Bilateral Phrenic Nerve Palsy Associated With Neuralgic Amyotrophy.

Neuralgic amyotrophy (NA) is a multifocal inflammatory neuropathy accompanied by acute pain and muscle atrophy. NA commonly affects the upper extremities, but rarely affects the phrenic nerve. Here, we report a male with neck pain, orthopnea, difficulty sleeping in the supine position, and inability to slurp. His saturated oxygen level decreased from 97% to 86% in the supine position. His right shoulder showed muscle atrophy. Chest X-ray examination in the supine position and a nerve conduction study showed phrenic palsy. We diagnosed it as bilateral phrenic nerve palsy associated with NA. NA sometimes causes phrenic nerve palsy and may cause slurping difficulty.

[A case of neurosarcoidosis initially diagnosed as cervical spondylotic myelopathy, leading to diagnosis by gadolinium contrast-enhanced MRI].

A 70-year-old female presented with bilateral numbness in her upper limbs. She was diagnosed with cervical spondylotic myelopathy and underwent cervical laminoplasty. However, there was no significant improvement in sensory disturbance, and at 6 months after surgery, she developed subacute motor and gait disturbance in four extremities. Spinal MRI revealed a long lesion of the spinal cord with edema, and a part of the lesion showed gadolinium contrast enhancement. Bronchoscopy revealed an elevated CD4/8 ratio, and gallium scintigraphy demonstrated an accumulation in the hilar lymph nodes, leading to a diagnosis of neurosarcoidosis. In case of rapid deterioration during the course of cervical spondylotic myelopathy, neurosarcoidosis should be considered as a differential diagnosis, which can be assessed by contrast-enhanced MRI.

A nationwide survey of facial onset sensory and motor neuronopathy in Japan.

The epidemiology and etiology of facial onset sensory and motor neuronopathy (FOSMN), a rare syndrome that initiates with facial sensory disturbances followed by bulbar symptoms, remain unknown. To estimate the prevalence of FOSMN in Japan and establish the characteristics of this disease, we conducted a nationwide epidemiological survey. In the primary survey, we received answers from 604 facilities (49.8%), leading to an estimated number of 35.8 (95% confidential interval: 21.5-50.2) FOSMN cases in Japan. The secondary survey collected detailed clinical and laboratory data from 21 cases. Decreased or absent corneal and pharyngeal reflexes were present in over 85% of the cases. Electrophysiological analyses detected blink reflex test abnormalities in 94.1% of the examined cases. Immunotherapy was administered in 81% of cases and all patients received intravenous immunoglobulin. Among them, 35.3% were judged to have temporary beneficial effects evaluated by the physicians in charge. Immunotherapy tended to be effective in the early stage of disease. The spreading pattern of motor and sensory symptoms differed between cases and the characteristics of the motor-dominant and sensory-dominant cases were distinct. Cases with motor-dominant progression appeared to mimic amyotrophic lateral sclerosis. This is the first nationwide epidemiological survey of FOSMN in Japan. The clinical course of FOSMN is highly variable and motor-dominant cases developed a more severe condition than other types of cases. Because clinical interventions tend to be effective in the early phase of the disease, an early diagnosis is desirable.

Lumbar Subarachnoid-Peritoneal Shunting Deteriorates Superficial Siderosis Associated with a Dural Defect.

Superficial siderosis is a disease in which hemosiderin is deposited under the leptomeninges and subpial layers of hindbrain structures, e.g., the cerebellum, brainstem, and eighth cranial nerve. The main symptoms of superficial siderosis are cerebellar ataxia, hearing loss, cognitive decline, and myelopathy. The activities of daily living of patients with superficial siderosis are severely impaired due to the progressive symptoms. Here, we report a patient with superficial siderosis whose symptoms deteriorated after lumbar subarachnoid-peritoneal (L-P) shunt surgery. She received L-P shunt surgery based on the diagnosis of idiopathic normal pressure hydrocephalus at another hospital. The patient had a history of cervical surgery, and a dural defect was identified at the C4-5 level by a detailed magnetic resonance imaging study. We hypothesized that the L-P shunt reduced cerebrospinal pressure and increased bleeding from the fragile vessels in the dural defect, which might have increased hemosiderin deposition.

