to practice on October 23, 2014.

Knut, a polar bear in the Berlin Zoological Garden who passed away on March 19, 2011, was diagnosed with anti-NMDA receptor encephalitis in August 2015. This is the first case discovered outside the human body.

Encephalitis is a whole group of diseases manifested by the inflammatory process of the brain. The disease is characterized by severe symptoms and can be caused by a number of factors, for example, the autoimmune process that causes Anti-NMDA receptor encephalitis. Inflammation of the brain requires qualified and timely treatment, otherwise the risk of death is high.

Encephalitis is an extensive group of diseases that manifest as an inflammatory process in the brain. They cause various pathological changes in the body and lead to the development of dementia (dementia). The disease can affect not only the brain, but also internal organs and joints.

Pathology can be caused by a number of factors. For the reason that provokes the development of the disease, the following types of pathology are distinguished:

infectious inflammation;
encephalitis of a bacterial or fungal breed;
illness caused by toxic effects on the body;
encephalitis autoimmune nature.

The disease affects different parts of the brain. The inflammatory process can be localized in the cerebral cortex, subcortical nuclei or cerebellum.

Each type is characterized by its own signs and symptoms, as well as treatment methods.

Infections of an infectious and bacterial nature

The causative agents of infectious encephalitis are the following viruses and bacteria:

herpes;
HIV infection;
encephalitis viruses;
tuberculosis bacteria;
streptococci and staphylococci;
toxoplasma.

Tick-borne encephalitis is a serious problem in some regions. This disease is of a viral nature, the virus is transmitted by some kind of ticks. The virus enters the human blood only by an insect bite, but it is not transmitted by airborne droplets. However, tick-borne encephalitis does not always affect the brain. In about half the cases, symptoms of fever are observed, and there are no symptoms of inflammation of the cerebral cortex.

Another type of viral encephalitis is Japanese. The disease is extremely dangerous and results in death in seven out of ten cases. The disease is characterized by a rapid course, as a result, a coma develops a few days after infection.

Encephalitis caused by the herpes virus causes death in nine out of ten cases. This is a very dangerous disease that is difficult to treat.

A striking example of bacterial encephalitis is a disease provoked by the action of meningococci. Pathology is characterized by the development of meningitis and the further spread of inflammation in the cerebral cortex.

Autoimmune diseases

There is a group of encephalitis caused by autoimmune processes in the body, in which a person’s own immunity begins to attack brain cells.

It is extremely difficult to diagnose and treat. As a rule, the disease causes rapid dementia and leads to impaired brain function and peripheral nervous system activity. In addition to dementia, the disease accompanies paralysis and seizures similar to epileptic.

Such diseases include limbic encephalitis. The disease causes an autoimmune response of the body to cancer cells, or to any infectious or viral disease. According to the rate of development, limbic encephalitis is divided into acute and subacute.

The acute syndrome develops rapidly, within three to five days, while the first symptoms in the subacute course become noticeable a few weeks after the onset of the development of the pathology.

Typical symptoms of pathology:

memory impairment;
cognitive impairment;
epileptic seizures;
mental disorders: depression, anxiety, panic attacks;
behavioral disorders.

The disease is characterized by progressive dementia. Patients often suffer from sleep disturbances, and epileptic seizures may be accompanied by hallucinations.

Very often, autoimmune brain damage is associated with the presence of cancer. In the vast majority of cases, such encephalitis is caused by lung cancer.

Anti NMDA Receptor Encephalitis

Anti-NMDA receptor inflammatory process or encephalitis is an autoimmune disease that young women are more susceptible to. In men, pathology is extremely rare.

Pathological Features Anti-NMDA receptor process or encephalitis are severe symptoms. The disease causes a number of psychoneurotic changes, so it is often confused with schizophrenia.

Women suffering from this disease showed psychiatric abnormalities, such as a growl, lack of coherent speech, and impaired consciousness. Another characteristic symptom that allows you to diagnose the Anti-NMDA receptor process or encephalitis is short-term memory impairment, characteristic of the limbic form of the disease.

Another feature of the pathology is a violation of muscle function. So, patients for no reason begin to contract their abdominal muscles, kick surrounding objects or try to harm others like in another way.

As a rule, pathology is associated with cancer of the ovaries. In about half of the cases, this cancer was discovered in patients.

It should be noted that they did not know about the disease until recently, what doctors did not find out more than ten years ago.

Diagnosis of autoimmune brain inflammation

An experienced doctor will suspect encephalitis when examining a patient. However, additional tests are needed to determine the nature of the disease.

Often prescribed magnetic resonance imaging. This method allows you to confirm suspected inflammation of the brain, however, to identify the cause of encephalitis will not help.

To determine the cause, a biochemical blood test is needed. In autoimmune diseases, such as the Anti-NMDA receptor process or encephalitis, it is necessary to analyze the presence of antibodies to the nmda receptor.

In some cases, a brain biopsy is also indicated. A biopsy is prescribed only as a last resort, when it is impossible to identify the cause of the pathology by other methods. A consultation with an oncologist and therapist is required.

