Pay attention to laboratory diagnosis, plasma exchange and rituximab treatment: autoimmune autonomic ganglion disease

Key points ➤The clinical symptoms of NIH cases are complicated, and they were once suspected of pure autonomic failure (PAF), which was then tested by ganglionic neuronal nicotinic receptors (nAChRs-Ab), combined with neuroimaging It took more than 1 year for AAG to be diagnosed as a result of the academic results-AAG disease is rare and its clinical symptoms are easily confused with other diseases.
The lack of effective diagnostic methods makes it difficult to diagnose the disease and delays the patient's condition-the necessity of antibody testing
.

➤Quantitative significance——The data in the article show that the antibody titer is consistent with the development of treatment and the improvement of symptoms
.

Translation: Yin Jian (Chief Physician), Li Kai (Deputy Chief Physician) Unit: Department of Neurology, National Center for Geriatrics, Beijing Hospital Abstract NIH case report describes a 74-year-old woman undergoing total plasma exchange (PLEX) and rituximab Successful treatment of autoimmune autonomic ganglion disease (AAG)
.

After two groups of plasma exchange treatments, the patients' orthostatic intolerance, orthostatic hypotension and baroreflex function were improved temporarily but significantly, and it was negatively correlated with nAChRs-Ab titer
.

After the patient was treated with rituximab, the antibody titer decreased slightly but continued.
The patient's symptoms and clinical laboratory evidence showed that the treatment effect lasted for at least 10 months, supporting the autoimmune pathogenesis of AAG
.

Introduction Autoimmune autonomic ganglion disease (AAG) is a recently recognized and rare neurological disease characterized by autonomic disorders, accompanied by increased levels of ganglion nAChRs-Ab [1,5]
.

In this disease, the sympathetic norepinephrine nerve activity deficiency is manifested as orthostatic hypotension; the parasympathetic cholinergic nerve activity deficiency causes constipation, urinary retention, decreased salivation, decreased tear secretion, and weakened pupil light reflex; sympathetic bile Insufficient alkaline nerve activity causes anhidrosis
.

Based on the clinical manifestations of AAG, some people believe that the ganglion nAChR antibody disrupts the cholinergic synaptic transmission of the autonomic ganglia, leading to autonomic nerve failure [1,4,5]
.

NIH reported a case of AAG.
Two sets of plasma exchange (PLEX) and a set of standard rituximab injections were performed at intervals of about 6 months, and nAChRs-Ab titer levels were continuously measured to assess the level of nAChRs-Ab and clinical Relationship to laboratory results
.

This is the first report on the treatment of AAG patients with rituximab
.

The AAG medical record reported that a 74-year-old female patient was suspected of being infected with a subacute viral disease in November 2004.
The symptoms were malaise and diarrhea, which caused her to stay in bed for several weeks
.

The patient developed persistent diarrhea for several months in January 2005
.

In May 2005, doctors noticed the onset of premonitory symptoms such as acute weakness and syncope associated with orthostatic hypotension
.

The above symptoms are becoming more frequent and severe
.

The combination of midodrine, flucortisone and prednisone can improve these symptoms
.

Around July 2005, the patient began to experience dry mouth, and pilocarpine treatment was effective
.

Treatment with brompyridosmine is ineffective
.

In August 2005, the doctor used prednisone for the first time to relieve severe pain in the back of the neck
.

Pathological findings of labial gland biopsy in September 2005: mild Sjogren’s syndrome manifestations
.

A CT scan showed a filling defect in the stomach, and endoscopy and biopsy showed that the surrounding mass was a benign tumor
.

Brain MRI showed a pituitary mass, presumably a microadenoma
.

Bone marrow biopsy showed negative amyloid deposits
.

In the NIH preliminary evaluation since January 2006, the patient complained of decreased mobility, dry mouth and syncope, using prednisone 10 mg/day, midodrine 2.
5 mg/day, and fludrocortisone 0.
1 mg/day , Free salt intake, levothyroxine 0.
137 mg/day, pilocarpine 5 mg/day
.

The patient believes that these drugs are well controlled
.

The patient no longer had diarrhea symptoms, but she reported urgency, frequent urination, nocturia, and insomnia
.

Physical examination: thin
.

Dry skin, oropharynx
.

The pupils are the same size, round, 5 mm in diameter, and the pupils reflect very low light
.

