Stage-dependent immunity orchestrates AQP4 antibody-guided NMOSD pathology: a role for netting neutrophils with resident memory T cells in situ.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the CNS characterized by the production of disease-specific autoantibodies against aquaporin-4 (AQP4) water channels. Animal model studies suggest that anti-AQP4 antibodies cause a loss of AQP4-expressing astrocytes, primarily via complement-dependent cytotoxicity. Nonetheless, several aspects of the disease remain unclear, including: how anti-AQP4 antibodies cross the blood-brain barrier from the periphery to the CNS; how NMOSD expands into longitudinally extensive transverse myelitis or optic neuritis; how multiphasic courses occur; and how to prevent attacks without depleting circulating anti-AQP4 antibodies, especially when employing B-cell-depleting therapies. To address these knowledge gaps, we conducted a comprehensive 'stage-dependent' investigation of immune cell elements in situ in human NMOSD lesions, based on neuropathological techniques for autopsied/biopsied CNS materials. The present study provided three major findings. First, activated or netting neutrophils and melanoma cell adhesion molecule-positive (MCAM+) helper T (TH) 17/cytotoxic T (TC) 17 cells are prominent, and the numbers of these correlate with the size of NMOSD lesions in the initial or early-active stages. Second, forkhead box P3-positive (FOXP3+) regulatory T (Treg) cells are recruited to NMOSD lesions during the initial, early-active or late-active stages, suggesting rapid suppression of proinflammatory autoimmune events in the active stages of NMOSD. Third, compartmentalized resident memory immune cells, including CD103+ tissue-resident memory T (TRM) cells with long-lasting inflammatory potential, are detected under "standby" conditions in all stages. Furthermore, CD103+ TRM cells express high levels of granzyme B/perforin-1 in the initial or early-active stages of NMOSD in situ. We infer that stage-dependent compartmentalized immune traits orchestrate the pathology of anti-AQP4 antibody-guided NMOSD in situ. Our work further suggests that targeting activated/netting neutrophils, MCAM+ TH17/TC17 cells, and CD103+ TRM cells, as well as promoting the expansion of FOXP3+ Treg cells, may be effective in treating and preventing relapses of NMOSD.

The effects of visual cues from optical stimulation devices on gait disturbance in patients with Parkinson's disease.

[Purpose] The purpose of this study was to identify the optimal visual cues for gait disturbance in patients with Parkinson's disease based on the luminous duration and the individual patient preferences for a wearable visual cue device. [Participants and Methods] Twenty-four patients with Parkinson's disease walked while wearing only a visual cue device in the control condition. They then walked while the device was set to two stimulus conditions: the luminous duration at 10% and 50% of the individual gait cycle. After walking under the two stimulus conditions, the patients were asked for their preferred visual cue condition. The walking results were compared between the two stimulus conditions and the control condition. Gait parameters were compared among the three conditions. The comparisons with preference, non-preference, and control conditions were also made for the same gait parameter. [Results] When compared to the control condition, walking with visual cues in the stimulus conditions reduced stride duration and increased cadence. The preference and non-preference conditions had shorter stride durations than the control condition. Furthermore, the preference condition also resulted in a faster gait speed than the non-preference condition. [Conclusion] This study suggests that a wearable visual cue device with the patient's preferred luminous duration may help manage gait disturbance in patients with Parkinson's disease.

Like a Rolling Stone: Year-Over-Year Growth of a Rectal Fecalith.

The inability to pass stool for a prolonged period can lead to the formation of fecaliths, which occurs most often in the colon or rectum. Although large fecaliths can lead to serious or life-threatening complications, the detailed process of their formation is unknown. This report describes a 65-year-old woman who presented with melena due to ischemic proctitis caused by a large fecalith. On computed tomography, the fecalith showed a unique multilayered calcification sign. We successfully dismantled and removed the fecalith transanally, assisted by a traction method using a balloon catheter. A review of imaging studies from 6 years ago revealed the growth of the fecalith over the previous year and provided an insight into the mechanism underlying the development of large fecaliths.

Reversible cerebral vasoconstriction syndrome with cardiac involvement during treatment for iron deficiency anemia: caser report.

