Detection of meningeal carcinomatosis by metagenomic next-generation sequencing and copy number variation analysis of cerebrospinal fluid / 中华神经科杂志

Objective:To evaluate the significance of copy number variation (CNV) and metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) in the diagnosis of meningeal carcinomatosis (MC).Methods:Ten patients with MC diagnosed in the Department of Neurology of Peking Union Medical College Hospital from March 2022 to June 2022 were consecutively enrolled in this study. The patients were diagnosed according to the criteria of the Chinese expert consensus on the diagnosis of MC by the Chinese Society of Infectious Diseases and Cerebrospinal Fluid Cytology, and the diagnosis of MC was confirmed by CSF cytology. The control group included 10 patients who were diagnosed as autoimmune encephalitis or viral encephalitis. CSF mNGS and CNV analysis were performed simultaneously in all the patients.Results:Of the 10 patients with MC, 6 had lung adenocarcinoma, 4 had breast cancer. CSF mNGS and CNV analysis detected large CNV in 8 of 10 patients with MC, including 4 patients with breast cancer and 4 patients with lung cancer. The results of pathogenic microorganism analysis of CSF mNGS in all the patients were negative. Meanwhile, large CNV was not detected in the control group.Conclusions:CSF CNV can serve as a diagnostic marker for MC. The combination of mNGS and CNV analysis has demonstrated a high positive rate in the diagnosis of MC. The dual-omics analysis of pathogenic microorganisms and CNV has been proposed as a potential strategy to further expand the clinical utility of CSF mNGS in the realm of auxiliary diagnosis.

Autoimmune cerebellar ataxia associated with anti-leucine-rich glioma-inactivated protein 1 antibodies: Two pediatric cases.

OBJECTIVES: To report two pediatric cases of autoimmune cerebellar ataxia associated with the anti-Leucine-rich glioma-inactivated protein 1 (LGI1)antibodies. METHODS: The clinical features of the two patients were described retrospectively. The indirect immunofluorescence using transfected cells (cell-based assay, CBA) and the rat cerebellum (tissue-based assay, TBA) with the multi-antigen co-plate biochip mosaic techniques were used to detect the antibodies. Clinical and laboratory characteristics were described. RESULTS: Two males were included. The onset ages were 2.7y and 4y, respectively. Patient 1 manifested as isolated acute cerebellar ataxia. Patient 2 had extra-cerebellar symptoms, including seizures, encephalopathy, faciobrachial dystonic seizures(FBDs), and significant cerebellar ataxia. The hyponatremia and tumors were not found. Both of them responded well to the immunotherapy. CONCLUSIONS: The autoimmune cerebellar ataxia might be a new phenotype of LGI1-Abs autoimmunity in children.

Anti-amphiphysin-associated paraneoplastic brainstem encephalitis with esophageal neuroendocrine carcinoma: a case report / 中华神经科杂志

Paraneoplastic neurological syndromes (PNS) are heterogeneous disorders caused by autoimmune responses of cancer, which can affect any part of the nervous system. Anti-amphiphysin antibody is one of the high-risk PNS antibodies, which is usually associated with small cell lung cancer and breast cancer. However, extrapulmonary neuroendocrine carcinoma is rare in patients with anti-amphiphysin antibody. A case of anti-amphiphysin-associated paraneoplastic brainstem encephalitis with esophageal neuroendocrine carcinoma is reported. The tumor was detected by fluorine 18 fluorodeoxyglucose positron emission tomography and pathologically confirmed by gastroscopic biopsy. The patient′s neurological symptoms were partially improved after treatment of intravenous immunoglobulin and glucocorticoids. However, the disease prognosis is closely related to the accompanying tumor.

Diagnosis and treatment of viral encephalitis / 中华神经科杂志

Viral encephalitis is one of the major neurological emergency and critical diseases. The clinical classification of encephalitis is an important basis for clinical etiological diagnosis. Virus nucleic acid detection of cerebrospinal fluid is the main diagnostic experiment of viral encephalitis, including polymerase chain reaction and metagenome next-generation sequencing. Specific antiviral drugs are effective for some types of viral encephalitis, and new therapeutic regimes need to be explored.

