Autoantibodies Against Dihydrolipoamide S-Acetyltransferase in Immune-Mediated Neuropathies.

BACKGROUND AND OBJECTIVES: This study aimed to identify disease-related autoantibodies in the serum of patients with immune-mediated neuropathies including chronic inflammatory demyelinating polyneuropathy (CIDP) and to investigate the clinical characteristics of patients with these antibodies. METHODS: Proteins extracted from mouse brain tissue were used to react with sera from patients with CIDP by western blotting (WB) to determine the presence of common bands. Positive bands were then identified by mass spectrometry and confirmed for reactivity with patient sera using enzyme-linked immunosorbent assay (ELISA) and WB. Reactivity was further confirmed by cell-based and tissue-based indirect immunofluorescence assays. The clinical characteristics of patients with candidate autoantibody-positive CIDP were analyzed, and their association with other neurologic diseases was also investigated. RESULTS: Screening of 78 CIDP patient sera by WB revealed a positive band around 60-70 kDa identified as dihydrolipoamide S-acetyltransferase (DLAT) by immunoprecipitation and mass spectrometry. Serum immunoglobulin G (IgG) and IgM antibodies' reactivity to recombinant DLAT was confirmed using ELISA and WB. A relatively high reactivity was observed in 29 of 160 (18%) patients with CIDP, followed by patients with sensory neuropathy (6/58, 10%) and patients with MS (2/47, 4%), but not in patients with Guillain-Barré syndrome (0/27), patients with hereditary neuropathy (0/40), and healthy controls (0/26). Both the cell-based and tissue-based assays confirmed reactivity in 26 of 33 patients with CIDP. Comparing the clinical characteristics of patients with CIDP with anti-DLAT antibodies (n = 29) with those of negative cases (n = 131), a higher percentage of patients had comorbid sensory ataxia (69% vs 37%), cranial nerve disorders (24% vs 9%), and malignancy (20% vs 5%). A high DLAT expression was observed in human autopsy dorsal root ganglia, confirming the reactivity of patient serum with mouse dorsal root ganglion cells. DISCUSSION: Reactivity to DLAT was confirmed in patient sera, mainly in patients with CIDP. DLAT is highly expressed in the dorsal root ganglion cells, and anti-DLAT antibody may serve as a biomarker for sensory-dominant neuropathies.

Granuloma, vasculitis, and demyelination in sarcoid neuropathy.

BACKGROUND: Despite the suggestion that direct compression by granuloma and ischemia resulting from vasculitis can cause nerve fiber damage, the mechanisms underlying sarcoid neuropathy have not yet been fully clarified. METHODS: We examined the clinicopathological features of sarcoid neuropathy by focusing on electrophysiological and histopathological findings of sural nerve biopsy specimens. We included 18 patients with sarcoid neuropathy who had non-caseating epithelioid cell granuloma in their sural nerve biopsy specimens. RESULTS: Although electrophysiological findings suggestive of axonal neuropathy were observed, particularly in the lower limbs, all but three patients showed ≥1 abnormalities in nerve conduction velocity or distal motor latency. Additionally, a conduction block was observed in 11 of the 16 patients for whom waveforms were assessed; five of them fulfilled motor nerve conduction criteria strongly supportive of demyelination as defined in the European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) guideline for chronic inflammatory demyelinating polyneuropathy (CIDP). In most patients, sural nerve biopsy specimens revealed a mild to moderate degree of myelinated fiber loss. Fibrinoid necrosis was observed in one patient, and electron microscopy analysis revealed demyelinated axons close to granulomas in six patients. CONCLUSIONS: Patients with sarcoid neuropathy may meet the EAN/PNS electrophysiological criteria for CIDP due to the frequent presence of conduction blocks. Based on our results, in addition to the ischemic damage resulting from granulomatous inflammation, demyelination may play an important role in the mechanism underlying sarcoid neuropathy.