BACKGROUND: The diagnosis and therapy of reversible cerebral vasoconstriction syndrome (RCVS) tends to focus on neurological symptoms, but less attention has been paid the occurrence of extracerebral lesion such as the myocardium. CASE PRESENTATION: A 40-year-old woman taking iron supplements for iron deficiency anemia due to menorrhagia had suffered from a thunderclap headache and seizure. Brain magnetic resonance imaging revealed high-intensity lesions bilaterally in the cerebellar and cerebral hemispheres. Her symptoms once subsided with steroids and anticonvulsant therapy; however, she experienced a severe headache again while bathing and was transferred to our hospital. Based on the clinical course and imaging data, she was diagnosed as having RCVS triggered by a rapid improvement of anemia. At the same time, she had cardiac involvement revealed by electro and echocardiographs despite without chest symptoms. After the administration of a calcium channel blocker and nitrite, her cerebral and cardiac involvements were rapidly improved. CONCLUSIONS: The case presented RCVS with transient myocardial damage. With RCVS, we should always pay attention to the complication of extracerebral lesions.

Elderly-Onset Multiple System Atrophy with Lewy Body Pathology: A Case Report.

An 81-year-old woman presented with a 2-year history of progressive dysarthria and gait disturbance. Subsequently, she developed orthostatic hypotension, obstructive sleep apnea, right-sided resting tremor, and rigidity. Together with characteristic findings of imaging studies, she was diagnosed with multiple system atrophy (MSA). Despite progressive dysphagia and repeated choking episodes, the patient elected not to use artificial feeding or tracheostomy. She died suddenly at age 91 after 12 years of illness. The autopsy revealed neuropathological features of both MSA and of Parkinson's disease. The peripheral autonomic ganglia revealed both pre- and postganglionic involvement by synucleinopathy, which may have underscored the sudden death of the patient. The patient survived 10 years after onset, despite the presence of multiple poor prognostic factors in MSA including the onset of old age and early appearance of orthostatic hypotension and falls, in addition to the complication of PD pathology found by autopsy. Multidisciplinary team approach and her preserved cognitive function may have been contributory to the long-term survival.

Wild-type Cu/Zn-superoxide dismutase is misfolded in cerebrospinal fluid of sporadic amyotrophic lateral sclerosis.

BACKGROUND: A subset of familial forms of amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene coding Cu/Zn-superoxide dismutase (SOD1). Mutant SOD1 proteins are susceptible to misfolding and abnormally accumulated in spinal cord, which is most severely affected in ALS. It, however, remains quite controversial whether misfolding of wild-type SOD1 is involved in more prevalent sporadic ALS (sALS) cases without SOD1 mutations. METHODS: Cerebrospinal fluid (CSF) from patients including sALS as well as several other neurodegenerative diseases and non-neurodegenerative diseases was examined with an immunoprecipitation assay and a sandwich ELISA using antibodies specifically recognizing misfolded SOD1. RESULTS: We found that wild-type SOD1 was misfolded in CSF from all sALS cases examined in this study. The misfolded SOD1 was also detected in CSF from a subset of Parkinson's disease and progressive supranuclear palsy, albeit with smaller amounts than those in sALS. Furthermore, the CSF samples containing the misfolded SOD1 exhibited significant toxicity toward motor neuron-like NSC-34 cells, which was ameliorated by removal of the misfolded wild-type SOD1 with immunoprecipitation. CONCLUSIONS: Taken together, we propose that misfolding of wild-type SOD1 in CSF is a common pathological process of ALS cases regardless of SOD1 mutations.

Neuromyelitis optica spectrum disorder with massive basal ganglia involvement: a case report.

BACKGROUND: Occurrence of basal ganglia involvement in neuromyelitis optica spectrum disorders (NMOSD) has rarely been reported and none documented pathologically. CASE PRESENTATION: A 73-year-old female was clinically diagnosed with a NMOSD based on the clinical and radiological features and positive serum autoantibodies to AQP4. One month before her death, she became acutely ill with disturbed consciousness and right hemiparesis, and was diagnosed and treated as having basal ganglia infarction based on the brain CT. She made a partial recovery but later died from heart failure. At autopsy, the corresponding basal ganglia process revealed a large fresh area of necrosis. Histologically, several pathological signatures of NMOSD could be recognized in the lesion, including inflammatory cell infiltrations by B and T lymphocytes, perivascular complement and fibrinogen deposition, and the appearance of numerous phagocytosed corpora amylacea within the infiltrating macrophages. CONCLUSIONS: The present case illustrates that basal ganglia may be directly involved in the pathological processes of NMOSD, although the possibility of modification of the lesions by superimposed regional ischemia could not be excluded.