The clinical characteristics of human pseudorabies virus infection: a case report and literature review / 中华神经科杂志

Objective:To explore the epidemiology, clinical features and prognosis of pseudorabies virus (PRV) infection in human.Methods:A case of human PRV encephalitis combined with acute retinal necrosis (ARN) in the First Affiliated Hospital of Zhengzhou University in May 2020 was reported. The epidemiology, clinical features, neuroimaging, cerebrospinal fluid (CSF), next-generation sequencing (NGS), treatment and prognosis of human PRV infection were summarized and analyzed with the previous published data.Results:The present case was a 38-year-old man who developed high fever, headache, cognitive decline, recurrent epileptic seizures after butchering a pig. Brain magnetic resonance imaging showed lesions in the insular lobes, temporal lobes, cingulate gyrus, frontal lobes, basal ganglia and hippocampus, with more significant signals on the left side. Afterwards, bilateral ARN occurred and resulted in his blindness. PRV DNA was detected from the aqueous humor. By literature review, a total of 20 cases (including this case) were analyzed. Most patients (95%, 19/20) had the history of direct contact with swine. The median incubation period was 7 days. The infection normally caused encephalitis (95%, 19/20), some cases with endophthalmitis (60%, 12/20). Based on the neuroimaging of the 19 patients, the lesions in neuroimaging were mainly in limbic system, especially in insular (17/19) and temporal lobes (17/19). The basal ganglia was often involved (9/19).The PRV-DNA was detected by NGS in CSF or intraocular fluid. Antiviral drugs and adjuvant treatment, including immunoglobulin and/or corticoid therapy, were effective to only few cases. Most patients (90%, 18/20) had the sequelae of severe impairment of daily living (modified Rankin Scale scores≥3).Conclusions:The cardinal clinical characteristics of human PRV infection are progressive panencephalitis and endophthalmitis, with an unfavorable outcome. The history of exposure to sick swine and typical neuroimaging suggest PRV infection. NGS of CSF and/or intraocular fluid is the dependable diagnostic method.

Research Progress in Antibodies Related to Autoimmune Encephalitis in Neuropsychiatric Systemic Lupus Erythematosus / 罕见病研究

Several anti-neural antibodies are associated with neuropsychiatric systemic lupus erythematosus (NPSLE) including anti-neuronal antibodies and anti-glial cell antibodies. The anti-neuronal antibodies has two types: anti-neuronal surface protein antibodies represented by anti-N-methyl-D-aspartate receptor (NMDAR) antibodies, and anti-neuronal intracellular protein antibodies. In this paper, we review and classify the anti-neural antibodies related to NPSLE.

Anti-Leucine-Rich Glioma-Inactivated 1 Encephalitis: A Single-Center Cohort Study in China / 罕见病研究

  Objective  To evaluate the clinical and paraclinical features of Chinese patients with anti- LGI1 encephalitis.  Methods  Patients with memory deficits, psychiatric symptoms, seizures or altered level of consciousness, suspicious of encephalitis, at presentation to Peking Union Medical College Hospital were recruited between July 2013 and January 2018, and tested for anti-LGI1 antibodies in their serum and/or cerebrospinal fluid(CSF) samples. Patients with anti-LGI1 antibodies were enrolled. The demographic characteristics, clinical manifestations, laboratory examination results, neuroimaging features, immunotherapy, follow-up practices and outcomes for included patients were registered and analyzed.  Results  The study enrolled 120 patients, of whom 66.7% were male. The median age was 61 years (interquartile range [IQR]: 49-66 years). Seizures(65.0%) were the most common initial symptoms. Most patients developed seizures (95.0%), including faciobrachial dystonic seizures (54.2%), memory deficits (92.5%), and psychiatric symptoms (69.1%). Brain MRI and 18F-FDG PET / CT showed that the lesions were mainly located in unilateral or bilateral medial temporal lobes, and (or) basal ganglia. Of the patients, 95.0% received intravenous immunoglobulin (IVIg) or corticosteroids, 47.5% received mycophenolate mofetil as long-term immunotherapy, and no one received second-line immunotherapy. The median follow-up was 34.2 months(IQR: 22.0-45.6 months). 91.2% had a good outcome (modified Rankin Scale score≤2 points). Residual mild memory deficits were present in 47.8% of the patients. Nine deaths were documented. Relapses occurred in 24.8% of the patients in the first year. In total, 24 (20%)cases were young patients(onset age ≤45 years).There were fewer males among the younger patients(37.5% vs. 74.0%, P < 0.01). Besides, there were fewer younger patients with psychiatric symptoms(50.0% vs. 74.0%, P=0.02), hyponatremia(33.3% vs. 68.8%, P < 0.01), and abnormalities on brain 18F-FDG PET/CT(20.8% vs. 47.9%, P=0.02). The relapse-free survival rate was significantly higher in the young patients.  Conclusions  Elderly males were predominant in patients with anti-LGI1 encephalitis. Most patients developed symptoms of limbic encephalitis and/or FDBS during the disease course. Several patients were young adults and lacked typical symptoms. Neuroimaging features were consistent with the involvement of limbic system or basal ganglia. Patients with anti-LGI1 encephalitis respond well to immunotherapy, irrespective of the age.