A Review of Anti-IL-5 Therapies for Eosinophilic Granulomatosis with Polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA), previously known as Churg-Strauss syndrome, is a systemic disorder characterized by asthma, eosinophilia, and vasculitis primarily affecting small vessels. Although this disease is classified as an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis along with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), observations suggest that eosinophils play a vital role in the pathophysiology of EGPA. Therefore, biopsy specimens derived from patients with EGPA demonstrated an increase in eosinophils within the vascular lumen and extravascular interstitium, especially in patients negative for ANCA. In addition, active secretion of eosinophil intracellular components by cytolysis and piecemeal degranulation occurs in the extravascular interstitium and bloodstream. Although the treatment for EGPA is described in the context of ANCA-associated vasculitis along with MPA and GPA, a therapeutic approach to suppress eosinophils is also considered. Monoclonal antibodies directed against interleukin-5 (IL-5) or its receptors are good therapeutic agents because IL-5 plays an important role in eosinophil growth, activation, and survival. Currently, mepolizumab (Nucala), reslizumab (Cinqair), and benralizumab (Fasenra) have been studied for use in patients with EGPA. These monoclonal antibodies were initially approved for use in patients with severe eosinophilic asthma. Mepolizumab is now approved for treating EGPA following the success of phase 3 randomized controlled trial. Therefore, further studies are needed to clarify long-term safety and efficacy of anti-IL-5 agents and establish indications of individual therapeutic agents tailored to individual conditions of patients with EGPA.

A case of childhood unilateral relapsing primary angiitis of the central nervous system.

The patient was a 17-year-old girl with transient right-sided weakness and dysesthesia associated with headache and nausea. Head magnetic resonance imaging (MRI) revealed white matter lesions confined to the left hemisphere. Initially, multiple sclerosis was suspected, and methylprednisolone (mPSL) pulse therapy was administered, followed by fingolimod hydrochloride. However, on day 267, the patient again experienced transient hypesthesia. Cranial MRI showed expansion of the highly infiltrated areas of the left hemisphere on fluid-attenuated inversion recovery (FLAIR) and T2 weighted image, accompanied by edema. Multiple contrasting areas were also observed. Susceptibility-weighted imaging demonstrated several streaks and some corkscrew-like appearances with low signals from the white matter to the cortex, suggestive of occluded or dilated collateral vessels. Multiple dotted spots indicating cerebral microbleeds (MBs) were also observed. A brain biopsy revealed lymphocytic, non-granulomatous inflammation in and around the vessels. Vascular occlusion and perivascular MBs were prevalent. The patient was diagnosed with relapsing primary angiitis of the central nervous system (PACNS), and immunosuppressive treatment was initiated, mPSL 1000 mg/day pulse therapy. The patient's clinical symptoms and neuroradiological abnormalities gradually improved. She is now receiving oral prednisolone (6 mg/day) and mycophenolate mofetil (1750 mg/day). This case corresponds to unilateral relapsing, which has recently been reported as a specific clinicopathological subtype of PACNS.

Persistent brain damage in reversible cerebral vasoconstriction syndrome on 99mTc-ethyl cysteinate dimer single-photon emission computed tomography: A long-term observational study.

BACKGROUND: Blood-brain barrier (BBB) breakdown is considered a key step in the pathophysiology of reversible cerebral vasoconstriction syndrome (RCVS); however, its temporal course remains unclear. Based on the characteristics and dynamics of 99mTc-ethyl cysteinate dimer (99mTc-ECD) as a tracer, 99mTc-ECD single-photon emission computed tomography (SPECT) can detect not only hypoperfusion but also BBB breakdown and/or brain tissue damage. Therefore, this study aimed to investigate this course using 99mTc-ECD SPECT. METHODS: Between 2011 and 2019, we enrolled seven patients (one male and six female patients) with RCVS without ischemic or hemorrhagic stroke or posterior reversible encephalopathy syndrome. 99mTc-ECD SPECT was performed repeatedly in each patient. SPECT data were statistically analyzed using an easy Z-score imaging system. RESULTS: Thunderclap headache was the initial symptom in all the patients and was most commonly triggered by bathing (three patients). All the patients exhibited vasoconstriction and reduced cerebral uptake of 99mTc-ECD during the acute stage. Follow-up assessment from 3 to 16 months showed that reduced cerebral uptake persisted in all the patients, even after the vasoconstriction had resolved. CONCLUSION: Reduced cerebral uptake of 99mTc-ECD persisted in the late stage of RCVS, even after vasoconstriction and headache subsided. BBB breakdown and/or brain tissue damage may underlie this phenomenon. 99mTc-ECD SPECT is an effective neuroimaging method to detect brain functional abnormalities, reflecting BBB breakdown or tissue damages, throughout the treatment course of RCVS.