[Altered antibody titers in patients with neuromuscular diseases after high-dose intravenous immunoglobulin therapy].

We investigated the changes in antibody titers after intravenous immunoglobulin (IVIg) administration in patients with neuromuscular diseases. Among patients who received IVIg from April 1, 2020, to August 31, 2022, we retrospectively evaluated 15 patients with antibody measurements before and after IVIg administration for any rise in the following antibody levels and examined the data for subsequent changes of false positive results to negative ones. The levels of anti SS-A, anti-thyroglobulin, anti-thyroid peroxidase, anti-glutamic acid decarboxylase, HBs, and HBc antibodies transiently increased after IVIg administration and showed false-positive results. However, levels of rheumatoid factor and anti-nuclear and antineutrophil cytoplasmic antibodies were not elevated. The false-positive results became negative after 3 months. Here, we report on the changes in antibody levels before and after IVIg administration and note that levels of hepatitis B virus-related antibodies and various autoantibodies transiently rise after IVIg administration.

[A case of very long chain acyl-CoA dehydrogenase deficiency diagnosed due to a trigger of hyperemesis gravidarum during pregnancy].

A 25-year-old Japanese woman with a history of repeated episodes of rhabdomyolysis since the age of 12 presented with rhabdomyolysis caused by hyperemesis gravidarum. Blood tests showed an elevated serum CK level (11,755 |IU/l; normal: 30-180 |IU/l). Carnitine fractionation analysis revealed low levels of total carnitine (18.3 |µmol/l; normal: 45-91 |µmol/l), free carnitine (13.1 |µmol/l; normal: 36-74 |µmol/l), and acylcarnitine (5.2 |µmol/l; normal: 6-23 |µmol/l). Tandem mass spectrometry showed high levels of C14:1 acylcarnitine (0.84 |nmol/ml: normal: <0.4 |nmol/ml) and a high C14:1/C2 ratio of 0.253 (normal: <0.013), indicating a potential diagnosis of very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. Enzyme activity measurement in the patient's peripheral blood lymphocytes confirmed the diagnosis of VLCAD deficiency, with low palmitoyl-CoA dehydrogenase levels (6.5% of normal control value). With the patient's informed consent, acyl-CoA dehydrogenase very long-chain (ACADVL) gene analysis revealed compound heterozygous mutations of c.1332G>A in exon 13 and c.1349G>A (p.R450H) in exon 14. In Japan, neonatal mass screening is performed to detect congenital metabolic diseases. With the introduction of tandem mass screening in 2014, fatty acid metabolism disorders, including VLCAD deficiency, are being detected before the onset of symptoms. However, it is important to note that mass screening cannot detect all cases of this disease. For patients with recurrent rhabdomyolysis, it is essential to consider congenital diseases, including fatty acid metabolism disorders, as a potential diagnosis.

Case of elderly onset possible neuro-Behçet's disease with HLA-B51 homozygosity.

Behçet's disease commonly affects 20-40-year-old men and shows ophthalmo-dermatological manifestations. Here, we report a man in his 70s with acute onset of dysarthria, dysphagia and hemiplegia showing brainstem and subcortical lesions, which responded to steroid and colchicine therapy. He had a history of uveitis and was homozygous for the human leucocyte antigen-B51 allele, and we clinically diagnosed him with acute neuro-Behçet's disease. Old-age onset neuro-Behçet's disease is uncommon, and as far as we know, this is the oldest case of the first attack of neuro-Behçet's disease. Clinicians should consider Behçet's disease even for elderly patients.

Metabolism-Mediated Thrombotic Microangiopathy in an Older Patient Without Malnutrition.