There is a 2/6 intensity systolic murmur on the lower edge of the left sternum
.

No movement delay or stiffness was found, and gait, sensation, cerebellar function, and physical strength were normal
.

The treatment history of AAG patients is shown in Table 1
.

Table 1 After treatment of AAG patients, patients had abnormal pulsatile blood pressure response to Valsalva action, which was consistent with the manifestation of baroreflex-sympathetic failure
.

The baroreflex-cardiac vagus nerve gain is calculated based on the slope between the heart beat interval (with a beating delay) and the systolic blood pressure in Phase II of the Valsalva maneuver, which is 0.
05 ms/mm Hg (Figure 1)
.

In the inclined table test at an angle of 70°, the patient's systolic and diastolic blood pressure dropped by 97 and 34 mmHg, respectively (Figure 1), while the heart rate did not change
.

The above results, combined with the too small change in the concentration of norepinephrine in the cubital fossa vein plasma (less than 20ng/mL), are jointly confirmed as neurogenic orthostatic hypotension, which is inferred to be pure autonomic failure (PAF)
.

The patient's positron emission tomography scan showed that the radioactivity of 6-[18F] fluorodopamine (6-[18F] fluorodopamine) of the heart was normal, indicating that the noradrenergic nerve function of the heart was intact
.

The patient did not detect sweat secretion in the quantitative sweating axon reflex test (QSART)
.

At the time of initial detection, the ganglion nAChRs-Ab titer level in plasma (determined by radioimmunoprecipitation method RIA [5]) was 1.
44 nmol/L (the upper limit of normal was 0.
05 nmol/L)
.

Because of these findings, the patient’s diagnosis was modified to AAG
.

Figure 1 69-week follow-up of a patient with autoimmune autonomic ganglionopathy A: plasma nAChRs-Ab titer; B: baroreflex-cardiac vagus gain during Valsalva maneuvers; C: change in systolic blood pressure (BP) to the upright state ; D: Heart rate changes when standing upright
.

The horizontal dashed line of −20mmHg represents the diagnostic threshold of orthostatic hypotension
.

Therapeutic total plasma exchange (PLEX) is performed in a course of approximately 10 days, and rituximab (RTX) is injected 4 times in 4 weeks
.

The patient participated in a clinical research program designed to evaluate the efficacy of AAG treatment after PLEX for up to two courses.
A series of follow-ups were performed for autonomic nerve function tests and blood sampling to determine the level of ganglion nAChRs-Ab titers
.

In the course of about 10 days, treatments are given every other day (5 times of PLEX in a course of treatment).
PLEX involves the continuous separation of blood cells from plasma by centrifugation and replacement with a solution of 5% human serum albumin and physiological saline.
Plasma continuously returns blood cells to the circulation in a ratio of approximately 80:20
.

The cardiopulmonary bypass uses citric acid for anticoagulation, and the ratio of whole blood to anticoagulant is 13:1
.

The patient received a "pretreatment" of 5% human serum albumin at a dose of 200 mL
.

The exchange volume is 1 plasma volume per time (40-50mL/kg body weight)
.

During and after the operation, blood pressure and heart rate were monitored
.

During the first 25 weeks of the follow-up, when two courses of PLEX were performed, the patient took 20-25 mg of prednisone per day
.

In January 2007 (the 27th week after treatment, Figure 1), the patient's private neurologist started treatment with rituximab
.

Four injections, 275mg/m2 each time, administered for more than 4 weeks
.

100 mg of prednisone was also given to prevent rituximab infusion reactions
.

After rituximab treatment, from January to June 2007 (27th to 48th week), the dose of prednisone was gradually reduced to 10mg, and then from June to September 2007 (48th to 48th) 69 weeks) to 5mg
.

Discontinue prednisone for at least 5 months thereafter
.

During the whole follow-up period, the patient's serum albumin level was relatively stable, at a low level between 3.
2-3.
7g/dL
.

After two courses of PLEX at 0 weeks and 19 weeks, the patient's pulsating blood pressure and heart rate change pattern during and after the Valsalva maneuver improved, and the baroreflex-cardiac vagus nerve gain increased (Figure 1)
.

Plasma norepinephrine response to orthotopic response is still low, but it is 61ng/mL higher than the baseline level.
At the same time, PLEX improves the patient's dizziness
.

