The clinical and molecular spectrum of ZFYVE26-associated hereditary spastic paraplegia: SPG15.

In the field of hereditary spastic paraplegia (HSP), progress in molecular diagnostics needs to be translated into robust phenotyping studies to understand genetic and phenotypic heterogeneity and to support interventional trials. ZFYVE26-associated hereditary spastic paraplegia (HSP-ZFYVE26, SPG15) is a rare, early-onset complex HSP, characterized by progressive spasticity and a variety of other neurological symptoms. While prior reports, often in populations with high rates of consanguinity, have established a general phenotype, there is a lack of systematic investigations and a limited understanding of age-dependent manifestation of symptoms. Here we delineate the clinical, neuroimaging and molecular features of 44 individuals from 36 families, the largest cohort assembled to date. Median age at last follow-up was 23.8 years covering a wide age range (11-61 years). While symptom onset often occurred in early childhood [median: 24 months, interquartile range (IQR) = 24], a molecular diagnosis was reached at a median age of 18.8 years (IQR = 8), indicating significant diagnostic delay. We demonstrate that most patients present with motor and/or speech delay or learning disabilities. Importantly, these developmental symptoms preceded the onset of motor symptoms by several years. Progressive spasticity in the lower extremities, the hallmark feature of HSP-ZFYVE26, typically presents in adolescence and involves the distal lower limbs before progressing proximally. Spasticity in the upper extremities was seen in 64%. We found a high prevalence of extrapyramidal movement disorders including cerebellar ataxia (64%) and dystonia (11%). Parkinsonism (16%) was present in a subset and showed no sustained response to levodopa. Cognitive decline and neurogenic bladder dysfunction progressed over time in most patients. A systematic analysis of brain MRI features revealed a common diagnostic signature consisting of thinning of the anterior corpus callosum, signal changes of the anterior forceps and non-specific cortical and cerebellar atrophy. The molecular spectrum included 45 distinct variants, distributed across the protein structure without mutational hotspots. Spastic Paraplegia Rating Scale scores, SPATAX Disability Scores and the Four Stage Functional Mobility Score showed moderate strength in representing the proportion of variation between disease duration and motor dysfunction. Plasma neurofilament light chain levels were significantly elevated in all patients (Mann-Whitney U-test, P < 0.0001) and were correlated inversely with age (Spearman's rank correlation coefficient r = -0.65, P = 0.01). In summary, our systematic cross-sectional analysis of HSP-ZFYVE26 patients across a wide age-range, delineates core clinical, neuroimaging and molecular features and identifies markers of disease severity. These results raise awareness to this rare disease, facilitate an early diagnosis and create clinical trial readiness.

Clinical Features and Neuroimaging Findings of Neuropil Antibody-Positive Idiopathic Sporadic Ataxia of Unknown Etiology.

Idiopathic sporadic ataxia (ISA) is the clinical term for nonfamilial ataxia with adult-onset and a slowly progressive course. However, immune-mediated cerebellar ataxia cannot be completely excluded from ISA. The current study investigated the neuropil antibodies against cell-surface antigens and clarified the clinical features and neuroimaging findings of patients with these antibodies. Using tissue-based immunofluorescence assays (TBAs), we examined antibodies against the cerebellum in serum samples from 67 patients who met the ISA diagnostic criteria, including 30 patients with multiple system atrophy with predominant cerebellar features (MSA-C) and 20 patients with hereditary ataxia (HA), and 18 healthy control subjects. According to the TBA results, we divided subjects into three groups: subjects positive for neuropil antibodies, subjects positive for intracellular antibodies only, and subjects negative for antibodies. We compared clinical features and neuroimaging findings in ISA patients among these three groups. The prevalence of neuropil antibodies in ISA (17.9%) was significantly higher than that in MSA-C (3.3%), HA (0%), or healthy subjects (0%). The neuropil antibody-positive ISA patients showed pure cerebellar ataxia more frequently than the other ISA patients. Two neuropil antibody-positive patients showed significant improvement of cerebellar ataxia after immunotherapy. We detected neuropil antibodies in 17.9% of ISA patients. Characteristic clinical features of neuropil antibody-positive ISA patients were pure cerebellar ataxia. Some cases of neuropil antibody-positive ISA responded to immunotherapy.

