Differential immunophenotypes of neuronal cytoplasmic inclusions in the dentate gyrus of multiple system atrophy and their association with clinicopathological features.

Although hippocampal pathologies of multiple system atrophy (MSA) and their association with dementia have been reported, no studies have reported clinicopathological differences among MSA patients with and without neuronal cytoplasmic inclusions (NCIs) in the dentate gyrus (dntNCIs). We investigated hippocampal NCI pathology in 18 MSA patient autopsies, focusing on phosphorylated α-synuclein (pAS)- and phosphorylated tau (pT)-positive dntNCIs. There were 8 MSA patients without and 10 with dntNCIs. The latter group was subclassified by immunophenotype: those with pAS-positive dntNCIs (pAS-dntNCI subtype), those with pT-positive dntNCIs (pT-dntNCI subtype), and those with both types of dntNCIs. MSA patients with dntNCIs survived longer with prolonged tracheostomy and had dementia more frequently than those without dntNCIs. The brain weights of patients with dntNCIs were lower than those without dntNCIs. The presence of dementia was similar among the dntNCI subtypes. The pAS-dntNCI subtype was associated with longer survival and smaller brain weights; the pT-dntNCI subtype exhibited more frequent tau pathologies than the pAS-dntNCI subtype. Thus, MSA with dntNCIs is a possible pathological subtype of longer survivors that correlates with longer disease duration, prolonged tracheostomy, and high frequency of dementia. Understanding clinicopathological differences in MSA patients with and without dntNCIs may lead to improved personalized management strategies.

An Autopsy Case of Elderly Onset Brainstem Acute Disseminated Encephalomyelitis.

Acute disseminated encephalomyelitis (ADEM), which is a disease that causes multifocal inflammatory demyelination of the central nervous system, occurs predominantly in children and young adults. We report an autopsy case of an elderly man with brainstem ADEM that progressed over a period of about 3 months. An 82-year-old man developed disturbance of consciousness, dysphagia, and ataxic gait over a period of about 3 months. He was admitted to another hospital for aspiration pneumonia and recovered but was transferred to our hospital due to prolonged disturbance of consciousness. The patient was able to follow simple commands but had a tendency to somnolence. In addition to meningeal stimulation signs, the patient had left-dominant upper and lower limb ataxia and right-dominant limb spasticity. Brain FLAIR/T2-weighted imaging showed high-intensity lesions from the brainstem to the middle cerebellar peduncle bilaterally, medulla oblongata and upper cervical spinal cord, and T1-weighted imaging revealed contrast-enhanced lesions in the left middle cerebellar peduncle and cervical spinal cord. Although spinal fluid examination revealed elevated proteins, other laboratory tests indicated no evidence of infection, vasculitis, collagen diseases or tumors, and anti-ganglioside, anti-AQP4 and anti-MOG antibodies were negative. After admission, the patient again developed aspiration pneumonia, which progressed to acute respiratory distress syndrome, and he died on the 15th day of hospitalization. Autopsy findings indicated acute and subacute demyelination mainly in the brainstem and cerebellum, and perivascular lymphocyte and macrophage infiltration in the areas of demyelination. A postmortem diagnosis of ADEM was made based on the generally monophasic course of the disease and the absence of regenerating myelinated sheaths. There are very few reports of elderly patients with brainstem ADEM. ADEM should be considered as a differential diagnosis in patients with brainstem encephalitis.

Leucine-rich Glioma-inactivated 1 Encephalitis Followed by Isaacs Syndrome: Alternating Presence of Pathogenic Autoantibodies to Leucine-rich Glioma-inactivated 1 and Contactin-associated Protein-like 2.