Vitamin B12 deficiency can cause thrombotic microangiopathy (TMA)-like symptoms such as purpura caused by platelet reduction, general fatigue caused by anemia, and renal and hepatic abnormalities caused by malnutrition. TMA-like symptoms are known as metabolism-mediated TMA (MM-TMA). In MM-TMA, blood cell production is altered, and both pancytopenia and schistocytes appear. The initial presentation of MM-TMA makes it challenging to distinguish between primary and secondary TMA when patients do not present risk factors for malnutrition. We encountered an older female patient with a chief complaint of unconsciousness and loss of appetite for two days. Laboratory tests revealed pancytopenia with schistocytes. Moreover, the laboratory data revealed low serum levels of vitamin B12, indicating MM-TMA. The patient was successfully treated with intravenous vitamin B12 supplementation and discharged home. The patient had atrophic gastritis, which could have impeded the absorption of vitamin B12 from food. Among older patients without prolonged appetite loss, TMA-like symptoms should be investigated as MM-TMA induced by vitamin B12 deficiency, and prompt initiation of appropriate treatment is essential to differentiate between MM-TMA and true TMA.

A human T-lymphotropic virus-1 carrier who developed progressive multifocal leukoencephalopathy following immunotherapy for sarcoidosis: a case report.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a devastating demyelinating disorder of the central nervous system caused by opportunistic infection of the JC virus (JCV). CASE PRESENTATION: A 58-year-old Japanese woman was admitted to our hospital for aphasia. She had a 5-year history of untreated sarcoidosis and was a human T cell lymphotropic virus-1 (HTLV-1) carrier. Serum angiotensin-converting enzyme, soluble interleukin-2 receptor, lysozyme, and calcium levels were elevated. JCV-DNA was not detected in cerebrospinal fluid by PCR testing. Skin biopsy revealed noncaseating granuloma formation. Bilateral multiple nodular lesions were present on chest X-ray. Brain magnetic resonance imaging showed left frontal and temporal lesions without gadolinium enhancement. As we suspected that systemic sarcoidosis had developed into neurosarcoidosis, we started steroid and infliximab administration. After treatment, the chest X-ray and serum abnormalities ameliorated, but the neurological deficits remained. At 1 month after immunotherapy, she developed right hemiparesis. Cerebrospinal fluid was positive for prototype (PML-type) JCV on repeated PCR testing. Brain biopsy revealed demyelinating lesions with macrophage infiltration, atypical astrocytes, and JCV antigen-positive cells. We diagnosed her with PML and started mefloquine, leading to partial remission. CONCLUSIONS: Sarcoidosis and HTLV-1 infection both affect T cell function, especially CD4+ T cells, and may developped the patient's PML. The comorbidity of sarcoidosis, PML, and HTLV-1 infection has not been reported, and this is the world's first report of PML associated with HTLV-1 infection and sarcoidosis.

Ultrashort Echo Time Magnetic Resonance Angiography as an Alternative Tool to Digital Subtraction Angiography in the Follow-up of Stent-Assisted Coil Embolization Outcomes.

BACKGROUND: Follow-up of aneurysms treated with stent-assisted coil embolization has been performed using digital subtraction angiography (DSA) because in time-of-flight magnetic resonance angiography, metal artifacts from the stent often affect visualization. OBJECTIVE: To confirm whether ultrashort echo time (TE) MRA may be an alternative for DSA during follow-up. METHODS: Patients with unruptured aneurysms initially treated with stent-assisted coil embolization between April 2019 and March 2021 were enrolled. After 3 months of treatment, follow-up DSA and ultrashort TE MRA were performed. All images were independently reviewed by neurosurgeons to evaluate in-stent flow and rated from 1 (not visible) to 4 (excellent). Aneurysmal embolization status was assessed as complete obliteration, residual neck, or residual aneurysm. Ultrashort TE MRA findings were classified as evaluative or nonevaluative state based on the presence of metal artifacts. We investigated the types of aneurysms that were evaluative and the agreement between ultrashort TE and DSA. RESULTS: Overall, 89 aneurysms were examined, of which 74% (n = 66) were classified as evaluative on ultrashort TE. Significant differences were observed in size and stent type. Evaluative cases had an aneurysm size of <7 mm ( P = .0007) and a higher rate of Neuroform Atlas ( P = .0006). The rate of agreement between ultrashort TE with evaluative state and DSA was 95%. CONCLUSION: Ultrashort TE MRA could evaluate an embolization status treated with stenting, and the findings are in excellent agreement with those of DSA. Aneurysms measuring <7 mm and treated with Neuroform Atlas are evaluative on ultrashort TE, and DSA might not be necessary.