Repeat conformation heterogeneity in cerebellar ataxia, neuropathy, vestibular areflexia syndrome.

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late-onset, slow-progressing multisystem neurodegenerative disorder. Biallelic AAGGG repeat expansion in RFC1 has been identified as causative of this disease, and repeat conformation heterogeneity (ACAGG repeat) was also recently implied. To molecularly characterize this disease in Japanese patients with adult-onset ataxia, we accumulated and screened 212 candidate families by an integrated approach consisting of flanking PCR, repeat-primed PCR, Southern blotting and long-read sequencing using Sequel II, GridION or PromethION. We identified 16 patients from 11 families, of whom seven had ACAGG expansions [(ACAGG)exp/(ACAGG)exp] (ACAGG homozygotes), two had ACAGG and AAGGG expansions [(ACAGG)exp/(AAGGG)exp] (ACAGG/AAGGG compound heterozygotes) and seven had AAGGG expansions [(AAGGG)exp/(AAGGG)exp] (AAGGG homozygotes). The overall detection rate was 5.2% (11/212 families including one family having two expansion genotypes). Long-read sequencers revealed the entire sequence of both AAGGG and ACAGG repeat expansions at the nucleotide level of resolution. Clinical assessment and neuropathology results suggested that patients with ACAGG expansions have similar clinical features to previously reported patients with homozygous AAGGG expansions, although motor neuron involvement was more notable in patients with ACAGG expansions (even if one allele was involved). Furthermore, a later age of onset and slower clinical progression were implied in patients with ACAGG/AAGGG compound heterozygous expansions compared with either ACAGG or AAGGG homozygotes in our very limited cohort. Our study clearly shows the occurrence of repeat conformation heterogeneity, with possible different impacts on the affected nervous systems. The difference in disease onset and progression between compound heterozygotes and homozygotes might also be suspected but with very limited certainty due to the small sample number of cases in our study. Studies of additional patients are needed to confirm this.

Progressive supranuclear palsy with predominant frontal presentation exhibiting progressive nonfluent aphasia due to crossed aphasia.

Progressive supranuclear palsy (PSP) with predominant frontal presentation (PSP-F) is a clinical phenotype of PSP that is characterized by frontal cognitive impairment and behavioral changes. Here, we report on a patient with pathologically diagnosed PSP-F in whom we were able to observe temporal changes of the clinical manifestations. A 77-year-old right-handed man developed progressive nonfluent aphasia (PNFA) at the age of 69 years, festinating gait, and clumsiness of his left arm at age 75, disinhibition at age 76, and unprovoked falls at age 77. Neurological examination at age 77 revealed limb-kinetic apraxia of the left upper and lower limbs, rigidity, cortical sensory loss, and vertical supranuclear gaze palsy. According to the Movement Disorder Society clinical diagnostic criteria for PSP, his clinical manifestations shifted from suggestive PSP with predominant speech/language disorder to probable PSP-F over nine years. Cerebral atrophy on brain magnetic resonance imaging and decreased accumulation of 99m Tc-ECD on cerebral blood flow single-photon emission computed tomography were noted with right side predominance. Pathologically, 4-repeat tau-immunoreactive globose-type neurofibrillary tangles, coiled bodies, tufted astrocytes, and neuropil threads were observed predominantly in the frontal cortex. Tau pathology of the substantia nigra, locus coeruleus and subthalamic nucleus was mild. These findings suggested that localized tau pathology involving the pars opercularis extended to the precentral gyrus, prefrontal cortex, and brainstem. This case report demonstrates that PSP-F can present as a PNFA due to crossed aphasia.

Persistent intrathecal interleukin-8 production in a patient with SARS-CoV-2-related encephalopathy presenting aphasia: a case report.