The coexistence of leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) autoantibodies in the same individual is surprisingly often observed. We herein report the first case of LGI1 encephalitis followed by Isaacs syndrome in which LGI1 and CASPR2 antibodies in the serum and cerebrospinal fluid (CSF) were measured during the entire disease course. After the resolution of limbic encephalitis, LGI1 antibodies disappeared from the CSF simultaneously with the appearance of CASPR2 antibodies in the serum. The alternating presence of these pathogenic autoantibodies along with the clinical and phenotypic alternations suggested that LGI1 encephalitis was associated with CASPR2 autoantibody production in the peripheral tissue, leading to CASPR2-associated Isaacs syndrome.

Myoclonic Epilepsy with Ragged-red Fibers with Intranuclear Inclusions.

We herein report a case of myoclonic epilepsy with ragged-red fibers (MERRF) harboring a novel variant in mitochondrial cysteine transfer RNA (MT-TC). A 68-year-old woman presented with progressive myoclonic epilepsy with optic atrophy and peripheral neuropathy. A skin biopsy revealed p62-positive intranuclear inclusions. No mutations were found in the causative genes for diseases known to be related to intranuclear inclusions; however, a novel variant in MT-TC was found. The association between intranuclear inclusions and this newly identified MERRF-associated variant is unclear; however, the rare complication of intranuclear inclusions in a patient with typical MERRF symptoms should be noted for future studies.

Saccharopinuria accompanied by hyperammonemia and hypercitrullinemia presented with elderly-onset epilepsy, progressive cognitive decline, and gait ataxia.

We report a case of saccharopinuria with hyperammonemia and hypercitrullinemia in a Japanese woman who presented with elderly-onset epilepsy, progressive cognitive decline, and gait ataxia. Blood amino acid analysis revealed an increase in citrulline, cystine, and lysine levels, and urine amino acid analysis showed increased citrulline and cystine levels. Urine metabolomics revealed an increased saccharopine level, leading to the definitive diagnosis of saccharopinuria. In western blots of liver biopsy samples, normal citrin levels were observed, suggesting that adult-onset citrullinemia type 2 (CTLN2) was not present. In addition, decreased argininosuccinate synthetase (ASS) levels were observed, and ASS1 gene, a causative gene for citrullinemia type 1 (CTLN1), was analyzed, but no gene mutations were found. Because the causes of hypercitrullinemia were not clear, it might be secondary to saccharopinuria. Muscle biopsy findings of the biceps brachii revealed diminished cytochrome c oxidase (COX) activity, mitochondrial abnormalities on electron microscopy and p62- positive structures in immunohistochemical analyses. Saccharopinuria is generally considered a benign metabolic variant, but our case showed elevated lysine and saccharopine levels causing ornithine circuit damage, mitochondrial dysfunction, and autophagy disorders. This may lead to so far unknown neurological disorders.

Immunoglobulin G4-related Disease Accompanied by Peripheral Neuropathy: A Report of Two Cases.

Due to its rarity and the limited literature, the clinicopathological characteristics of peripheral nerve involvement in immunoglobulin G4 (IgG4)-related disease are unknown. We present two cases of IgG4-related disease, accompanied by peripheral neuropathy, presenting as unilateral ptosis (case 1) and sclerosing cholangitis (case 2), respectively. In both cases, sural nerve biopsy indicated vasculitis as the underlying pathophysiology; the peripheral neuropathy was refractory to corticosteroid therapy. In contrast to the previously proposed pathomechanism of IgG4-related neuropathy (direct lymphoplasmacytic infiltration), the pathological findings in our cases suggest that vasculitis occurs secondary to systemic autoimmune conditions.

Clinical characteristics of children and adults with anti-N-methyl-D-aspartate receptor encephalitis.