Cerebellar ataxia and myeloradiculopathy associated with AP3B2 antibody: a case report and literature review.

BACKGROUND: AP3B2 is one of the subunits of vesicle coat protein AP3 and is specifically expressed in central nervous system neurons. AP3B2 antibody has been reported in patients with autoimmune cerebellar ataxia and various extracerebellar symptoms. However, there have been few reports on its clinical features and treatment response. METHODS: We report a 47-year-old man with AP3B2 antibody who presented with insidious-onset paresthesia and gait disturbance. His serum and cerebrospinal fluid (CSF) showed reactivity with the cytoplasm of Purkinje cells and granular layer synapses comparable to the reported specific pattern of anti-AP3B2 IgG, and this was confirmed by a cell-based assay. His symptoms improved after the administration of intravenous immunoglobulin, and oral prednisone and mycophenolate mofetil. Extensive examination and long-term follow-up showed no evidence of malignancy. A literature review was included to emphasize the neurological syndrome associated with this rare autoantibody. RESULTS: Eleven cases with AP3B2 antibody, including our patient, were identified. The diversity of symptoms, including cerebellar and sensory ataxia, paresthesia, and weakness, was in line with the extensive binding of AP3B2 antibody to the spinal cord gray matter, dorsal root ganglia, cerebellar cortex, and nucleus. In the CSF, half of patients had elevated white blood cell counts, increased protein concentrations, or CSF-specific oligoclonal bands. All previous cases had subacute onsets and no improvement was noted after immunotherapy. CONCLUSION: Our case indicated that disorders associated with AP3B2 antibody can also start insidiously. Immunotherapy is warranted given the possibility of clinical improvement.

Progress in clinical phenotype and pathogenesis of neuroimmunological diseases associtated with anti-glutamic acid decarboxylase antibody / 中华神经科杂志

Antibodies to glutamic acid decarboxylase (GAD) have been associated with several neurological syndromes, including stiff-person syndrome, cerebellar ataxia and epilepsy. This article critically reviews the main clinical characteristics and the evidence on the pathogenicity of GAD antibodies.

Progress in diagnosis and treatment of antibody-related autoimmune cerebellar ataxia / 中华神经科杂志

Cerebellar ataxia mediated by autoimmune mechanisms is a common cause of sporadic cerebellar ataxia. According to the presence of underlining malignancy, autoimmune cerebellar ataxia (ACA) can be divided into paraneoplastic ACA and non-paraneoplastic ACA. The typical manifestations of various types of ACA include gait disorder, limb and trunk ataxia, mild inflammatory response and specific oligoclonal bands in cerebrospinal fluid. Immunosuppressive therapy might be effective. Anti-neuronal antibodies are of great significance to the diagnosis of ACA, and the discovery of the new antibody profile has promoted a deeper understanding of ACA. This article reviews the clinical features and progress of diagnosis and treatment of ACA.

Clinical analysis of anti-N-methyl-D-aspartate receptor encephalitis patients with cerebellar ataxia / 中华神经科杂志