Early ultrastructural lesions of anti-neutrophil cytoplasmic antibody- versus complement-associated vasculitis.

This study aims to describe electron microscopic findings of vasculitis associated with anti-neutrophil cytoplasmic antibody (ANCA) and complement. Sural nerve biopsy specimens were obtained from 10 patients with microscopic polyangiitis (MPA), a representative ANCA-associated vasculitis, and six patients with nonsystemic vasculitic neuropathy (NSVN), who were negative for ANCA but positive for complement deposition. In patients with MPA, attachment of neutrophils to epineurial vascular endothelial cells, migration of neutrophils to the extravascular space via the penetration of the endothelial layer, and release of neutrophil components to the extracellular space were observed. Such neutrophil-associated lesions were not observed in patients with NSVN. Nonetheless, morphological changes in epineurial vascular endothelial cells, such as increases in cytoplasmic organelles and cytoplasmic protrusions into the vascular lumen, were observed in patients with NSVN. Since these findings were observed where light microscopy-based findings suggestive of vasculitis (e.g., the disruption of vascular structures and fibrinoid necrosis) were absent, they were considered early lesions that preceded the formation of the so-called necrotizing vasculitis. In conclusion, this study enabled the visualization of distinctive early ultrastructural lesions associated with ANCA and complement. Further studies are needed to elucidate the molecular basis of the induction of these fine structural changes, which will contribute to the development of targeted therapies based on specific mechanisms of vasculitis.

Dosage effects of PMP22 on nonmyelinating Schwann cells in hereditary neuropathy with liability to pressure palsies.

Focal thickening of the myelin sheath, also known as tomacula, is a characteristic pathological feature of patients with hereditary neuropathy with liability to pressure palsies (HNPP). However, a deeper understanding of the pathology underlying unmyelinated fibers and nonmyelinating Schwann cells is required. Electron microscopic examination of sural nerve biopsy specimens was performed for 14 HNPP patients with peripheral myelin protein 22 (PMP22) deletion, and their results were compared to 12 normal controls and 14 Charcot-Marie-Tooth disease type 1A (CMT1A) patients with PMP22 duplication. The number of unmyelinated axons in a single axon-containing nonmyelinating Schwann cell subunit in the HNPP group significantly increased compared with that in normal controls (1.99 ±â€¯0.66 vs. 1.57 ±â€¯0.52, p < 0.05). Conversely, these numbers significantly decreased in the CMT1A group compared with those in normal controls (1.16 ±â€¯0.16, p < 0.05). Some unmyelinated axons in patients with HNPP were incompletely surrounded by the cytoplasm of Schwann cells, almost as if the Schwann cells failed to form mesaxons; such failure in mesaxon formation was not observed in normal controls or in patients with CMT1A. These findings suggest that PMP22 dosage affects nonmyelinating as well as myelinating Schwann cells.

In vivo visualization of eosinophil secretion in eosinophilic granulomatosis with polyangiitis: An ultrastructural study.

BACKGROUND: Although eosinophilic granulomatosis with polyangiitis (EGPA) has been considered as a single disease entity belonging to anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, several studies have suggested that in addition to the mechanisms associated with ANCA, those associated with eosinophils play a vital role in tissue damage. Nevertheless, the morphological bases underlying eosinophil-associated lesions have not been completely elucidated. METHODS: We investigated the electron microscopic findings of sural nerve biopsy specimens obtained from 18 patients with EGPA by focusing on the behavior of eosinophils, particularly the mode of secretion. RESULTS: Eosinophils tended to be located at sites close to endothelial cells within the lumina of epineurial small vessels. Attachment of eosinophils to endothelial cells was observed, particularly at the junction between neighboring endothelial cells, and some of these eosinophils appeared to escape from the vascular lumen to migrate into the extravascular interstitium. Furthermore, we observed eosinophil degranulation via piecemeal degranulation and cytolysis. Degranulating eosinophils were identified in both intravascular and extravascular compartments. Some of the small vessels appeared to be occluded by numerous eosinophils, and eosinophils attached by platelets were also observed, suggesting that coagulopathy occurs in EGPA. CONCLUSIONS: Both extravascular and intravascular eosinophils can induce tissue damage unrelated to classical necrotizing vasculitis associated with ANCA in patients with EGPA. Further research is necessary to elucidate the molecular basis of the induction of these fine structural changes, which will contribute to the development of targeted therapies based on specific mechanisms of eosinophil-related diseases.