BACKGROUND: Neurological manifestations of coronavirus disease 2019 (COVID-19) are increasingly recognized and include encephalopathy, although direct infection of the brain by SARS-CoV-2 remains controversial. We herein report the clinical course and cytokine profiles of a patient with severe SARS-CoV-2-related encephalopathy presenting aphasia. CASE PRESENTATION: An 81-year-old man developed acute consciousness disturbance and status epileptics several days after SARS-CoV-2 infection. Following treatment with remdesivir and dexamethasone, his consciousness and epileptic seizures improved; however, amnestic aphasia and agraphia remained. Two months after methylprednisolone pulse and intravenous immunoglobulin, his neurological deficits improved. We found increased levels of interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1), but not IL-2 and IL-10 in the serum and cerebrospinal fluid (CSF), and the levels of serum IL-6 and MCP-1 were much higher than those in the CSF. The level of IL-8 in the CSF after immunotherapy was four times higher than that before immunotherapy. CONCLUSION: The cytokine profile of our patient was similar to that seen in severe SARS-CoV-2-related encephalopathy. We demonstrated (i) that the characteristic aphasia can occur as a focal neurological deficit associated with SARS-CoV-2-related encephalopathy, and (ii) that IL8-mediated central nervous system inflammation follows systemic inflammation in SARS-CoV-2-related encephalopathy and can persist and worsen even after immunotherapy. Monitoring IL-8 in CSF, and long-term corticosteroids may be required for treating SARS-CoV-2-related encephalopathy.

Clinicopathological findings of a mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes/Leigh syndrome overlap patient with a novel m.3482A>G mutation in MT-ND1.

We report clinicopathological findings of a patient with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes/Leigh syndrome (MELAS/LS) associated with a novel m.3482A>G mutation in MT-ND1. A 41-year-old woman had experienced multiple stroke-like episodes since age 16. She developed akinetic mutism two months before admission to our hospital. Neurological examination revealed akinetic mutism, bilateral deafness, and muscular atrophy. Cerebrospinal fluid tests revealed elevated pyruvate and lactate levels. Fluid-attenuated inversion recovery images on magnetic resonance imaging showed hyperintense areas in the right frontal and both sides of temporal and occipital lobes, both sides of the striatum, and the midbrain. Muscle biopsy revealed strongly succinate dehydrogenase-reactive blood vessels. L-arginine therapy improved her consciousness and prevented further stroke-like episodes. However, she died from aspiration pneumonia. Postmortem autopsy revealed scattered infarct-like lesions with cavitation in the cerebral cortex and necrotic lesions in the striatum and midbrain. The patient was pathologically confirmed as having MELAS/LS based on two characteristic clinicopathological findings: presenting MELAS/LS overlap phenotype and effectiveness of L-arginine treatment.

Albumin-bilirubin score for predicting neuropsychiatric symptoms in patients receiving ifosfamide-based chemotherapy.

WHAT IS KNOWN AND OBJECTIVE: Ifosfamide, an alkylating agent, is widely used in the treatment of malignant diseases. However, these treatments are often limited due to the incidence of neuropsychiatric symptoms such as delirium, seizures, hallucinations and agitation. In this study, we examined risk factors for neuropsychiatric symptoms in patients receiving ifosfamide-based chemotherapy. METHODS: The study cases were patients with cancer receiving ifosfamide-based chemotherapy between April 2007 and March 2018. Risk analysis for ifosfamide-related neuropsychiatric symptoms was determined by time-dependent Cox proportional hazard regression analysis. RESULTS AND DISCUSSION: Of 183 eligible patients, 32 patients (17.5%) experienced ifosfamide-related neuropsychiatric symptoms. Time-dependent Cox proportional hazard model showed that the albumin-bilirubin (ALBI) score was significantly correlated with the incidence of ifosfamide-related neuropsychiatric symptoms (hazard ratio [HR] =1.45, 95% confidence interval [CI] = 1.05-2.01, p = 0.025). Additionally, there were correlations between the predicted risk of neuropsychiatric symptoms and ifosfamide-dose per cycle (HR =0.51, 95% CI = 0.27-0.94, p = 0.030) and creatinine clearance (Ccr) (HR = 0.53, 95% CI = 0.28-1.00, p = 0.050). In contrast, neither serum albumin nor total bilirubin was a significant risk factor for neuropsychiatric symptoms. WHAT IS NEW AND CONCLUSION: These findings indicate that ALBI score may be a useful biomarker for predicting neuropsychiatric symptoms in patients receiving ifosfamide-based chemotherapy.