Objective:To analyze and summarize the clinical characteristics of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis patients with cerebellar ataxia.Methods:The clinical manifestations, laboratory examinations, treatment and prognosis of anti-NMDAR encephalitis patients with cerebellar ataxia diagnosed and treated in Peking Union Medical College Hospital from 2011 to 2019 were retrospectively analyzed.Results:About 4.3% (15 cases) of a total of 347 anti-NMDAR encephalitis patients were complicated with cerebellar ataxia, of which one patient had ovarian teratoma. There were seven male cases and eight female cases, with a median age of 28 years. The average duration from the onset of encephalitis to the onset of cerebellar symptoms was 30.8 days.The average modified Rankin Scale (mRS) score was 3.73. In the acute phase, the median cerebrospinal fluid leukocyte count was 28×10 6/L. All patients received first-line immunotherapy, of which one case additionally received second-line immunotherapy with rituximab and nine patients received long-term immunotherapy with mycophenolate mofetil. The follow-up time ranged from seven to 66 months. The average mRS score of the last time was 2.73, and only six patients (6/15) had good prognosis (mRS score≤2). Conclusions:Patients with anti-NMDAR encephalitis and cerebellar ataxia are rare, and have relatively poor prognosis in terms of neurological function. Symptoms of cerebellar ataxia in anti-NMDAR encephalitis patients should be recognized in time, and standardized immunotherapy regimens and long-term immunotherapy should be adopted to improve the prognosis.

Clinical and laboratory findings of patients with anti-dipeptidyl-peptidase-like protein 6 encephalitis: two cases report / 中华神经科杂志

Objective:To identify anti-dipeptidyl-peptidase-like protein 6 (DPPX) antibody in patients with encephalitis of unknown etiology and describe the clinical features of anti-DPPX antibody-associated encephalitis in Chinese patients.Methods:For patients registered in the Peking Union Medical College Hospital Encephalitis and Paraneoplastic Syndrome Registration Project from 2016 to 2019 with negative findings in autoimmune encephalitis routine antibody profile and paraneoplastic antibody profile, but with positive tissue-based assay (TBA) results, further tests for rare antibodies, including cell-based assay (CBA) of anti-DPPX antibody, were performed. Patients positive for anti-DPPX antibody were enrolled and the clinical data were collected.Results:Two patients with anti-DPPX antibody-associated encephalitis were found from 2016 to 2019 among about 15 000 patients. Both were females, aged 46 and 75 years. One patient had diarrhea, cachexia, cognitive dysfunction, agitation, myoclonus, tremor, and seizures. The other had cognitive impairment, restlessness, memory loss, disorientation, and sleep disturbance. The second patient had medical history of systemic lupus erythematosus and secondary Sj?gren′s syndrome.Conclusions:TBA should be combined with CBA in identification of anti-DPPX antibody to confirm the diagnosis. Anti-DPPX antibody-associated encephalitis has clinical manifestations of encephalopathy with diarrhea and cachexia, and can coexist with systemic lupus erythematosus.

Overlapping syndrome of antibody-related autoimmune encephalitis / 中华神经科杂志

With the understanding of autoimmune encephalitis many novel types of autoimmune encephalitis and related antibodies have been identified. There are some cases of autoimmune encephalitis with autoantibody overlapping syndromes or phenotype overlapping syndromes, which bring challenges to diagnosis and treatment in practice. The relevant literature was reviewed and the clinical characteristics, pathological mechanism and treatment of overlapping syndromes associated with autoimmune encephalitis were summarized, in order to provide a reference for the management of autoimmune encephalitis with overlapping syndromes.

Clinical features and immunotherapy outcomes of anti-glutamic acid decarboxylase 65 antibody-associated neurological disorders.

We described the clinical and neuroimaging characteristics of seven Chinese patients with anti-GAD65 antibody-associated neurological disorders of whom epileptic seizures were the initial and main symptoms. All patients were given immunotherapy and followed up monthly. The outcome demonstrates that immunotherapy is helpful for non-seizure manifestations of anti-GAD65-associated neurological autoimmunity and is less effective in the treatment of seizures, yet partial responses can still occur in the early stage. Taken together we suggest a trial with immunotherapy in all patients in the early stage of the disease, and in patients with non-epilepsy symptoms in the later stage.

A case of coronavirus disease 2019 with tuberculous meningitis / 中华神经科杂志

Novel coronavirus pneumonia, also known as coronavirus disease 2019 (COVID-19), is caused by a new coronavirus that infects the lungs. Although some patients with COVID-19 may be combined with neurological symptoms, there is no direct evidence that this new coronavirus can directly invade nerve system. A case of COVID-19 with tuberculous meningitis is reported to remind that when patients with COVID-19 present symptom of encephalitis or meningitis, a comprehensive pathogen examination is recommended.

