Cerebral Tuberculoma with Mild Posterior Cervical Pain as the Main Symptom Despite Extensive Brain Lesions.

A 59-year-old woman with a diabetes history experienced mild neck pain. A neurological examination revealed only mild neck stiffness. Magnetic resonance imaging showed extensive T2-weighted high-intensity lesions with patchy gadolinium enhancement mainly involving the white matter in the right parietal lobe. A cerebrospinal fluid analysis revealed increased protein levels and pleocytosis. While QuantiFERON-TB Gold was positive, computed tomography (CT) and fluorodeoxyglucose on positron emission tomography-CT of the whole body showed no abnormal accumulation, suggesting tuberculosis. A brain biopsy revealed cerebral tuberculoma. As cerebral tuberculoma can show minimal neurological symptoms despite extensive lesions, a cautious examination and early treatment are required to prevent a devastating prognosis.

Early postnatal allergic airway inflammation induces dystrophic microglia leading to excitatory postsynaptic surplus and autism-like behavior.

Microglia play key roles in synaptic pruning, which primarily occurs from the postnatal period to adolescence. Synaptic pruning is essential for normal brain development and its impairment is implicated in neuropsychiatric developmental diseases such as autism spectrum disorders (ASD). Recent epidemiological surveys reported a strong link between ASD and atopic/allergic diseases. However, few studies have experimentally investigated the relationship between allergy and ASD-like manifestations, particularly in the early postnatal period, when allergic disorders occur frequently. Therefore, we aimed to characterize how allergic inflammation in the early postnatal period influences microglia and behavior using mouse models of short- and long-term airway allergy. Male mice were immunized by an intraperitoneal injection of aluminum hydroxide and ovalbumin (OVA) or phosphate-buffered saline (control) on postnatal days (P) 3, 7, and 11, followed by intranasal challenge with OVA or phosphate-buffered saline solution twice a week until P30 or P70. In the hippocampus, Iba-1-positive areas, the size of Iba-1-positive microglial cell bodies, and the ramification index of microglia by Sholl analysis were significantly smaller in the OVA group than in the control group on P30 and P70, although Iba-1-positive microglia numbers did not differ significantly between the two groups. In Iba-1-positive cells, postsynaptic density protein 95 (PSD95)-occupied areas and CD68-occupied areas were significantly decreased on P30 and P70, respectively, in the OVA group compared with the control group. Immunoblotting using hippocampal tissues demonstrated that amounts of PSD95, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor 2, and N-methyl-D-aspartate (NMDA) receptor 2B were significantly increased in the OVA group compared with the control group on P70, and a similar increasing trend for PSD95 was observed on P30. Neurogenesis was not significantly different between the two groups on P30 or P70 by doublecortin immunohistochemistry. The social preference index was significantly lower in the three chamber test and the number of buried marbles was significantly higher in the OVA group than in the control group on P70 but not on P30, whereas locomotion and anxiety were not different between the two groups. Compared with the control group, serum basal corticosterone levels were significantly elevated and hippocampal glucocorticoid receptor (GR) amounts and nuclear GR translocation in microglia, but not in neurons or astrocytes, were significantly decreased in the OVA group on P70 but not on P30. Gene set enrichment analysis of isolated microglia revealed that genes related to immune responses including Toll-like receptor signaling and chemokine signaling pathways, senescence, and glucocorticoid signaling were significantly upregulated in the OVA group compared with the control group on P30 and P70. These findings suggest that early postnatal allergic airway inflammation induces dystrophic microglia that exhibit defective synaptic pruning upon short- and long-term allergen exposure. Furthermore, long-term allergen exposure induced excitatory postsynaptic surplus and ASD-like behavior. Hypothalamo-pituitary-adrenal axis activation and the compensatory downregulation of microglial GR during long-term allergic airway inflammation may also facilitate these changes.

Discriminative clinical and neuroimaging features of motor-predominant hereditary diffuse leukoencephalopathy with axonal spheroids and primary progressive multiple sclerosis: A preliminary cross-sectional study.