Possible complications

Autoimmune inflammation of the brain is difficult to diagnose. As a result, many patients end up in a psychiatric hospital due to an incorrect diagnosis.

Without proper treatment, the disease leads to the development of psychiatric disorders and dementia, which are often irreversible. There is also a high risk of developing coma, from which the patient may not exit.
Without treatment, a vegetative state quickly develops, and in a third of cases - a fatal outcome.

Treatment

For the diagnosis, consultation and examination by a neurologist is necessary. Diagnosis is based on the presence of specific antibodies.

The peculiarity of such brain lesions is that they are often mistaken for schizophrenia and appropriate treatment is prescribed in a psychiatric clinic. However, if an autoimmune encephalitis is suspected, an oncologist consultation is also necessary. In most cases, cancer treatment allows for long-term remission.

A good stable result is achieved by treatment with immunomodulators. However, such treatment is effective only if the suspicion of cancer has not been confirmed.

To reduce the symptoms of mental disorder, patients are shown sedatives. They help normalize sleep and reduce symptoms. If seizures are observed, it is necessary to take antispasmodic drugs.

Corticosteroids are prescribed to relieve acute inflammation. They are administered intramuscularly, and the duration of the course of treatment is selected by the doctor.

Autoimmune encephalitis in most cases cannot be completely cured. Therapy helps stop the further progression of the disease and avoid the development of irreversible neurological disorders. However, if the disease is caused by cancer, the removal of the tumor gives a stable result and in 70% of cases a full recovery occurs.

Prevention

Prevention of viral and bacterial encephalitis consists in careful outdoor behavior during the encephalitis tick migration. Wear closed clothing and use special spray repellents.

Pathology can develop against the background of a serious viral disease, so it is important not to let the disease go by its own accord and contact the clinic in time for qualified help.

Autoimmune brain diseases cannot be prevented.

69 - instability of the autonomic nervous system, 66 - hypoventilation. Antitumor therapy was associated with a greater number of remissions and fewer subsequent exacerbations. 75 patients recovered without consequences or with slight residual deviations; for 26, the result was severe impairment or death.

Often young women with this disease are admitted to psychiatric hospitals with a preliminary diagnosis of schizophrenia, catatonia, drug addiction or simulation, and only with the onset of neurological symptoms do they begin to suspect an organic disorder. In more rare cases, the disease makes its debut with severe short-term memory impairments resembling limbic encephalopathy. Increasingly, the disease is diagnosed in children and adolescents: a 2009 study found that out of 81 people, 32 (40%) were under the age of 18, and more often than not, tumors were found in younger patients and in male patients. In one small study published in 2009, of the 19 women with a sudden onset of epilepsy of unclear etiology, 5 patients had antibodies to the NMDA receptor, and this, according to the authors, suggests that anti-NMDA receptor encephalitis can make up a noticeable proportion of unexplained cases of epilepsy with psychiatric symptoms.

Disease example

A brief description of a clinical case from an abstract of an article in the journal Nature Clinical Practice Neurology, 2007:

A 34-year-old woman went to the doctors for a headache, fever and anxiety. Soon, these symptoms were followed by ideas of harming, aggressive agitation, convulsions, hypoventilation, hyperthermia and severe instability of the autonomous system, requiring intubation and sedation. There were episodes of hypotension and bradycardia with asystolic periods of up to 15 seconds. With the cancellation of sedatives - opening the eyes without reaction to external stimuli. Muscular rigor was noted, frequent facial grimaces, rhythmic contractions of the abdominal muscles, kicking leg movements, alternating dystonic poses of the right hand.

Story

Alternative names

The names used in the literature to describe the complex of symptoms before the discovery of communication with the NMDA receptor:

acute diffuse lymphocytic meningoencephalitis - Eng. acute diffuse lymphocytic meningoencephalitis
acute transient limbic encephalitis - English. acute reversible limbic encephalitis
acute early female nonherpetic encephalitis - English. acute juvenile female nonherpetic encephalitis
acute nonherpetic encephalitis of the young juvenile acute nonherpetic encephalitis