An Autopsy Case of Respiratory Failure Induced by Repetitive Cervical Spinal Cord Damage due to Abnormal Movement of the Neck in Athetoid Cerebral Palsy.

We herein report the clinical and autopsy findings of a 48-year-old right-handed man with athetoid cerebral palsy who suffered from cervical myelopathy due to abnormal neck movement, and who died of respiratory failure. Pathologically, the external appearance of the ventral surface of the cervical spinal cord revealed a linear indentation running obliquely at the level between the C4 and C5 segments. In the most severely compressed lesion, the gray matter was predominantly affected and severely atrophic. Microscopically, clusters of oligodendrocytes associated with thinly myelinated axons were also observed in the lateral funiculus. The latter findings are unique, and could be interpreted as regenerative and/or restorative phenomena of the central nervous system following chronic repetitive spinal cord compression.

Fatal Encephalopathy Associated with Influenza in a Health Care Professional.

A 41-year-old nurse was referred to our hospital with a fever and disturbed consciousness. She tested positive for influenza antigen. CT and MRI findings revealed low density and intensity areas in the right occipital and lateral lobes with remarkable brain edema, which led to a diagnosis of influenza encephalopathy. Influenza A antibodies in the serum were below the detection limit despite the patient receiving previous vaccination three months earlier. A PCR analysis revealed that the influenza HA gene was classified into clade 3C.2a, subclass AH3N2. The present case indicates the potential development of encephalopathy in adults under certain conditions.

Development of primary central nervous system lymphoma associated with human immunodeficiency virus and JC virus infection.

We report here a case of a 37-year-old man with human immunodeficiency virus (HIV) infection followed by JC virus (JCV) infection and primary central nervous system lymphoma (PCNSL). The patient had been infected with HIV type 1 due to blood products for hemophilia A during infancy. He had progression of nervous symptoms and was diagnosed with progressive multifocal leukoencephalopathy (PML) clinically at the age of 36, when his CD4-positive lymphocyte counts ranged between 350 and 450/µl. Oral mefloquine, intravenous methylprednisolone pulse therapy, and intravenous immunoglobulin were not effective for the PML, and the patient entered a vegetative state. Brain biopsy revealed JCV infection without pathological findings of PML. Eight months after the clinical diagnosis of PML, he developed respiratory failure and brain magnetic resonance imaging revealed a mass lesion in the brain stem. The patient died 19 months after the diagnosis of PML. Autopsy findings were compatible with PCNSL. EBV-encoded small RNA-1-positive cells were not detected. We present a case of JCV-positive PCNSL with HIV infection complicated with clinical PML.

Meningeal inflammation and demyelination in a patient clinically diagnosed with acute disseminated encephalomyelitis.

Acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) are both CNS inflammatory demyelinating diseases with overlapping clinical features. A case is reported of a 51-year-old female who presented with headache, progressive aphasia and hemiparesis without preceding infection or vaccination. Brain MRI revealed multiple, often confluent, subcortical white matter lesions without enhancement, affecting predominantly the left cerebral hemisphere. CSF examination failed to reveal oligoclonal bands. Brain biopsy revealed both pathological features of ADEM and findings are consistent with the early stage of MS, including meningeal B and T lymphocytic infiltration, perivenular demyelination, subpial demyelination and discrete confluent plaque-like foci of demyelination. Steroid treatment resulted in remarkable clinical and radiological improvement and there has been no recurrence in six years of follow-up. This case highlights the difficulties in differentiating between ADEM and the first attack of MS and further suggests that ADEM and the early stage of MS, and its tumefactive variant, may have a common underlying pathologic mechanism, which may have a therapeutic implication in treating these diseases.

α-Synuclein coaggregation in familial amyotrophic lateral sclerosis with SOD1 gene mutation.

Immunohistochemical studies were performed on postmortem brain and spinal cord from a patient with familial amyotrophic lateral sclerosis characterized by a C111Y mutation in the Cu/Zn superoxide dismutase gene. Clinically, the patient presented with classical amyotrophic lateral sclerosis and died of respiratory failure at age 53 years without ventilator dependence, 4 years after the onset. Pathologically, loss of motor neurons was more extensive than upper motor neurons. Lower motor neurons developed massive intracellular cytoplasmic neuronal inclusions, which were immunoreactive for Cu/Zn superoxide dismutase and phosphorylated α-synuclein, often colocalized. The inclusions were TAR DNA-binding protein 43 negative. The clinicopathologic significance of coaggregation of α-synuclein and Cu/Zn superoxide dismutase protein, a novel finding in neurodegenerative disorders, needs further investigation.