Retinal dystrophy associated with a single-base deletion mutation in mitochondrial DNA 3271 in patient with MELAS syndrome.

PURPOSE: Mitochondrial encephalopathy with lactic acid and stroke-like episodes (MELAS) is caused by mutations in the mitochondrial DNA. Approximately 80% of MELAS patients have an A > G transition mutation at nucleotide pair 3243 in the mitochondrial DNA, m.3243A > G. There are also MELAS patients with a one-base deletion at nucleotide pair 3271 in the mitochondrial DNA, m.3271delT, but these cases are very rare. We report a case of MELAS with the m.3271delT and describe the retinal structure and electrophysiological alterations. METHODS: The retinal structure and function of a 37-year-old woman who was referred to our clinic for of nyctalopia were studied. Standard ophthalmological examinations including the medical history, measurements of the best-corrected visual acuity, intraocular pressures, and slit-lamp biomicroscopy, ophthalmoscopy, fluorescein angiography, fundus autofluorescence, spectral-domain optical coherence tomography (SD-OCT), full-field electroretinography (ERG), and multifocal electroretinography (mfERG) were performed. RESULTS: Fundus examination showed bilateral hypopigmentary changes of the retinal pigment epithelium which extended from the posterior pole to the equator. Fluorescein angiography showed patchy hyperfluorescence due to window defects at the atrophic areas. Fundus autofluorescence demonstrated mild hyperfluorescent lesions in both eyes. SD-OCT showed that the interdigitation zone was indistinct in both eyes, and the inner nuclear layer was slightly thinner. The amplitudes of the rod, cone, and 30-Hz flicker ERGs were severely reduced, and the implicit times were prolonged. The a- and b-waves of the bright-flash mixed rod-cone ERGs were also reduced. The dark-adapted oscillatory potentials were reduced. The amplitudes of the mfERGs were severely depressed except at the fovea in both eyes. CONCLUSIONS: These findings indicate that the RPE atrophy was wider and the rod dysfunction was more severe affected than that of previously reported MELAS cases with the m.3243A > G mutation.

Higher levels of progranulin in cerebrospinal fluid of patients with lymphoma and carcinoma with CNS metastasis.

Assessing central nervous system (CNS) involvement in patients with lymphoma or carcinoma is important in determining therapy and prognosis. Progranulin (PGRN) is a secreted glycosylated protein with roles in cancer growth and survival; it is highly expressed in aggressive cancer cell lines and specimens from many cancer types. We examined PRGN levels by Enzyme Immuno-Assay (EIA) in cerebrospinal fluid (CSF) samples from 230 patients, including 18 with lymphoma [12 with CNS metastasis (CNS+); 6 without CNS metastasis (CNS-)], 21 with carcinomas (10 CNS+; 11 CNS-), and 191 control patients with non-cancer neurological diseases, and compared PRGN levels among these disease groups. Median CSF PGRN levels in the CNS+ lymphoma group were significantly higher than in the CNS- lymphoma and control non-cancer groups; and were also significantly higher in the CNS+ carcinoma group than in the CNS- carcinoma and control groups, except for patients with infectious neurological disorders. Receiver operating characteristic curve analyses revealed that CSF PGRN levels distinguished CNS+ lymphoma from CNS- lymphoma and non-cancer neurological diseases [area under curve (AUC): 0.969]; and distinguished CNS+ carcinomas from CNS- carcinomas and non-cancer neurological diseases (AUC: 0.918). We report here, for the first time, that CSF PGRN levels are higher in patients with CNS+ lymphoma and carcinomas compared to corresponding CNS- diseases. This would imply that measuring CSF PGRN levels could be used to monitor CNS+ lymphoma and metastasis.

Characteristic microglial features in patients with hereditary diffuse leukoencephalopathy with spheroids.