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Notes

Iizuka T, Sakai F, Ide T, Monzen T, Yoshii S, Iigaya M, Suzuki K, Lynch DR, Suzuki N, Hata T, Dalmau J (February 2008). "". Neurology 70 (7): 504–11. DOI:. PMID 17898324.
Dalmau J, Tüzün E, Wu HY, Masjuan J, Rossi JE, Voloschin A, Baehring JM, Shimazaki H, Koide R, King D, Mason W, Sansing LH, Dichter MA, Rosenfeld MR, Lynch DR (January 2007). "". Ann. Neurol. 61 (1): 25–36. DOI:. PMID 17262855.
Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M, Dessain SK, Rosenfeld MR, Balice-Gordon R, Lynch DR (December 2008). "". Lancet neurol 7 (12): 1091–8. DOI:. PMID 18851928.
Shimazaki H, Ando Y, Nakano I, Dalmau J (March 2007). "". J. Neurol. Neurosurg. Psychiatr. 78 (3): 324–5. DOI:. PMID 17308294.
Florance NR, Davis RL, Lam C, Szperka C, Zhou L, Ahmad S, Campen CJ, Moss H, Peter N, Gleichman AJ, Glaser CA, Lynch DR, Rosenfeld MR, Dalmau J (July 2009). "". Ann. Neurol. 66 (1): 11–8. DOI:. PMID 19670433.
Niehusmann P, Dalmau J, Rudlowski C, Vincent A, Elger CE, Rossi JE, Bien CG (April 2009). "". Arch. Neurol. 66 (4): 458–64. DOI:. PMID 19364930.
"Glutamate (NMDAr) hypothesis of schizophrenia":
- - Bita Moghaddam, the portal "Forum for the study of schizophrenia";
- - translation blog neuroscience.ru
Nasky KM, Knittel DR, Manos GH (August 2008). "". CNS Spectr 13 (8): 699–703.
Sansing LH, Tüzün E, Ko MW, Baccon J, Lynch DR, Dalmau J (May 2007). "". Nat Clin Pract Neurol 3 (5): 291–6. DOI:. PMID 17479076.
Neurology Today 15 May 2008; Volume 8 (10); p 18-19

References

- O. A. Levada, Zaporizhzhya Medical Academy of Postgraduate Education
- “quick therapy reverses anti-NMDA receptor encephalitis”; Medscape portal, October 20, 2008, ed. Allison gandey
- pharmed.uz, medical news
- The educational article “The Case of Sudden Psychosis”, demonstrating the typical course of the disorder in a young woman. Current Psychiatry, 2009; author Anthony Cavalieri, MD, Cathy Southammakosane, MD, and Christopher White, MD, JD, FCLM
“My Mysterious Lost Month of Madness,” an article by Suzanne Kalahan in the newspaper New York PostOctober 4, 2009.

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Excerpt from Anti-NMDA Receptor Encephalitis