One week after PLEX, orthostatic hypotension was no longer obvious, and the heart rate increased by 11 beats/min when he was upright
.

At the same time, the plasma titer of ganglion nAChRs-Ab was significantly reduced to 0.
1 nmol/L (Figure 1)
.

After the first round of PLEX, the effect of PLEX on the response to Valsalva and the severity of orthostatic hypotension gradually disappeared, and nAChRs-Ab increased (Figure 1)
.

Therefore, the second round of PLEX was performed on the 19th week.
The nAChRs-Ab titer also decreased rapidly, the baroreflex-cardiac vagus nerve gain improved, and orthostatic hypotension improved
.

In the QSART measurement, unlike the mild and delayed effect of the first group of PLEX on sweat production, the second group of PLEX doubled the sweat secretion after 1 week
.

However, 4 weeks after the second PLEX, the above symptoms recurred, the antibody level exceeded 4 times, orthostatic intolerance and hypotension recurred
.

After being injected with rituximab, the patient developed flu-like symptoms, including dizziness, drowsiness, and nausea
.

These problems gradually disappeared
.

During the follow-up period after the rituximab injection, the symptoms of orthostatic intolerance slowly improved, and the patient did not develop orthostatic hypotension during the follow-up period of at least 42 weeks after the rituximab injection
.

During the follow-up period after rituximab, the baroreflex-cardiac vagus nerve gain was still below the normal level.
In the QSART sweat output test performed after rituximab treatment, only 2 of the 4 tests were in the normal range Inside
.

The ganglion nAChRs-Ab titer level in plasma gradually decreased to less than 50% of the initial concentration when rituximab treatment was started
.

The plasma ganglion nAChRs-Ab titer level below 0.
6 nmol/L is related to the normal systolic blood pressure response in standing position (Figure 2)
.

Figure 2 The relationship between the changes of plasma systolic blood pressure (BP) in the upright position and the plasma (nAChR-Ab) titer in AAG patients.
Note: The horizontal dashed line of −20 mm Hg represents the diagnostic threshold of orthostatic hypotension
.

Discussion The results of this study further support the hypothesis of AAG autoimmune pathogenesis based on the function of nAChRs, nAChRs-Ab interference-mediated ganglion nerve signal transmission [4]
.

Consistent with other studies, our study confirmed the short-term but significant effect of PLEX as a treatment for AAG [2]
.

In addition, we also proved that the use of the monoclonal antibody rituximab to remove CD20+ cells can gradually stop prednisone, while reducing the plasma concentration of recognized pathogenic antibodies (nAChRs-Ab), mild but continuous To improve clinical results
.

In our study, the main objective indicator of the therapeutic effect of rituximab is the improvement effect of orthostatic blood pressure on tilt response
.

On the other hand, after rituximab treatment, we failed to find similar improvements in other objective indicators of baroreflex function such as baroreflex-cardiac vagus nerve gain
.

The limitations of rituximab treatment include the high cost of treatment compared with traditional immunosuppressive treatment, potential side effects and inconvenience caused by repeated intravenous administration
.

In the first 4 weeks after receiving rituximab treatment, the antibody titer decreased relatively mildly, which formed a mismatch with the significant improvement of the patient's subjective symptoms and orthostatic hypotension
.

This contradictory finding may be explained by the cellular mechanism of rituximab
.

The depletion of pre-mature B cells carrying the CD20 marker will not only significantly affect mature B cells and differentiated immunoglobulin secreting cells, but also other immune cells [3]
.

Similarly, in AAG, the pathogenesis may not be limited to ganglion nAChR antibodies
.

Therefore, in the pathogenesis of AAG, it should be considered that CD20+ B cells can regulate the role of other immune cells
.

AAG is a serious disease that can be cured
.

Due to the rarity of the disease, the clinical similarity with other types of autonomic failure, and the lack of routine and specific diagnostic tools, the disease usually cannot be diagnosed within a few months after the visit
.

Our patient received PET with 6-[18F]fluoro-L-dopa as the imaging agent, suggesting that the heart's sympathetic nerve function is intact, and the clinical diagnosis has been inferred to be simple autonomic failure (PAF)
.

The combination of neuroimaging and nAChRs-Ab detection seems to provide a reliable diagnostic basis for AAG patients suspected of PAF
.