ANCA-Associated Vasculitic Neuropathies: A Review.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a systemic disorder that frequently affects the peripheral nervous system and consists of three distinct conditions: microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA, previously Wegener's granulomatosis), and eosinophilic granulomatosis with polyangiitis (EGPA, previously Churg-Strauss syndrome). The neuropathic features associated with this condition usually include mononeuritis multiplex, which reflects the locality of lesions. Findings suggestive of vasculitis are usually found in the epineurium and occur diffusely throughout the nerve trunk. Nerve fiber degeneration resulting from ischemia is sometimes focal or asymmetric and tends to become conspicuous at the middle portion of the nerve trunk. The attachment of neutrophils to endothelial cells in the epineurial vessels is frequently observed in patients with ANCA-associated vasculitis; neutrophils play an important role in vascular inflammation by binding of ANCA. The positivity rate of ANCA in EGPA is lower than that in MPA and GPA, and intravascular and tissue eosinophils appear to participate in neuropathy. Immunotherapy for ANCA-associated vasculitis involves the induction and maintenance of remission to prevent the relapse of the disease. A combination of glucocorticoids along with cyclophosphamide, rituximab, methotrexate, or mycophenolate mofetil is considered depending on the severity of the condition of the organ to induce remission. A combination of low-dose glucocorticoids and azathioprine, rituximab, methotrexate, or mycophenolate mofetil is recommended to maintain remission. The efficacy of anti-interleukin-5 therapy (i.e., mepolizumab) was demonstrated in the case of refractory or relapsing EGPA. Several other new agents, including avacopan, vilobelimab, and abatacept, are under development for the treatment of ANCA-associated vasculitis. Multidisciplinary approaches are required for the diagnosis and management of the disorder because of its systemic nature. Furthermore, active participation of neurologists is required because the associated neuropathic symptoms can significantly disrupt the day-to-day functioning and quality of life of patients with ANCA-associated vasculitis.

Case Report: Severe Osteoporosis and Preventive Therapy in RNA Polymerase III-Related Leukodystrophy.

RNA polymerase III (POLR3)-related leukodystrophy is an autosomal recessive form of leukodystrophy caused by homozygous or compound heterozygous mutations of the RNA polymerase III subunit genes, including subunit A (POLR3A). With respect to the manifestation triad, hypomyelination, hypodontia, and hypogonadotropic hypogonadism, it is also known as 4H leukodystrophy. Here, we report a 41-year-old woman of POLR3-related leukodystrophy by carrying compound heterozygous pathogenic variants of c.2554A>G (p.M852V) and c.2668G>T (p.V890F) in the POLR3A gene. She was amenorrheic and became a wheelchair user from the age of 15 years and suffered from multiple episodes of pathologic fractures, starting with a subtrochanteric fracture of the right femur after a tonic seizure at age 30 years. Head magnetic resonance imaging demonstrated hypomyelination and atrophies of the cerebellum, brainstem, and corpus callosum. Laboratory examination revealed a marked decrease of gonadotropins and estrogen, low bone density, and high bone resorption markers. Administration of anti-receptor activator of nuclear factor kappa-B ligand monoclonal antibody restored bone resorption markers to a normal level and prevented further pathological bone fractures. Our case emphasizes that osteoporosis should be recognized as a potential but serious complication in POLR3-related leukodystrophy. It may be feasible to prevent pathologic fractures by intensive osteoporosis therapy after endocrinological examinations and evaluation of bone metabolism.