OBJECTIVE: To clarify the histopathological alterations of microglia in the brains of patients with hereditary diffuse leukoencephalopathy with spheroids (HDLS) caused by mutations of the gene encoding the colony stimulating factor-1 receptor (CSF-1R). METHODS: We examined 5 autopsied brains and 1 biopsy specimen from a total of 6 patients with CSF-1R mutations. Detailed immunohistochemical, biochemical, and ultrastructural features of microglia were examined, and quantitative analyses were performed. RESULTS: In layers 3 to 4 of the frontal cortex in HDLS brains, microglia showed relatively uniform and delicate morphology, with thin and winding processes accompanying knotlike structures, and significantly smaller areas of Iba1 immunoreactivity and lower numbers of Iba1-positive cells were evident in comparison with control brains. On the other hand, in layers 5 to 6 and the underlying white matter, microglia were distributed unevenly; that is, in some areas they had accumulated densely, whereas in others they were scattered. Immunoblot analyses of microglia-associated proteins, including CD11b and DAP12, revealed that HDLS brains had significantly lower amounts of these proteins than diseased controls, although Ki-67-positive proliferative microglia were not reduced. Ultrastructurally, the microglial cytoplasm and processes in HDLS showed vesiculation of the rough endoplasmic reticulum and disaggregated polyribosomes, indicating depression of protein synthesis. On the other hand, macrophages were immunonegative for GLUT-5 or P2ry12, indicating that they were derived from bone marrow. INTERPRETATION: The pathogenesis of HDLS seems to be associated with microglial vulnerability and morphological alterations. Ann Neurol 2016;80:554-565.

Association between naturally occurring anti-amyloid ß autoantibodies and medial temporal lobe atrophy in Alzheimer's disease.

BACKGROUND: Naturally occurring autoantibodies against amyloid ß (Aß) peptide exist in the serum and cerebrospinal fluid (CSF) of healthy individuals. Recently, it was reported that administration of intravenous immunoglobulin at the mild cognitive impairment (MCI) stage of Alzheimer's disease (AD) reduces brain atrophy. OBJECTIVE: To examine the association between naturally occurring anti-Aß autoantibodies and brain atrophy in patients with cognitive impairment. METHODS: Serum and CSF levels of anti-Aß autoantibodies and CSF biomarkers were evaluated in 68 patients with cognitive impairment, comprising 44 patients with AD, 19 patients with amnestic MCI and five patients with non-Alzheimer's dementia. The degree of brain atrophy was assessed using the voxel-based specific regional analysis system for AD, which targets the volume of interest (VOI) in medial temporal structures, including the whole hippocampus, entorhinal cortex and amygdala. RESULTS: CSF levels of anti-Aß autoantibodies were inversely correlated with the extent and severity of VOI atrophy, and the ratio of VOI/grey matter atrophy in patients with AD, but not in MCI or non-AD patients. Serum levels of anti-Aß autoantibodies were not associated with these parameters in any of the patient groups. CONCLUSIONS: These results indicate that CSF levels of naturally occurring anti-Aß autoantibodies are inversely associated with the degree of the VOI atrophy in patients with AD. Although the mechanism is unclear, CSF levels of naturally occurring anti-Aß autoantibodies may be implicated in the progression of atrophy of the whole hippocampus, entorhinal cortex and amygdala, in AD.

A first case of adrenomyeloneuropathy with mutation Y174S of the adrenoleukodystrophy gene.

The patient first noticed spasticity and weakness in his legs. He was diagnosed with chronic myelogenous leukemia (CML); the symptoms were attributed to neuropathy associated with CML. By treatment with dasatinib, he achieved complete hematological remission, but his difficulty in walking was not improved. His neurological symptom worsened together with an increase in body temperature and then disappeared together with a normalized body temperature, which may be attributed to the Uhthoff's phenomenon often observed in multiple sclerosis. He later developed acute fever, vomiting and a high adrenocorticotropic hormone (ACTH) level, which was diagnosed as adrenal insufficiency. Eventually, he was diagnosed with a milder form of adrenoleukodystrophy (ALD), adrenomyeloneuropathy (AMN) by increased levels of Very Long Chain Fatty Acids (VLCFAs) and genetic testing of the ATP binding cassette subfamily D member 1 (ABCD1) gene. A missense mutation (c.521A>C, p.Tyr174Ser), previously reported to induce severe cerebral ALD, was detected in exon1. Thus, clinical manifestation of ALD is determined by interaction between the primary ABCD1 mutation and modifying genetic and environmental factors. Physicians should be aware of the differing symptoms of AMN and determine the level of VLCFAs in patients having primary adrenal insufficiency, especially those complicated with neurological dysfunction. This is the first report of an AMN patient complicated with CML.