- Surely! This is the simplest thing you can do. You just don’t believe in yourself, therefore you don’t try ...
- I don’t try it?! .. - I gasped from such terrible injustice ... - I just do what I try! Only maybe not that ...
Suddenly I remembered how many times, many times, Stella repeated that I could do much more ... But I could - what?! .. I had no idea what they were all talking about, but now I felt that I was starting to calm down and think a little that in any difficult circumstances always helped me. Life suddenly seemed not so unjust at all, and little by little I began to come to life ...
Inspired by the positive news, of course, all the following days I “tried” ... I completely spared myself, and tormenting my physical body, which was already exhausted, I went to the “floors” dozens of times before showing myself to Stella , because she wanted to make her a pleasant surprise, but did not hit her face in the dirt, making some stupid mistake.
But, finally, she decided - stop hiding and decided to visit her little girlfriend.
“Oh, it's you?! ..”, a familiar voice immediately sounded with happy bells. - Is it really you ?! But how did you come here? .. Have you come yourself?
Questions, as always, rained from her in a hail, a cheerful face shone, and for me it was a sincere pleasure to see this bright, beating fountain, joy.
- Well, let's go for a walk? - smiling, I asked.
But Stella still could not calm down from the happiness that I was able to come myself, and that now we can already meet when we wish, and even without outside help!
“You see, I told you that you can do more! ..” - the baby tweeted happily. - Well, now everything is fine, now we don’t need anyone! Oh, and it’s just very good that you came, I wanted to show you something and was waiting for you very much. But for this we have to take a walk to a place where it’s not very pleasant ...
“Do you mean the lower floor?” - Realizing what she was talking about, I asked immediately.
Stella nodded.
“What did you lose there?”
“Oh, I didn’t lose, I found! ..” the baby exclaimed triumphantly. “Remember, I told you that there are also good entities, but you didn’t believe me then?”
Frankly, I didn’t really believe now, but, not wanting to offend my happy girlfriend, she nodded.
“Well, now you will believe! ..” Stella said fairly. - Let's go?
This time, apparently having gained some experience, we easily “slipped” down the “floors”, and again I saw, very similar to the depressing picture seen earlier ...
Some black, smelly liquid slurped underfoot, and streams of muddy, reddish water flowed from it ... The scarlet sky darkened, blazing with bloody glare, and, still hanging very low, drove off a crimson mass of heavy clouds. .. And those, not giving in, hung heavy, swollen, pregnant, threatening to give birth to a terrible, sweeping waterfall ... From time to time a wall of brown-red, opaque water broke out of them with a booming roar, hitting the ground so hard that it seemed - the sky is crumbling ...
The trees stood bare and faceless, lazily moving drooping, spiky branches. Further beyond them stretched a bleak, burnt-out steppe, lost in the distance behind a wall of dirty, gray fog ... Many gloomy, drooping human beings roamed recklessly back and forth, meaninglessly searching for something, not paying any attention to the world around them, which, and True, it did not cause the slightest pleasure, so that he would like to look at him ... The whole landscape brought about horror and longing, seasoned with hopelessness ...
“Oh, how scary it is here ...” Stella whispered, shivering. “No matter how many times I come here, I just can’t get used to it ... How can these poor things live here ?!”
- Well, probably, these “poor things” were too guilty once, if they were here. After all, no one sent them here - they just got what they deserved, right? - still not giving up, I said.
“Now look ...” Stella whispered mysteriously.
Before us suddenly appeared a cave overgrown with grayish greenery. And from her, squinting, came a tall, stately man who in no way fit into this wretched, chilling landscape ...
- Hello, Sad! - affectionately greeted the stranger Stella. - So I brought my friend! She does not believe that you can find good people here. And I wanted to show her to you ... Aren't you against it?
“Hello dear ...” the man answered sadly, “I’m not so good as to show me to someone.” In vain are you this ...
Oddly enough, but I really liked this sad person right away. Strength and warmth blew from him, and it was very pleasant to be with him. In any case, he did not at all look like those weak-willed, heartbroken, surrendered to the mercy of the fate of the people with whom this “floor” was jam-packed.
“Tell us your story, sad man ...” Stella asked, smiling brightly.
“There’s nothing to tell there, and there’s nothing much to be proud of ...” the stranger shook his head. - And what do you need it for?
For some reason I felt sorry for him ... Still not knowing anything about him, I was almost sure that this person could not do something really bad in any way. Well, I just couldn’t! .. Stela, smiling, watched my thoughts, which she apparently really liked ...
“Well, okay, I agree - you're right! ..” - seeing her contented face, I finally honestly admitted.
“But you still don’t know anything about him, and yet it’s not so simple with him,” Stella said quite slyly. - Well, please tell her, Sad ...
The man smiled sadly at us, and said quietly:
“I am here because I killed ... I killed many.” But not by desire, but by need it was ...
I was terribly upset right away - I was killing! .. But I, stupid, believed! .. But for some reason I persistently did not have the slightest feeling of rejection or hostility. I clearly liked the man, and no matter how hard I tried, I couldn’t do anything about it ...
“Is it the same guilt — killing at will or out of necessity?” I asked. “Sometimes people don't have a choice, do they?” For example: when they have to defend themselves or protect others. I always admired the heroes - warriors, knights. I generally always adored the latter ... Is it possible to compare ordinary killers with them?
He looked at me for a long time and sadly, and then also answered quietly:
- I don’t know, dear ... The fact that I am here says that the guilt is the same ... But by the way I feel this guilt in my heart, it’s not ... I never wanted to kill, I just he defended his land, I was a hero there ... But here it turned out that I was just killing ... Is that right? I think no...
“So you were a warrior?” I asked hopefully. “But then, it's a big difference - you defended your home, your family, your children!” And you don’t look like a killer! ..
- Well, we all are not like the ones that others see us ... Because they see only what they want to see ... or just what we want to show them ... And about the war - I, too, first just as you thought, even proud ... But here it turned out that there was nothing to be proud of. Murder - it is murder, and it does not matter how it happened.
“But this is not right! ..” I was indignant. - What then turns out - the maniac killer turns out the same as the hero?! .. This simply cannot be, this should not be!
Everything was raging in me with indignation! And the man sadly looked at me with his sad, gray eyes, in which understanding was read ...
“The hero and the killer take life in the same way.” Only, probably, there are “mitigating circumstances”, since a person who protects someone, even if it takes life, is for a bright and righteous reason. But, one way or another, they both have to pay for it ... And pay very bitterly, you really believe me ...

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MALIGNANT NEUROLEPTIC SYNDROME OR AUTOIMMUNE ANTI-SHYA RECEPTOR ENCEPHALitis? Fatal Case Study

DI. Malin, V.N. Gladyshev

Moscow Research Institute of Psychiatry - branch of FSBI

"The Federal Medical and Pharmaceutical Center named after V. P. Serbsky »Ministry of Health of Russia, Clinical Psychiatric Hospital No. 4 named after P. B. Gannushkina DZ Moscow

Malignant antipsychotic syndrome (ZNS) is a rare but extremely dangerous complication of antipsychotic therapy occurring with central hyperthermia, catatonic symptoms with muscle hypertonicity, impaired consciousness and a complex of somatovegetative disorders. The course of ZNS is accompanied by changes in the basic parameters of homeostasis and the function of vital organs and systems of the body and can lead to death. Mortality in ZNS according to various publications is from 5.5 to 10%, and the frequency of development is from 2 to 0.01% of all patients receiving antipsychotics. Most often, ZNS develops during neuroleptic therapy in patients with schizophrenia or schizoaffective disorder. In the world literature, cases of the development of complications in patients with affective disorders, dementia and organic psychoses are described. The development of ZNS can be noted when prescribing antipsychotics of various chemical groups, regardless of their dosages. Most often, the development of complications was noted with the appointment of a traditional antipsychotic - haloperidol. There are descriptions of the development of ZNS and the use of atypical antipsychotics - clozapine, risperidone, quetiapine and olanzapine, as well as against the background of the simultaneous cancellation of psychotropic drugs.