OBJECTIVES: To investigate the clinical characteristics of children and adults with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. METHODS: Patients who tested positive for the anti-NMDAR antibody (by a cell-based assay) in the cerebrospinal fluid were enrolled. They were divided into two groups based on age (<16 years or older). RESULTS: Three children (two males and one female) and four adults (one male and three females) were examined. The age at onset was 3.0 ± 1.41 years (range: 2-5 years) for the children and 31.8 ± 6.80 years (range: 20-36 years) for the adults. The follow-up duration was 82.7 ± 23.80 months (range: 52-110 months) for the children and 61.5 ± 12.54 months (range: 43-78 months) for the adults. Prodromal symptoms such as fever and headache were observed in three adults. Two children received influenza vaccination before the onset of encephalitis. Brain magnetic resonance imaging abnormalities were observed in three children and one adult. Basal ganglia lesions were observed in two children and one adult, and the two children showed dystonia. Two children and one adult without neoplasms experienced recurrences. The modified Rankin Scale scores at the final follow-up tended to be worse in children than in adults. CONCLUSION: Three patients had basal ganglia lesions, and two of them showed dystonia. Dystonia with basal ganglia lesions has been rarely reported in anti-NMDAR encephalitis but should be noted as a significant symptom, which severely affects the activities of daily life.

T-Cell/Histiocyte-Rich Large B-Cell Lymphoma Presented as T-Lymphoid Hyperplasia Involving the Central Nervous System.

We herein report a case of T-cell/histiocyte-rich large B-cell lymphoma which initially presented as a self-limiting T-lymphoproliferative disorder involving multiple extranodal and extrapulmonary organs, such as the salivary gland, the liver, and the central nervous system. Repeated biopsies only revealed polyclonal T-lymphocytosis without the presence of atypical B-cells. Angiocentric cellular infiltration was absent, thus ruling out lymphomatoid granulomatosis. A recurrence in the lymphatic system finally revealed a small population of pathognomonic atypical B-cells, which led to the diagnosis. The clinical dilemma in the diagnosis and management of this indeterminate condition points to limitations in the current nosology.

Mutations in MME cause an autosomal-recessive Charcot-Marie-Tooth disease type 2.

OBJECTIVE: The objective of this study was to identify new causes of Charcot-Marie-Tooth (CMT) disease in patients with autosomal-recessive (AR) CMT. METHODS: To efficiently identify novel causative genes for AR-CMT, we analyzed 303 unrelated Japanese patients with CMT using whole-exome sequencing and extracted recessive variants/genes shared among multiple patients. We performed mutation screening of the newly identified membrane metalloendopeptidase (MME) gene in 354 additional patients with CMT. We clinically, genetically, pathologically, and radiologically examined 10 patients with the MME mutation. RESULTS: We identified recessive mutations in MME in 10 patients. The MME gene encodes neprilysin (NEP), which is well known to be one of the most prominent beta-amyloid (Aß)-degrading enzymes. All patients had a similar phenotype consistent with late-onset axonal neuropathy. They showed muscle weakness, atrophy, and sensory disturbance in the lower extremities. All the MME mutations could be loss-of-function mutations, and we confirmed a lack/decrease of NEP protein expression in a peripheral nerve. No patients showed symptoms of dementia, and 1 patient showed no excess Aß in Pittsburgh compound-B positron emission tomography imaging. INTERPRETATION: Our results indicate that loss-of-function MME mutations are the most frequent cause of adult-onset AR-CMT2 in Japan, and we propose that this new disease should be termed AR-CMT2T. A loss-of-function MME mutation did not cause early-onset Alzheimer's disease. Identifying the MME mutation responsible for AR-CMT could improve the rate of molecular diagnosis and the understanding of the molecular mechanisms of CMT.

[Headache as a manifestation of SAPHO syndrome with a lesion extending to the dura mater, parietal bone, and temporal muscle].