[Clinical features and effects of shunt surgery in patients with progressive supranuclear palsy and idiopathic normal pressure hydrocephalus].

This study aimed to retrospectively review the frequency and clinical features of 13 patients with progressive supranuclear palsy (PSP) and idiopathic normal pressure hydrocephalus (iNPH). All patients were found to have PSP-Richardson's syndrome (PSP-RS). Shunt surgery was effective in 5 of 11 patients (45.5%). A comparison of these 5 patients who responded to shunt surgery versus the remaining 6 patients revealed a significant difference in the reduction of frontal lobe blood flow on cerebral perfusion single-photon emission computed tomography (SPECT) (P = 0.018). These results suggest that PSP-RS is common in patients with PSP and iNPH and indicate the usefulness of cerebral perfusion SPECT in estimating the effect of shunt surgery.

Corticosteroid therapy in a patient with cerebral amyloid angiopathy-related inflammation.

We studied longitudinal changes of the levels of anti-amyloid ß (anti-Aß) antibody, amyloid ß (Aß) protein, and interleukin 8 (IL-8) in cerebrospinal fluid (CSF) of a patient with cerebral amyloid angiopathy-related inflammation (CAA-ri) in whom steroid treatment resulted in clinical improvement. The diagnosis of CAA-ri was established with brain biopsy. Levels of anti-Aß 42 antibody, Aß 40, Aß 42 and IL-8 in CSF were measured in the CAA-ri patient at 23 time points in the 8-month clinical course. These CSF samples were divided into 2 groups: those obtained before (n = 12) and those after (n = 11) oral corticosteroid therapy was started. We compared these levels between CSF samples obtained before and after therapy. The mean levels of anti-Aß 42 antibody and IL-8 were significantly higher in CSF samples of the CAA-ri patient before oral corticosteroid therapy than those after therapy. A positive correlation was noted between levels of anti-Aß 42 antibodies and IL-8 in CSF of this patient. There were no significant differences of mean levels of Aß 40 and Aß 42 between CSF samples obtained before and after oral corticosteroid therapy. It was possible that the autoinflammatory process with anti-Aß 42 antibodies and IL-8 may have been involved in the pathogenesis of CAA-ri, and that corticosteroid therapy directly affected levels of anti-Aß 42 antibody and IL-8. In summary, CAA-ri encephalopathy is a relapsing or progressive disorder and may be treatable by adequate immunosuppressive therapy. The anti-Aß 42 antibody in CSF is a useful biological marker for therapeutic monitoring of CAA-ri.

Anti-N-methyl-d-aspartate receptor encephalitis preceded by meningitis lasting up to 60 days.

Long-lasting meningitis complicated by N-methyl-d-aspartate receptor (NMDAR) encephalitis has not been discussed widely in the literature. Herein, we present two cases of anti-NMDAR encephalitis preceded by meningitis. The patients had 60- and 22-day periods of preceding meningitis, which improved with intravenous methylprednisolone and plasmapheresis. No tumors were detected in either of the patients. Although meningitis preceding anti-NMDAR encephalitis is not rare, our patients, especially those who had it for a duration of 60 days, had longer durations of meningitis. This manuscript foregrounds that anti-NMDAR encephalitis might be included in the differential diagnosis of long-lasting meningitis.

Possible Autoimmune Encephalitis Associated with the Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Variant Successfully Treated with Steroids.

We encountered a 55-year-old woman with possible autoimmune encephalitis associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant. She was not vaccinated against coronavirus disease 2019 (COVID-19). Consciousness disturbance, myoclonic-like movements and gait disturbance occurred 10 days after the COVID-19 symptom onset. Her neurological symptoms improved two days after methylprednisolone pulse therapy. Cerebrospinal fluid (CSF) was negative for SARS-CoV-2 reverse transcription-polymerase chain reaction, the CSF-to-serum albumin quotient was mildly elevated, and interleukin 6 and 8 levels were normal in serum but mildly elevated in CSF. Omicron variant infection may increase blood-brain barrier permeability and intrathecal inflammation, causing autoimmune encephalitis.