The etiology and pathogenesis of ZNS have not yet been fully studied. Most researchers attribute the development of the central nervous system to the blockade of dopamine receptors in the basal ganglia and hypothalamus, rather than the direct toxic effect of antipsychotics. In patients with ZNS, dopaminegric suppression and an increase in adrenergic and serotonergic activity are noted. A number of researchers consider ZNS as a manifestation of acute antipsychotic encephalopathy. In this case, signs of metabolism are detected on the EEG

encephalopathy with generalized inhibition of the electrical activity of the brain. The results of clinical and pathogenetic studies have established that immunological disorders and increased permeability of the blood-brain barrier, with neurosensitization of the body and subsequent autoimmune damage to the central nervous system, mainly the hypothalamus and visceral organs, play an important role in the pathogenesis of ZNS and febrile schizophrenia. Proof of this is the high humoral sensitization to various autoantigens of the brain with the detection of antibodies to the frontal lobe, optic tubercle and the maximum amount (up to 66%) to the hypothalamus. The cause of death is increasing disturbances of homeostasis and, first of all, water-electrolyte balance and hemodynamics, the phenomena of cerebral edema.

Analysis of pathomorphological changes in patients with fatal central nervous system in the world literature is not presented. The revealed pathological and morphological changes in the brain during febrile (hypertoxic) schizophrenia, and a number of researchers consider CNS as a form of lethal catatonia caused by antipsychotics (drug-induced), do not fit into any specific nosological form and can be attributed to the toxic-dystrophic process in combined with generalized discirculatory disorders. The following changes are detected in the thalamo-pituitary region of the brain in these patients: 1) acute swelling, vacuilization, ischemia and death of nerve cells; 2) swelling and swelling of the myelin sheaths of the gangliocytic fibers; 3) hypertrophy and degenerative changes of microgliocytes.

Risk factors for the development of ZNS are the presence of residual cerebral organic insufficiency in patients (transferred antenatal and perinatal hazards, craniocerebral trauma, infections and intoxications). Supposed

that physical exhaustion and dehydration arising against the background of psychomotor agitation can lead to increased sensitivity to antipsychotics and contribute to the development of central nervous system. The presence of catatonic disorders is also a risk factor for CNS.

Diagnosis of ZNS is based on identifying the main symptoms of the complication: central hyperthermia, catatonic symptoms with the development of stupor and muscle rigidity, impaired consciousness, as well as characteristic changes in laboratory parameters (moderate leukocytosis without a stab shift, leukopenia and accelerated ESR, sharp CPK activity in blood plasma).

The earliest sign of the development of ZNS in patients with schizophrenia and schizoaffective psychosis, important for the diagnosis of complications, is the appearance of extrapyramidal symptoms with an exacerbation of psychosis and the development of catatonic disorders in the form of a stupor with the phenomena of negativity and catalepsy. In this regard, some researchers consider ZNS as a neuroleptic variant of malignant or febrile catatonia, referring them to diseases of the same spectrum. This is confirmed both by the commonality of the clinical manifestations of febrile schizophrenia and central nervous system, and the similarity of biochemical and immunological disorders, as well as by the general principles of therapy. They include the abolition of antipsychotics, the appointment of tranquilizers, conducting infusion therapy and ECT. The effectiveness of the dopamine receptor agonist bromocriptine and dorethrolene myorelaxant in ZNS has not been confirmed by evidence-based studies. There is evidence of the effectiveness of plasmapheresis and hemosorption. The prognosis of the course of ZNS depends on how quickly neuroleptic therapy is canceled and intensive infusion therapy is prescribed that corrects homeostasis. With the timely abolition of antipsychotics, the adequacy of infusion therapy, the differentiated use of ECT methods, it is possible to achieve a therapeutic effect in the majority of patients within the first 3-7 days, in accordance with the recommendations of B8M-5 ZNS, it is necessary to differentiate with such diseases as viral encephalitis, volumetric, vascular and autoimmune lesions of the central nervous system, as well as conditions associated with the use of other drugs (amphetamines, phencyclidine, monoamine oxidase inhibitors, serotonergic other antidepressants and a number of other drugs).

In 2007, a series of cases were described for the first time, autoimmune KMBL receptor encephalitis occurring with psychotic symptoms and catatonia, autonomic disorders and hyperthermia, and the risk of death. Symptom

the math of this disease is similar to ZNS and febrile catatonia and causes difficulties in the differential diagnosis. The disease is caused by antibodies to QW1 and QW2 subunits of the glutamate KMBL receptor. Initially, anti-KMBL receptor encephalitis has been described in young women with ovarian teratomas. Subsequently, out of touch with the tumor process in people of both sexes and of different ages. Diagnosis of anti-MSCL receptor encephalitis is based on the detection of autoantibodies to QW1 and QW2 subunits of the glutamate KMBL receptor in plasma and cerebrospinal fluid. In recent years, cases of autoimmune encephalitis have been identified in patients with psychiatric hospitals with initial diagnoses of schizophrenia, schizo-affective disorder, narcolepsy, and major depressive disorder. Treatment of the disease involves immunotherapy with the appointment of immunoglobulin and methylprednisolone. The second-line drugs that are used in the absence of effect are rituximab in combination with cyclophosphamide. To stop psychomotor agitation, tranquilizers, atypical antipsychotics, or clompromazine can be used. There is positive experience with ECT and plasmapheresis.