[A case of multiple sclerosis with a tumefactive lesion during long-term treatment with fingolimod, leading to decompressive craniotomy].

We report a 57-year-old man with multiple sclerosis since his 30s who was treated with fingolimod for 9 years. He developed left hemiparesis and consciousness disturbance. Brain MRI revealed a mass lesion in the right frontal lobe with gadolinium enhancement. Cerebrospinal fluid examination showed no pleocytosis. The lesion continued to expand after admission, and on the 9th day after admission, decompressive craniectomy and brain biopsy were performed. Brain pathology revealed demyelination in the lesion, leading to the diagnosis of a tumefactive demyelinating lesion. Corticosteroid therapy ameliorated the brain lesion, and we inducted natalizumab. Tumefactive demyelinating lesions requiring decompressive craniotomy are rare, and we report this case for the further accumulation of similar cases.

[Chronic progressive external ophthalmoplegia that could not be diagnosed by biceps muscle biopsy, but was genetically diagnosed by extraocular muscle biopsy].

A 48-year-old Japanese male experienced slowly progressive diplopia. He had no family history and was negative for the edrophonium chloride test. Blood analysis showed elevated lactic acid and pyruvic acid levels, suggesting mitochondrial disease. A muscle biopsy from the biceps brachii was performed, but no pathological or genetical mitochondrial abnormalities were detected. Subsequently, he underwent muscle plication for diplopia in which the right inferior rectus muscle was biopsied. Genetic examination of genomic DNA extracted from the extraocular muscle tissue revealed multiple mitochondrial gene deletions, with a heteroplasmy rate of approximately 35%, resulting in the diagnosis of chronic progressive external ophthalmoplegia. In mitochondrial diseases, the tissue distribution of mitochondria with disease-associated variants in mtDNA should be noted, and it is important to select the affected muscle when performing a biopsy for an accurate diagnosis.

Identifying Hyperreflective Foci in Diabetic Retinopathy via VEGF-Induced Local Self-Renewal of CX3CR1+ Vitreous Resident Macrophages.

Intraretinal hyperreflective foci (HRF) are significant biomarkers for diabetic macular edema. However, HRF at the vitreoretinal interface (VRI) have not been examined in diabetic retinopathy (DR). A prospective observational clinical study with 162 consecutive eyes using OCT imaging showed significantly increased HRF at the VRI during DR progression (P < 0.01), which was reversed by anti-vascular endothelial growth factor (VEGF) therapy. F4/80+ macrophages increased significantly at the VRI in Kimba (vegfa+/+) or Akimba (Akita × Kimba) mice (both P < 0.01), but not in diabetic Akita (Ins2+/-) mice, indicating macrophage activation was modulated by elevated VEGF rather than the diabetic milieu. Macrophage depletion significantly reduced HRF at the VRI (P < 0.01). Furthermore, BrdU administration in Ccr2rfp/+Cx3cr1gfp/+vegfa+/- mice identified a significant contribution of M2-like tissue-resident macrophages (TRMs) at the VRI. Ki-67+ and CD11b+ cells were observed in preretinal tissues of DR patients, while exposure of vitreal macrophages to vitreous derived from PDR patients induced a significant proliferation response in vitro (P < 0.01). Taken together, the evidence suggests that VEGF drives a local proliferation of vitreous resident macrophages (VRMs) at the VRI during DR. This phenomenon helps to explain the derivation and disease-relevance of the HRF lesions observed through OCT imaging in patients.

Gadolinium-enhanced MR improved motion sensitized driven equilibrium (iMSDE) for intracranial vessel imaging in giant cell arteritis.