Alternating Amaurosis Fugax in Trousseau Syndrome: A Case Report.

Amaurosis fugax (AmF) is defined as transient monocular visual loss secondary to retinal ischemia. In most patients presenting with AmF, the attack of visual loss occurs in the same eye. A 64-year-old woman experienced transient visual loss in her right eye. Three days after that, an attack happened on the left side. In total, she had 5 episodes of AmF in 2 months. AmF occurred on both sides at different times, and so may be referred to as "Alternating AmF". Diffusion-weighted magnetic resonance imaging showed high-intensity lesions in various parts of brain, and laboratory examination revealed elevated D-dimer and ovarian tumor marker. We suspected Trousseau syndrome and found a giant ovary tumor. After removal of the tumor, no recurrence was observed. When a patient with alternating AmF is encountered, screening for malignancy is essential.

Ten-Year Evaluation of the TOYOTA Prehospital Stroke Scale for Tissue Plasminogen Activator Intravenous Therapy in the Real World.

BACKGROUND: Emergency medical services are an important part of acute stroke management. We devised a prehospital stroke scale, the TOYOTA prehospital stroke scale for tissue plasminogen activator (t-PA) intravenous therapy (TOPSPIN) for triaging patients with ischemic stroke and especial indications for intravenous t-PA therapy in December 2006; this scale comprises 5 items including consciousness, atrial fibrillation, language disorder, disturbance of the upper extremities, and disturbance of the lower extremities. The aim of this study was to analyze the results of 10 years of TOPSPIN implementation and to distinguish ischemic stroke from hemorrhagic stroke in the real world. METHODS: We prospectively enrolled consecutive patients who were transferred to our hospital and evaluated by Toyota city ambulance services using the TOPSPIN from December 2006 to January 2017. We examined definite diagnosis at the time of hospital discharge (ischemic stroke, hemorrhagic stroke, or stroke mimic), positive-predictive value of the stroke, the rate of the recanalization therapy, and clinical differentiation among patients with hemorrhagic stroke, ischemic stroke, and stroke mimics. RESULTS: A total of 1,482 consecutive patients were enrolled; 1,134 (76.5%) were patients with stroke (628 ischemic-type, 34 transient ischemic attack-type, and 472 hemorrhagic-type) and 348 (23.5%) without stroke (80 with seizure, 42 with syncope, 27 with hypoglycemia, and 199 other). Among 628 patients with ischemic stroke, 130 (20.7%) received intravenous recombinant t-PA treatment, endovascular therapy, or both. The presence of atrial fibrillation, older age, lower blood pressure, and lower total TOPSPIN score was more commonly associated with ischemic stroke than with hemorrhagic stroke. In multivariable logistic regression analysis, the presence of atrial fibrillation was independently associated with ischemic stroke (OR 2.33; 95% CI 1.61-3.40). CONCLUSIONS: The TOPSPIN is a simple prehospital stroke scale that includes an assessment of atrial fibrillation. Detection of atrial fibrillation in the prehospital stage may point to a higher probability of ischemic stroke.

A case of intracranial arterial dolichoectasia with 4 repeated cerebral infarctions in 6 months and enlargement of basilar artery.

A 78-year-old man was admitted to our hospital because of sudden right hemiparesis and dysarthria. His cranial MRI showed an area of hyperintensity in left pons on DWI and MRA revealed dilated, elongated and tortuous intracranial artery. We diagnosed as acute phase ischemic stroke and intracranial arterial dolichoectasia (IADE). Intravenous infusion of rt-PA was performed 157 minutes after the onset of symptoms, and his hemiparesis improved. However, he subsequently suffered from cerebral infarction 4 times in 6 months, and we treated him twice with thrombolytic therapy. Although thrombolytic therapy was effective in the short term and antithrombotic therapy was continued, he had bilateral hemiplegia and severe dysphagia because of repeated cerebral infarctions. Hence basilar artery was dilated with intramural hemorrhage over 6 months, and we discontinued antithrombolytic therapy. It is possible that antithrombolytic therapy affects enlargement of IADE. Antithrombolytic therapy for IADE should be done carefully.