Standardization and individualization of diagnosis and treatment of autoimmune encephalitis / 中华神经科杂志

Standardization and individualization are two important aspects in the diagnosis and treatment of autoimmune encephalitis. The Chinese expert consensus on the diagnosis and management of autoimmune encephalitis (2017) is the major reference for neurological practice in China, while individualization of treatment is mainly based on the specific types of autoimmune encephalitis and the dynamic observation of clinical response and immune parameters. The results of recent clinical research provide evidence for new treatment strategy.

Retrospective analysis of metagenomic next-generation sequencing in the diagnosis of central nervous system infectious disease / 中华神经科杂志

Objective:To assess the clinical value of metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid in pathogenic diagnosis of neurological infectious disease.Methods:Patients who were clinically diagnosed with infectious encephalitis and meningitis and treated in Department of Neurology, Affiliated Hospital of Chifeng University from March 2018 to September 2019 were retrospectively analyzed, including the clinical characteristics and data of mNGS and traditional laboratory test of pathogens.Results:Totally 104 patients with infectious encephalitis and meningitis were eligible for enrollment, and mNGS detected 22 bacterial species(22/104,21.15%), 24 viral species (24/104,23.08%), one fungal species (1/104,0.96%), one parasitic species (1/104,0.96%) and one mycoplasma species (1/104,0.96%).The three leading positive detections were varicella-zoster virus ( n=19), streptococcus ( n=7) and Mycobacterium tuberculosis ( n=4). Combined with traditional pathogen detection methods, clinical manifestations, final diagnosis and treatment results, the number of cases diagnosed by mNGS was 49 cases. The positive rate of the mNGS was 47.12% (49/104).False positives occurred in 21 (20.19%) patients. False negatives occurred in 34 (32.69%) patients. Conclusions:mNGS is more sensitive in evaluating the pathogens causing the infectious encephalitis and meningitis. It has advantages in accurate diagnosis of infectious encephalitis and meningitis.

A case of COVID-19 with tuberculous meningitis / 中华神经科杂志

COVID-19 is caused by a new coronavirus that infects the lungs. Although some patients with COVID-19 may be combined with neurological symptoms, there is no direct evidence that this new coronavirus can directly invade nerve system. A case of COVID-19 with tuberculous meningitis is reported to remind that when patients with COVID-19 present symptom of encephalitis or meningitis, a comprehensive pathogen examination is recommended.

Standardization and individualization of diagnosis and treatment of autoimmune encephalitis / 中华神经科杂志

Standardization and individualization are two important aspects in the diagnosis and treatment of autoimmune encephalitis.The Chinese expert consensus on the diagnosis and management of autoimmune encephalitis (2017) is the major reference for neurological practice in China,while individualization of treatment is mainly based on the specific types of autoimmune encephalitis and the dynamic observation of clinical response and immune parameters.The results of recent clinical research provide evidence for new treatment strategy.

Neurochondrin Antibody Serum Positivity in Three Cases of Autoimmune Cerebellar Ataxia.

To report three cases of autoimmune ataxia patients with positive neurochondrin (NCDN) antibodies. Patients with unknown cerebellar ataxia were screened for autoimmune cerebellar ataxia (ACA)-related antibodies, including glutamic acid decarboxylase 65 (GAD65), delta/notch-like epidermal growth factor-related receptor (Tr/DNER), zinc finger protein 4 (ZIC4), inositol 1,4,5-triphosphate receptor 1 (ITPR1), Homer protein homologue 3 (Homer-3), neurochondrin (NCDN), Purkinje cell antibody 2 (PCA-2) and carbonic anhydrase-related protein VII (CARPVII). The antibodies were assessed by indirect immunofluorescence using transfected cells (cell-based assay, CBA) and monkey cerebellum (tissue-based assay, TBA) with the multi-antigen co-plate biochip mosaic technique. Patients with positive antibodies received immunotherapy and were followed up in the clinic. Clinical characteristics, laboratory data, and outcomes of antibody-positive patients were described, analysed and compared with previously reported cases. The NCDN antibody was positive in three male patients in whom the onset ages were four years and 11 months, two years and seven months and 67 years old. Serum antibody titres were 1:32, 1:100 and 1:320. Cerebral ataxia was the most prominent presentation. Cerebellar atrophy was found in one of the patients. Immunotherapy was effective in all three patients. The NCDN antibody is associated with autoimmune ataxia, and it has been suggested that the NCDN antibody should be tested in patients with cerebellar ataxia who are negative for routine ACA antibodies. Early immunotherapy may have a beneficial impact on prognosis.