BACKGROUND: Giant cell arteritis (GCA) generally affects extracranial large and medium-sized vessels. It rarely causes intracranial vessel stenosis, presenting as cerebral infarction (CI). Consequently, accurate diagnosis of CI induced by GCA is often challenging. Improved motion-sensitized driven-equilibrium (iMSDE) is one of the advanced high-resolution magnetic resonance (MR) vessel wall imaging techniques that enables direct visualization of the vessel wall because of a strong reduction in blood flow artifacts, leading to higher quality images. Herein, we effectively used gadolinium-enhanced MR iMSDE imaging to diagnose a patient presenting with recurrent CI due to right intracranial internal carotid artery (ICA) stenosis as GCA. CASE DESCRIPTION: A 64-year-old man with polymyalgia rheumatica for several years and who had experienced CI due to moderate intracranial ICA stenosis one year ago, presented to the emergency room with dysarthria and left hemiparesis. Diffusion-weighted MR imaging showed high signals in the right centrum ovale, and MR angiography revealed severe stenosis of the right intracranial ICA. Gadolinium-enhanced MR iMSDE imaging showed marked concentric enhancement in the vessel wall of the right stenosed ICA, which led to a definitive diagnosis of GCA via biopsy from the right superficial temporal artery. The patient's symptoms gradually improved after initiation of steroid treatment. Three months later, gadolinium-enhanced MR iMSDE imaging revealed improvement in the contrast enhancement in the vessel wall and vascular stenosis. CONCLUSION: Gadolinium-enhanced MR iMSDE imaging is useful to diagnose and evaluate GCA with intracranial vessel involvement.

A novel quantitative indicator for disease progression rate in amyotrophic lateral sclerosis.

OBJECTIVE: The current study sought to develop a new indicator for disease progression rate in amyotrophic lateral sclerosis (ALS). METHODS: We used a nonparametric method to score diverse patterns of decline in the percentage of predicted forced vital capacity (%FVC) in patients with ALS. This involved 6317 longitudinal %FVC data sets from 920 patients in the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database volunteered by PRO-ACT Consortium members. To assess the utility of the derived scores as a disease indicator, we examined changes over time, the association with prognosis, and correlation with the Risk Profile of the Treatment Research Initiative to Cure ALS (TRICALS). Our local cohort (n = 92) was used for external validation. RESULTS: We derived scores ranging from 35 to 106 points to construct the FVC Decline Pattern scale (FVC-DiP). Individuals' FVC-DiP scores were determined from a single measurement of %FVC and disease duration at assessment. Although the %FVC declined over the disease course (p < 0.0001), the FVC-DiP remained relatively stable. Low FVC-DiP scores were associated with rapid disease progression. Using our cohort, we demonstrated an association between FVC-DiP and the survival prognosis, the stability of the FVC-DiP per individual, and a correlation between FVC-DiP scores and the TRICALS Risk Profile (r2 = 0.904, p < 0.0001). CONCLUSIONS: FVC-DiP scores reflected patterns of declining %FVC over the natural course of ALS and indicated the disease progression rate. The FVC-DiP may enable easy assessment of disease progression patterns and could be used for assessing treatment efficacy.

Case Report: Paraneoplastic Tumefactive Demyelination Associated With Seminoma.