Clinical case

Patient Sh., Born in 1988, was admitted for treatment to the Clinical Psychiatric Hospital No. 4 named after P.B.Gannushkina 06/18/2015, with a diagnosis of acute polymorphic psychotic disorder.

Anamnesis. The heredity of psychopathology is not burdened. Pregnancy and childbirth in the mother of the patient proceeded without pathology. Born on time. The eldest of 2 children. Has a younger sister. Previously, the development is correct. She was calm, balanced, sociable and active in character. She was ill with childhood infectious diseases without complications. I went to school from the age of 7. She studied well. She graduated from 9 classes of a secondary school, then a pedagogical college and a pedagogical institute. At the age of 22, she got married. She lived with her husband, a child of 3 years old from marriage, family relations are good. He works at the school as a primary school teacher. Has no bad habits. According to her husband, the patient’s mental state first changed since the beginning of June 2015. She became distracted, forgetful, anxious. She constantly asked her relatives: “did she feed the child?”, “Did she go to the toilet”, said that she had “a head to be separate from the body”, sometimes unexpectedly fell to the floor, but immediately got up. 06.16.2015 applied for examination at the Federal State Budgetary Scientific Institution of the National Center for Neurology. Signs on brain MRI

plot of gliosis in the right parietal lobe (8 mm-13 mm-18 mm), which must be differentiated from ischemic and demyelinating or volumetric process. Data for the presence of aneurysms, arteriovenous malformations at the studied levels have not been received. On the evening of the same day, she became anxious, restless, confused, asking "what is happening around?" There was a rise in systolic blood pressure to 180 mmHg. The night was restless. The next day, she began to express ridiculous ideas, believed that she was “bitten by a tick”, that she was pregnant. She claimed that songs sounded in her head. From time to time she felt fear, anxiety, was worried that she would not be able to work, believed that she would be “taken away from her child”, said “I will die”, noted that as if someone was controlling her, movements were taking place against her will. 06/18/2015, she again turned to the center of neurology. She was excited at the reception, shouting “where is my mommy?”, Talking to herself, randomly waving her arms, growling, spitting. In connection with inadequate behavior, she was examined by a psychiatrist on duty and was hospitalized in PKB No. 4 in an involuntary manner.

Mental state at admission. Delivered to the department accompanied by orderlies with measures of physical restraint. Inspected within the bed. Productive contact is little available. Tense, anxious, listens to something, looks around. Responds only to whispering speech. Answers are quiet, concise, more often nods or shakes his head. From the conversation it is possible to reveal that she did not sleep for several nights, experiences the influx of thoughts in her head, the “sound of thoughts”. He does not deny the presence of “voices” that interfere with sleep and prohibit answering questions. Answers mainly "I do not know." At times she screams loudly, wriggles, spits.

Somatic condition: high growth, proper physique, satisfactory nutrition. The skin and visible mucous membranes of normal color. On the right elbow, there are traces of injections. On the face of a single red rash. Body temperature is normal. Zev is calm. In the lungs, vesicular breathing, no wheezing. NPV 16 min Heart sounds are muffled, rhythmic. Heart rate 82 beats / min. HELL 130/80 mm Hg The tongue is clean, moist. The abdomen on palpation is soft, painless. The liver and spleen are not palpable. The symptom of “generation” is negative on both sides. No swelling.

Neurological status: face symmetrical, pupils B \u003d 8, photoreaction saved. An increase in tendon reflexes is noted. Muscle tone is not increased. There are no meningeal signs, focal neurological symptoms are absent.

Laboratory examination data. The study of general clinical and biochemical blood and urine tests did not reveal any significant pathological changes, К ^ HIV, HBSAg, ISU -

negative, WB, BB - not identified. RPGA - tetanus - 0.77, diphtheria - 0.17. ECG - sinus rhythm, heart rate 55-62 per minute. Normal EOS.