Marked intrafamilial phenotypic variation in a family with SOD1 C111Y mutation.

Our objectives were to identify the disease-causing mutation in, and report on the clinical features of, a Japanese family that had coexisting phenotypes of amyotrophic lateral sclerosis and spinal muscular atrophy. The family comprised nine patients (six men and three women). We reviewed their clinical records and performed mutation analysis of the copper/zinc superoxide dismutase (SOD1) gene in some of these patients. The patients either had a rapid (n=7) or an extremely long (n=2) clinical course. The mean age at onset was 39.0±13.7 years (range 20-68 years). The initial symptoms were bulbar palsy (n=2), upper (n=4) or lower (n=2) limb muscle weakness, or leg cramps (n=1). The total disease duration varied widely, ranging from one year to >69 years. We identified a SOD1 C111Y mutation among patients in this family. In conclusion, the family showed a marked intrafamilial phenotypic variation associated with the SOD1 C111Y mutation. Elucidating the biological basis of disease expression in patients with the SOD1 C111Y mutation may provide us with useful information to develop therapeutic approaches and to prevent disease progression.

Adult or late-onset triple A syndrome: case report and literature review.

Triple A syndrome is caused by mutations in the gene encoding ALADIN, leading to achalasia, alacrima and addisonism. Neurologic manifestations of the disease include motor neuron disease-like presentations, motor-sensory or autonomic neuropathy, optic atrophy, cerebellar ataxia, Parkinsonism, and mild dementia. We report a 60-year-old Japanese man with triple A syndrome. He was born to non-consanguineous parents. He underwent a surgical operation for achalasia at age 40, and thereafter, he developed a slowly progressive gait disturbance. Neurological examinations at age 60 revealed limb muscle wasting and weakness with pyramidal tract signs, distal-dominant sensory disturbance, optic atrophy, and autonomic dysfunction. Alacrima was detected using Schirmer test. All of these features were consistent with typical triple A syndrome. He lacked adrenal insufficiency that is frequently observed in patients with the classic phenotype of triple A syndrome. His sural nerve biopsy showed a moderate loss of myelinated fibers and hypomyelination. He was homozygous for a missense mutation, p.R155H, in the disease-causing gene, AAAS. Seven patients with genetically-confirmed, adult or late-onset triple A syndrome, including ours, have been reported to date. All the patients showed upper and lower motor neuron signs (100%), while sensory disturbance (29%) and autonomic dysfunction (57%) were less frequent. Careful assessment for alacrima followed by molecular genetic analysis of AAAS should be considered in patients who show a combined phenotype of motor neuron disease and sensory/autonomic disturbance, even in elderly patients.

Citrin deficiency as a cause of chronic liver disorder mimicking non-alcoholic fatty liver disease.

BACKGROUND/AIMS: Citrin deficiency caused by SLC25A13 gene mutations develops into adult-onset type II citrullinemia (CTLN2) and may be accompanied with hepatic steatosis and steatohepatitis. As its clinical features remain unclear, we aimed to explore the characteristics of fatty liver disease associated with citrin deficiency. METHODS: The prevalence of hepatic steatosis in 19 CTLN2 patients was examined, and clinical features were compared with those of non-alcoholic fatty liver disease (NAFLD) patients without known SLC25A13 gene mutations. RESULTS: Seventeen (89%) CTLN2 patients had steatosis, and 4 (21%) had been diagnosed as having NAFLD before appearance of neuropsychological symptoms. One patient had steatohepatitis. Citrin deficiency-associated fatty livers showed a considerably lower prevalence of accompanying obesity and metabolic syndrome, higher prevalence of history of pancreatitis, and higher serum levels of pancreatic secretory trypsin inhibitor (PSTI) than fatty livers without the mutations. Receiver operating characteristic curve analyses revealed that a body mass index < 20kg/m(2) and serum PSTI>29ng/mL were associated with citrin deficiency. CONCLUSIONS: Patients presenting with non-alcoholic fatty liver unrelated to obesity and metabolic syndrome might have citrin deficiency, and serum PSTI may be a useful indicator for distinguishing this from conventional NAFLD.