Paraneoplastic tumefactive demyelination (TD) is a rare disorder of the central nervous system that can be challenging to diagnose. Here, we describe a 32-year-old Japanese man with a TD associated with testicular seminoma. He presented with symptoms of right-sided motor and sensory impairment 2 days after vaccination for coronavirus disease 2019 (COVID-19). Brain magnetic resonance imaging (MRI) showed a high-intensity lesion in the left internal capsule. He had a 3-year history of enlargement of the left testicle. Blood examination showed tumor marker elevation and the presence of anti-amphiphysin antibodies. Whole-body computed tomography (CT) revealed mass lesions in the left testicle and enlargement of the retroperitoneal lymph nodes. Radical orchiectomy was performed. As the pathology showed testicular seminoma, chemotherapy was administered. After surgery, his neurological symptoms deteriorated. MRI revealed that the brain lesion had enlarged and progressed to a tumefactive lesion without gadolinium enhancement. The cerebrospinal fluid (CSF) examination was normal without pleocytosis or protein elevation. Steroid pulse therapy was added; however, his symptoms did not improve. A brain stereotactic biopsy was performed and the sample showed demyelinating lesions without malignant cells. As the initial corticosteroid therapy was ineffective, gamma globulin therapy was administered in parallel with chemotherapy, and the clinical symptoms and imaging findings were partially ameliorated. TD seldom appears as a paraneoplastic neurological syndrome. In addition, there are few reports of COVID-19 vaccination-associated demyelinating disease. Clinicians should recognize paraneoplastic TD, and the further accumulation of similar cases is needed.

Blood transfusion-induced posterior reversible encephalopathy syndrome presenting severe brain atrophy: A report of two cases.

Several cases of posterior reversible encephalopathy syndrome (PRES) after blood transfusion have been reported, but the long-term prognosis is unknown. Here, we report two cases of blood transfusion-associated PRES with severe brain atrophy at 1 year after onset. We report the case with a discussion of pathological mechanisms.

Pathological findings of hypertrophic pachymeningitis associated with eosinophilic granulomatosis with polyangiitis.

The most common neurological manifestation of eosinophilic granulomatosis with polyangiitis (EGPA), formerly called Churg-Strauss syndrome, is mononeuritis multiplex caused by small-vessel vasculitis. In contrast, central nervous system involvement is rare. Among EGPA-associated central nervous system disorders, there are only a few reported cases of hypertrophic pachymeningitis (HP). Here, we report a patient with EGPA with headache and ophthalmoplegia who presented with HP and had a dural biopsy. The biopsy specimen showed lymphocytic inflammatory cell infiltration without EGPA-specific findings, that is, eosinophilic infiltration, granuloma or angiitis. To the best of our knowledge, there are no previous reports of EGPA-associated HP pathology. Here, we report the first case presentation of a patient with EGPA-associated HP with pathological findings.

Clearance of peripheral nerve misfolded mutant protein by infiltrated macrophages correlates with motor neuron disease progression.

Macrophages expressing C-C chemokine receptor type 2 (CCR2) infiltrate the central and peripheral neural tissues of amyotrophic lateral sclerosis (ALS) patients. To identify the functional role of CCR2+ macrophages in the pathomechanisms of ALS, we used an ALS animal model, mutant Cu/Zn superoxide dismutase 1G93A (mSOD1)-transgenic (Tg) mice. To clarify the CCR2 function in the model, we generated SOD1G93A/CCR2Red fluorescence protein (RFP)/Wild type (WT)/CX3CR1Green fluorescence protein (GFP)/WT-Tg mice, which heterozygously express CCR2-RFP and CX3CR1-GFP, and SOD1G93A/CCR2RFP/RFP-Tg mice, which lack CCR2 protein expression and present with a CCR2-deficient phenotype. In mSOD1-Tg mice, mSOD1 accumulated in the sciatic nerve earlier than in the spinal cord. Furthermore, spinal cords of SOD1G93A/CCR2RFP/WT/CX3CR1GFP/WT mice showed peripheral macrophage infiltration that emerged at the end-stage, whereas in peripheral nerves, macrophage infiltration started from the pre-symptomatic stage. Before disease onset, CCR2+ macrophages harboring mSOD1 infiltrated sciatic nerves earlier than the lumbar cord. CCR2-deficient mSOD1-Tg mice showed an earlier onset and axonal derangement in the sciatic nerve than CCR2-positive mSOD1-Tg mice. CCR2-deficient mSOD1-Tg mice showed an increase in deposited mSOD1 in the sciatic nerve compared with CCR2-positive mice. These findings suggest that CCR2+ and CX3CR1+ macrophages exert neuroprotective functions in mSOD1 ALS via mSOD1 clearance from the peripheral nerves.