Dynamics of the condition and ongoing therapy. From the first day of admission, the patient was prescribed haloperidol 15 mg / day i / m, trihexyphenidyl 6 mg / day, tiapride 400 mg / day i / m, chlorpromazine 25 mg / day i / m. Psychomotor agitation was stopped only in the evening. In the early days, the patient's condition remained unstable, there were episodes of psychomotor agitation with an influx of hallucinatory experiences, shouted incoherent phrases, talked to herself, lying in bed covered with a blanket with her head. I took treatment with duress, ate very little with persuasion. Productive contact remained unavailable. Gradually, psychomotor agitation was completely stopped during therapy. However, inhibition began to increase with an increase in muscle tone. All the time the patient lay motionless in bed, sometimes moving her lips. Answered only in a whisper. Symptoms of “wax flexibility” and “air cushion” appeared. In connection with the refusal of food, from June 23, 2015, infusion therapy with saline and glucose solutions up to 800 ml per day was prescribed. However, to improve the condition of the patient failed. On July 1, 2015, haloperidol and tiapride were canceled and olanzapine was prescribed at a dose of 20 mg / day, phenazepam 1 mg at night against the background of infusion therapy. After a relatively short period of improvement, when the patient began to independently move around the department and take food, deterioration occurred. From July 6, 2015, an increase in body temperature to 38.5 ° C and tachycardia to 110 beats began to be noted. in min, rigidity of the muscles of the lower and upper extremities, the phenomenon of catalepsy with the symptom of "air cushion" reappeared. High blood CPK values \u200b\u200b(2,427 units / L) were detected in the blood in a biochemical blood test, slight leukocytosis (8.4 thousand), and S0E 15 mm per hour. In order to exclude somatic pathology, the patient was repeatedly examined by a general practitioner: data for somatic pathology were not identified. On radiography of the lungs dated 07/14/2015, there were no pathological shadows. In order to prevent pneumonia, antibacterial therapy is prescribed - ceftriaxone at 1.0 v / m 2 times a day. On July 13, 2015, olanzapine was canceled and infusion therapy was increased to 1,200 ml / day. Despite the ongoing therapeutic measures, the condition remained serious. The patient lay in bed all the time, refused to eat, practically did not respond to treatment, sometimes responded only to whispering, symptoms of “wax flexibility” were noted, hyperthermia and muscle rigidity persisted. July 15, 2015 was examined by the emergency neurologist on duty.

Conclusion: the phenomena of cerebral edema on the background of intoxication syndrome. A CT scan of the brain, MRI with contrast, and transfer to a hospital with intensive care unit are recommended. At 19:50, accompanied by a resuscitation team, the patient was transferred to the PSO GKB them. S.P. Botkin to continue treatment and examination. Upon receipt, the condition was regarded as serious. Retardation with stunning elements persisted, did not respond to inverted speech, weakly responded to pain stimuli. An increase in tone in the muscles of the limbs and neck was noted. Inhibition, which was periodically replaced by excitement limited by the limits of the bed, with the repetition of individual words according to the type of speech stereotypes. In somatic status, pallor of the skin, tachycardia up to 110 beats were noted. in min., hyperthermia. For the differential diagnosis of demyelinating disease and encephalitis, lumbar puncture was performed - cytosis 40 in 3 ml, protein 0.33, lymphocytes 37, neutrophils 3. Antibodies to Epstein-barr virus, herpes virus, mycobacterium tuberculosis and to treponema pallidum were not found in cerebrospinal fluid. After examination by an infectious disease specialist, the diagnosis of viral encephalitis was withdrawn. On the MRI of the brain with contrast from July 21, 2015, an area of \u200b\u200bacute edema was detected in the semi-oval centers on the right. which should be differentiated from acute cerebrovascular accident according to the ischemic type, tumor, dimyelinating and autoimmune disease. The results of immunotyping of cerebrospinal fluid lymphocytes and lymphoproliferative disease have not been confirmed. In the intensive care unit, infusion therapy of up to 2 liters was carried out. per day under the control of diuresis, detoxification therapy, antibiotic therapy (cefritiaxon, amoxicycline). From July 24, 2015, dexamethasone 12 mg / day iv was added to the treatment regimen. Despite the therapy, the patient's condition remained severe, there was an increase in body temperature up to 40 ° C, a drop in blood pressure.

The conclusion of the consultation of doctors from 07.29.2015. The patient's condition is serious, febrile fever and catatonic symptoms persist. The most likely seems to be the presence of febrile schizophrenia in a patient. The changes revealed on an MRI study, given their inconsistency of clinical symptoms, appear to be an accidental find and may be a consequence of a previous cerebrovascular accident.

07/29/2015, there was a respiratory arrest and cardiac activity. The started resuscitation measures did not lead to the restoration of breathing and cardiac activity. At 2215 hours biological death was observed.

At autopsy. Autoimmune encephalitis with a predominant lesion of the subcortical structures of the brain: the hippocampus, thalamus, hypothalamus. Perivascular lymphoplasmacytic infiltrates with the release of immunocompetent cells into the substance of the subcortical structures of the brain; perivascular and pericellular edema; dystrophy of gangliocytes with partial cytosis and reactive gliosis, with the formation of gliomesodermal foci. Cause of death: the patient's death (primary cause) occurred from autoimmune encephalitis, complicated by cerebral edema with dislocation of its trunk into a large occipital foramen (immediate cause of death).