The 18-month follow-up results of this case showed that once diagnosed with AAG, relatively simple monitoring of baroreflex-cardiovagus nerve gain during supine rest and blood pressure response during erection can track the disease state
.

The values ​​of these parameters reflect the spontaneous or treatment-induced fluctuations in the level of nAChRs-Ab and the improvement of the patient's symptoms
.

The improvement in orthostatic hypotension symptoms observed after PLEX can theoretically be attributed to acute changes in plasma volume, because the process includes supplementation of body fluids and serum albumin
.

Although the changes in plasma volume were not monitored in this study, the relatively stable serum albumin concentration during follow-up indicated that the effect of PLEX on albumin had no significant effect on changes in orthostatic hypotension symptoms
.

In short, PLEX temporarily improved the clinical symptoms and abnormal laboratory data of the AAG patient
.

Rituximab causes a slight decrease in antibody levels and continues to improve symptoms for at least a few months
.

Expert profile Professor Yin Jian • Chief Physician, National Center for Geriatrics, Department of Neurology, Beijing Hospital
.

Core member of Neuroimmune and Muscle Disease Diagnosis and Treatment Center, Core Member of Neuroimmune Laboratory
.

• Main research areas: clinical research on geriatric neurology and neuroimmunology, focusing on difficult myasthenia gravis, LEMS (myasthenia syndrome), neuromyelitis optica spectrum diseases, multiple sclerosis, and CIDP and GBS (Gilamba) Ray syndrome), diagnosis, treatment and management of autoimmune encephalitis; clinical basis and translational research of neuroimmune-related laboratory tests
.

• Participated in the establishment of the ICU of the Department of Neurology of Beijing Hospital, the first domestic and internationally pioneered non-invasive ventilator to treat and rescue myasthenia gravis crisis and achieved success
.

Obtained the Chinese brain death assessment certificate and the Chinese brain death teacher training qualification
.

In 20 years, there have been more than 3800 patients with neuroimmune-related diseases cohort management experience
.

There have been rescue records of more than 1,000 cases of myasthenia crisis, and more than 20,000 hours of experience in ventilator use
.

• The main members and conveners of multiple difficult neuroimmune MDT diagnosis and treatment groups in Beijing and Beijing hospitals, corresponding to the diagnosis and management of difficult and rare neuroimmune diseases, laboratory consultation and related series of problems (such as refractory myasthenia crisis, NMOSD , Guillain Barre syndrome, rescue and blood purification and biological targeted therapy of autoimmune encephalitis; surgery and multiple operations for complex malignant thymoma and lung masses with myasthenia gravis and myasthenia syndrome.
Chemotherapy and minimally invasive biopsy, tumor reduction and implantation of internal radiation; puerperal management of patients with myasthenia gravis; diagnosis and biopsy of difficult demyelinating leukoencephalopathy; consultation on DMT treatment strategies for multiple sclerosis)
.

• Participated in a number of national-level (national nature, 973 sub-projects), provincial and ministerial-level, and bureau-level scientific research projects
.

Won the third prize of Beijing Municipal Science and Technology Progress Award, and many awards such as outstanding teachers of Beijing Hospital
.

He has published more than 55 articles (including SCI) and participated in the compilation of 6 monographs
.

Concurrently serving as a reviewer for the journal "Journal of Stroke and Neurology", a reviewer of the Beijing Natural Science Foundation; "Deputy Chairman of the Committee of Neurology, Beijing Association of Chinese and Western Medicine"; "Executive Member of the Beijing Association of Neurology and Integrative Medicine"
.

• Participated in many international and domestic neuroimmunological new therapeutic drug researches and IVD reagent clinical researches since 1996 (such as participating in Libby, Betalone, Teriflunomide, Fingolimod, Sinimod in the treatment of multiple sclerosis DMT All Chinese market registration studies of the drug, the national first-class new drug Tai'ai and HM9161 for the treatment of myasthenia gravis and NMOSD in China)
.

Assisted the first domestic AQP4 antibody detection kit in China registration (IVD) marketing research
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Original: Imrich R, Vernino S, Eldadah BA, et al.
Autoimmune autonomic ganglionopathy: treatment by plasma exchanges and rituximab[J].
Clinical Autonomic Research Official Journal of the Clinical Autonomic Research Society, 2009, 19(4):259.
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