The Usefulness of Swallowing Pressure Assessment in the Identification of Mild Pharyngeal Weakness of Myasthenia Gravis: A Case Report.

Despite the clinical impact of dysphagia in myasthenia gravis (MG), a standard protocol for diagnosing dysphagia reliably has not yet been established. High-resolution manometry (HRM) provides precise information on pharyngeal pressure. We hypothesized that swallowing pressure assessment using HRM during the edrophonium chloride (EC) test could identify mild bulbar symptoms with no abnormalities on videoendoscopic (VE) and videofluorographic (VF) examination of swallowing, and we tested this hypothesis on a 72-year-old female patient diagnosed with ocular MG who developed slight pharyngeal discomfort over 3 months. The patient's ocular symptoms were stable with pyridostigmine medication. VE and VF revealed no abnormalities. The swallowing pressure along the pharynx was measured using HRM during the EC test. HRM parameters, including velopharyngeal contractile integral and meso-hypopharyngeal contractile integral, were evaluated. These parameters were assessed for three swallows using 3 mL of water. After EC injection, the values of the velopharyngeal contractile integral (78.0 ± 5.4 vs. 134.7 ± 1.3 mm Hg cm·s) and the meso-hypopharyngeal contractile integral were both higher (130.6 ± 1.5 vs. 284.2 ± 11.9 mm Hg cm·s) than those observed before EC injection. Chest computed tomography revealed a thymoma that had not been observed in previous examinations. The patient was diagnosed with thymoma-associated MG. Intravenous immunoglobulin therapy improved the mild dysphagia. We concluded that swallowing pressure assessment during the EC test may be helpful in identifying mild bulbar symptoms in patients with MG.

Favorable Outcome with Intravenous Immunoglobulin Therapy in Late-Onset Anti-mGluR1 Encephalitis: A Case Report and Literature Review.

Anti-metabotropic glutamate receptor 1 (mGluR1) encephalitis is a rare autoimmune disorder manifesting with cerebellar syndrome. Patients with mGluR1 encephalitis have been treated with immunomodulatory therapies; however, little is known about the efficacy of this therapy. A 58-year-old Japanese woman presented with dizziness when walking and standing up. Symptoms persisted and the patient gradually deteriorated. The neurological examination revealed a broad-based gait, horizontal and slightly gaze-evoked nystagmus, noticeable head titubation, and truncal ataxia without limb ataxia. Magnetic resonance imaging was normal. The 123I-isopropyl-iodoamphetamine single-photon emission-computed tomography scans showed normal cerebellar perfusion. Based on a positive antibody test for anti-mGluR1, the patient was diagnosed with anti-mGluR1 encephalitis. She was treated with intravenous methylprednisolone and intravenous immunoglobulin (IVIg). Symptoms gradually improved over 1 month and almost disappeared after additional IVIg therapy. Anti-mGluR1 encephalitis is a rare disease, and effective treatment is unclear. In this case, a favorable outcome was obtained with immunomodulatory therapy, even though the neurological disability of the disease course is worse. We emphasize the importance of early diagnosis and therapeutic intervention, suspecting the disease on the basis of its characteristic symptoms.

[Novel Autoantibody-Related Encephalitis: anti-mGluR1 encephalitis, anti-IgLON5 disease, autoimmune GFAP astrocytopathy].

Various neurological syndromes are associated with autoimmune encephalitis. Anti-mGluR1 antibody encephalitis presents mainly as subacute cerebellar ataxia, while behavioral changes and involuntary movements also occur. Anti-IgLON5 disease presents mainly as a sleep disorder. It is sometimes difficult to distinguish these diseases from other neurodegenerative diseases. Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is seen in meningoencephalomyelitis of unknown origin. Because these new autoimmune encephalitis diseases might be treatable, early diagnosis and treatment are necessary and important to improving the condition of patients with these diseases.