Parsing. This clinical case demonstrates the difficulties of differential diagnosis and treatment of CNS. A 26-year-old patient developed an acute psychotic attack of a polymorphic psychopathological structure with acute sensory delusions, verbal pseudo-hallucinations and mental automatisms. From the first days of the manifestation, catatonic disorders in the form of impulsivity, negativism (responded only to whispering speech), and elements of hebephrenic excitation (growled, spat) were noted in the structure of the attack. Thus, the structure of psychosis was characteristic of manifest attacks traditionally described in schizophrenia and schizoaffective psychosis. Against the background of neuroleptic therapy with haloperidol and tiapride, there is an increase in inhibition with an increase in muscle tone, catalepsy with symptoms of “wax flexibility” and “air cushion” appears. The indicated transformation of psychosis is characteristic of the initial stage of development of the central nervous system. The abolition of haloperidol and tiapride and the appointment of the atypical antipsychotic olanzapine during infusion therapy only for a short time led to an improvement in the patient's condition. In the future, there is an increase in catatonic disorders - a stupor, alternating with excitation, somatic disorders appear in the form of hyperthermia, tachycardia, instability of blood pressure, characteristic changes in laboratory parameters (slight leukocytosis without a wand-nuclear shift, accelerated ESR and a sharp (10-fold) increase in CPK activity in blood serum). A thorough somatic, laboratory and instrumental examination, including a study of cerebrospinal fluid and MRI of the brain with contrasting, could not establish the cause that could underlie the development of a severe mental and somatic state. The patient died on the background of hyperthermia and the growing phenomena of cerebral edema, despite the abolition of antipsychotics, intensive care and the appointment of dexamethasone. The data of a pathoanatomical study revealed a manifestation of autoimmune encephalitis in a patient with a lesion

subcortical structures of the brain, which was the basis for the divergence of the diagnosis. At the same time, the patient was not tested for blood and cerebrospinal fluid to identify autoantibodies to KMBA receptors, on the basis of which autoimmune encephalitis is diagnosed. In addition, the results of a pathomorphological study do not contradict the diagnosis of ZNS, since the clinical and pathogenetic studies have proved the important role of autoimmune pathology with a primary lesion of the hypothalamus in the pathogenesis of the development of febrile seizures of schizophrenia. It is known that, when combined with blood plasma proteins, antipsychotics acquire the properties of haptens to which antibodies begin to form, blocking their antipsychotic effect. Under certain conditions, they are likely to provoke the development of an autoimmune process and cause the development of central nervous system. It should be noted,

that the algorithm for the diagnosis of ZNS until recently did not imply a study of blood and cerebrospinal fluid for the presence of autoantibodies to KMBA receptors. Moreover, in the world literature there are descriptions of cases when the originally diagnosed ZNS was revised after the detection of autoantibodies to KMBA receptors in the blood and cerebrospinal fluid. It can be assumed that early diagnosis of ZNS with the abolition of antipsychotics, the appointment of adequate infusion therapy and ECT would prevent a fatal outcome. However, the peculiarity of this case was that even before the manifestation of psychosis, the patient revealed changes in the MRI of the brain in the form of a portion of gliosis, which did not completely exclude the presence of a current organic central nervous system disease and diagnosed an endogenous disease - schizophrenia or schizoaffective psychosis based on the structure of psychopathological disorders.

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MALIGNANT NEUROLEPTIC SYNDROME OR AUTOIMMUNE ANTI-NMDA

RECEPTOR Encephalitis? Fatal Case Study

DI. Malin, V.N. Gladyshev

The article is devoted to the analysis of a clinical case that ended in a fatal outcome, with a discrepancy between the clinical diagnosis and the data of the pathological study. It addresses the problem of the complexity of diagnosis and differential diagnosis of malignant antipsychotic syndrome and the so-called autoimmune

kMEL receptor encephalitis. A detailed consecration of the state of the problem under study with the analysis of modern publications is given.

Key words: lethal (febrile) catatonia, malignant antipsychotic syndrome, autoimmune UMBL receptor encephalitis, ECT, plasmapheresis, immunotherapy.

NEUROLEPTIC MALIGNANT SYNDROME OR AUTOIMMUNE ANTI-NMDA RECEPTOR ENCEPHALITIS?

Analysis of a fatal clinical case

D.I. Malin, V.N. Gladyshev

The authors analyze a fatal clinical case, when the pathologist "s investigation questioned the clinical diagnosis. The article discusses difficulties in diagnosis as well as differential diagnosis between neuroleptic malignant syndrome and the so called autoimmune NMDA receptor

encephalitis. The authors provide a state-of-the art description and a review of recent literature on the subject.

Key words: lethal (febrile) catatonia, neuroleptic malignant syndrome, autoimmune NMDA receptor encephalitis, ECT, plasmapheresis, immunotherapy

Malin Dmitry Ivanovich - Chief Researcher, Department of Therapy of Mental Illness, Moscow Research Institute of Psychiatry, a branch of the FSBI named after V.P. Serbsky "of the Ministry of Health of Russia; e-mail: [email protected].

Gladyshev Vitaliy Nikolaevich - Deputy Chief Physician of the Clinical Psychiatric Hospital No. 4 named after P.B.Gannushkina DZ of Moscow