Ten-year follow-up of peripheral nerve function in patients with familial amyloid polyneuropathy after liver transplantation.

BACKGROUND: The electrophysiological long-term effects of liver transplantation on peripheral nerve function in patients with familial amyloid polyneuropathy (FAP) have not been evaluated. METHODS: Eight FAP patients with a proven ATTRVal30Met gene were observed for 10 years after liver transplantation. We performed repeated measurement of maximal motor nerve conduction velocity (MCV), distal latency, size of compound muscle action potential (CMAP) and maximal sensory nerve conduction velocity (SCV) in both the ulnar and tibial nerves. We also recorded the coefficients of variance in the R-R interval on the electrocardiogram (CV(R-R)). RESULTS: Some autonomic symptoms subsided but motor and sensory symptoms 10 years after transplantation were either slightly improved or almost the same as before surgery in 7 of 8 patients. These 7 have returned to their previous social lives including their jobs. The MCV of the tibial nerve slightly improved, and other parameters of motor and sensory nerve function and CV(R-R) did not show any deterioration during the 10-year observation period. CONCLUSIONS: Liver transplantation can halt the progression of peripheral neuropathy in FAP patients.

Marked regression of abdominal fat amyloid in patients with familial amyloid polyneuropathy during long-term follow-up after liver transplantation.

To elucidate whether the amount of tissue-deposited amyloid in familial amyloid polyneuropathy (FAP) patients decreases or increases over the long-term course after liver transplantation (LT), we examined changes in histopathological and biochemical characteristics of abdominal fat amyloid in the transplanted patients with a postoperative history of more than 10 years. Using a series of aspirated abdominal fat tissues from 6 FAP patients with transthyretin (TTR) Val30Met variant, the severity of amyloid deposits was examined and the composition ratio of wild type-to-variant TTR in fat amyloid was assayed by liquid chromatography-ion trap mass spectrometry (LC-MS/MS). Histopathological examination of abdominal fat tissues demonstrated a significant decrease or disappearance of amyloid deposits in all 6 patients. On LC-MS/MS analysis, the contribution of wild-type TTR to the composition ratio in amyloid fibrils was markedly increased in all patients after LT. This is the first report showing pathological evidence that deposited amyloid in FAP patients with long posttransplantation courses can gradually regress or disappear.

Hemophagocytic syndrome associated with rheumatoid arthritis.

We report a patient with rheumatoid arthritis (RA) who showed bicytopenia with hyperferritinemia and hepatic dysfunction ascribable to hemophagocytic syndrome (HPS) 2 weeks after commencement of bucillamine. Pathology of the bone marrow showing infiltration of macrophages confirmed the diagnosis of HPS. On the basis of renal dysfunction with an increase in fibrin degradation products, disseminated intravascular coagulation was considered to be concurrent with HPS. Oral prednisolone and cyclosporine A were started right after cessation of bucillamine, and yielded complete normalization of hepatic and renal function and hematology. As there was neither disease activity of RA nor associated infection throughout the clinical course, bucillamine was suspected of being the cause of HPS in our patient. HPS is a very rare complication in RA, but should be actively considered when abnormalities in laboratory data, especially pancytopenia and hepatic dysfunction, quickly worsen.

Severe amyloid deposition in mammary glands of familial amyloid polyneuropathy patients.

Clinical pictures of familial amyloid polyneuropathy (FAP) vary considerably, perhaps because of the many gene mutations of transthyretin (TTR), but even in patients having the most common mutation of TTR (the substitution of methionine for valine at position 30 (ATTRVal30Met)), the age of onset ranges from the late 20s to the early 60s. Although genetic anticipation has been considered to play a role in producing this wide range of ages of onset, the precise pathogenesis is incompletely understood. It has been experimentally shown that murine systemic AA and AApoAII amyloidoses can be transmitted by ingestion of amyloid fibrils themselves or amyloid-like pathological agents. In this study, we examined biopsied mammary glands obtained from three female ATTRVal30Met FAP patients who were of gestation age. Amyloid deposition was commonly seen in the glands and, in the two patients with apparent FAP symptoms, heavy deposits of amyloid surrounded many lactiferous alveoli and ducts, where some deposits of amyloid actually faced the central lumens. These findings raise the possibility that milk from FAP mothers contains ATTR-derived amyloid fibrils and/or fragments, which might be causally related to the development of genetic anticipation in this disease.