A 50-year-old woman with a history of palmoplantar pustulosis, femur osteomyelitis, and sterno-costo-clavicular hyperostosis presented with a chronic severe left temporal headache that had progressed during the previous year. Her CRP level was elevated. Cranial images showed Gadolinium-enhancement of the left temporal muscle, left parietal bone and dura mater. (99m)Tc-HMDP scintigram showed increased uptake in the left parietal bone, left sterno-costo-clavicular joint, right femoral head and intervertebral joints. Biopsy of the lesion demonstrated 1) proliferation of connective tissue in both perimysium and endomysium of the temporal muscle with mild inflammatory cell infiltration within the interstitium, 2) marked infiltration of granulocytes to the bone marrow of the parietal bone, 3) necrosis and moderate fibrosis in the interstitium with inflammatory cell infiltration in the parietal bone, and 4) moderate fibrosis and slight infiltration of inflammatory cells in the dura mater. The patient was diagnosed with a cranial lesion of synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome. There was a moderate response to treatment with intravenous steroid pulse therapy and subsequent methotrexate. In a case of headache accompanied by inflammatory response, palmoplantar pustulosis and joint lesions such as hyperostosis, the possibility of a rare cranial manifestation of SAPHO syndrome should be considered.

Spinal segmental myoclonus during postural maintenance in a patient with cervical spondylosis: a case report.

Spinal segmental myoclonus is defined as a rare involuntary movement characterized by myoclonic jerks of spinal origin. We describe the case of a 62-year-old woman who developed spinal segmental myoclonus 4 months after undergoing cervical laminoplasty for ossification of the posterior longitudinal ligament. Myoclonic jerks were observed in the upper trapezius innervated by C3-4, which corresponded to the level of myelomalacia. These jerks were elicited and aggravated in the sitting and standing positions but were completely suppressed in the supine position. The myoclonus was refractory to medication but improved with the use of a soft neck brace.

[Experimental vocal cord abduction impairment with an artificial vocal cord].

Non-invasive positive pressure ventilation (NPPV) has recently been applied to the patients with multiple system atrophy (MSA) with various respiratory complications including vocal cord abduction impairment and respiratory disturbance by the central origin. Any consensus guidelines on setting up the inspiratory positive airway pressure (IPAP) and expiratory one (EPAP), however, have not been raised yet. To investigate this problem, we made the upper airway tract model with moderately and severely narrow glottis using a training/test lung and the artificial vocal cord which was developed for a humanoid talking robot in Waseda University. The artificial vocal cord was molded out of a high performance thermoplastic rubber in imitation of the human larynx. Previous studies using with a high-speed camera and a sound analyzer showed that the artificial vocal cord resembled human larynx closely both morphologically and functionally. The opening and closing movements of the artificial vocal cord were observed fiberscopically under various conditions of IPAP (4-20 cmH2O) and EPAP (4-10 cmH2O). The maximal glottic width during inspiration and expiration were measured by a pair of calipers on the video-monitored display. Both of the moderately and the severely narrow artificial vocal cords without non-paralytic factors showed typical paradoxical movement showing adduction in inspiration and abduction in expiration, which is characteristic to vocal cord abductor impairment seen in MSA. In the model with moderately severe narrow glottis, this paradoxical movement was released under any positive pressures of continuous (CPAP) and bilevel (Bilevel PAP) modes. In the model with severely narrow glottis, however, there existed a threshold in setting up the optimal EPAP to release the paradoxical movement. In conclusion, EPAP-leading procedure seems to be preferable to IPAP-leading procedure to dilate the narrow glottis as a pneumatic splint in the managements of the patients with MSA presenting with a paralytic type of vocal cord abductor impairment.

A variant form of nasogastric tube syndrome.

Nasogastric tube syndrome named by Sofferman et al in 1981 is a laryngeal complication presenting with life-threatening vocal cord abductor paralysis derived from peroforation of the NG tube-induced esophageal ulcer. As compared with the previously reported cases of this syndrome, our 4 autopsied patients were so peculiar in the following two points that vocal cord abductor paralysis developed repeatedly and no esophageal ulcer was present in spite of the presence of the laryngeal abductor muscle injury. We hypothesized that the etiology of such a variant form was circulatory injury of the laryngeal abductor muscle which was caused by the compression of the postcricoid blood vessels perfusing this muscle. Nasogastric tube syndrome, which is treatable by decannulation, cannot be ruled out even if no esophageal ulcer is detected by fiberoptic laryngoscopy.