BACKGROUND: Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal-dominant white matter disease, typically characterized by juvenile cognitive decline and frontoparietal white matter lesions. A portion of HDLS patients exhibit preferential motor dysfunctions as their initial symptoms, mimicking multiple sclerosis (MS). However, there is no study comparing this phenotype of HDLS and primary progressive multiple sclerosis (PPMS), which greatly resemble each other. This is the first preliminary study to clarify the clinical and neuroimaging features of motor-predominant HDLS, and compare it with PPMS, using cases whose colony stimulating factor 1 receptor (CSF1R) were sequenced. METHODS: Clinical and radiological data from Japanese patients at the Department of Neurology, Kyushu University Hospital, Fukuoka, Japan, were evaluated retrospectively and cross-sectionally. Twenty-nine brain and 18 spinal cord magnetic resonance imaging (MRI) scans from four motor-predominant HDLS patients with CSF1R mutations and 15 PPMS patients without CSF1R mutations, were evaluated using an HDLS MRI scoring system. RESULTS: Two patients with HDLS were initially diagnosed with MS and received immunotherapy. Clinically, motor-predominant HDLS and PPMS patients resembled each other in onset age and disability. However, motor-predominant HDLS patients had a significantly higher frequency of frontal release signs, lower positivity rates of oligoclonal IgG bands (OCB), and lower IgG index values. Total HDLS MRI scores, total white matter lesions (WMLs), and brain atrophy were similar between the diseases. However, motor-predominant HDLS patients had more marked atrophy of the corpus callosum (CC) body, more WMLs in the deep and subcortical regions of the frontoparietal lobes, fewer WMLs in the occipitotemporal periventricular regions, and more restricted diffusivity lesions on MRI than PPMS patients. There was a stronger association between disease duration and CC index in HDLS, suggesting more rapid progression compared with PPMS. CONCLUSIONS: Motor-predominant HDLS has characteristic frequent frontal release signs, normal findings for OCB and the IgG index, severe CC body atrophy, abundant deep and subcortical WMLs in the frontoparietal lobes, subtle occipitotemporal lobe periventricular WMLs, and more restricted diffusivity lesions on MRI. Although the present study was limited by the small number of HDLS cases, we propose that immunotherapy should be avoided in such cases.

A Novel Autoantibody against Plexin D1 in Patients with Neuropathic Pain.

OBJECTIVE: To identify novel autoantibodies for neuropathic pain (NeP). METHODS: We screened autoantibodies that selectively bind to mouse unmyelinated C-fiber type dorsal root ganglion (DRG) neurons using tissue-based indirect immunofluorescence assays (IFA) with sera from 110 NeP patients with various inflammatory and allergic neurologic diseases or other neuropathies, and 50 controls without NeP including 20 healthy subjects and 30 patients with neurodegenerative diseases or systemic inflammatory diseases. IgG purified from IFA-positive patients' sera was subjected to Western blotting (WB) and immunoprecipitation (IP) using mouse DRG lysates. Immunoprecipitates were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify target autoantigens. RESULTS: Antiunmyelinated C-fiber type DRG neuron antibodies were more frequent in patients with NeP than non-NeP subjects (10% vs 0%; p < 0.05). These autoantibodies were all from the IgG2 subclass and colocalized mostly with isolectin B4- and P2X3-positive pain-conducting small neurons but not with S100ß-positive myelinated neurons. WB revealed a common immunoreactive band (approximately 220kDa). IP and LC-MS/MS studies identified plexin D1 as a target autoantigen. Immunoadsorption tests with recombinant human plexin D1 in IFA revealed that all 11 anti-small DRG neuron antibody-positive patients had anti-plexin D1 antibodies. Application of anti-plexin D1 antibody-positive patient sera to cultured DRG neurons increased membrane permeability, leading to cellular swelling. NeP patients with anti-plexin D1 antibodies commonly developed burning pain and current perception threshold abnormalities for C-fibers. Main comorbidities were atopy and collagen-vascular disease. Immunotherapies ameliorated NeP in 7 treated cases. INTERPRETATION: Anti-plexin D1 antibodies are a novel biomarker for immunotherapy-responsive NeP. Ann Neurol 2018;84:208-224.

[A case of chronic progressive motor-dominant multiple mononeuritis associated with primary Sjögren's syndrome].

A 45-year-old female with a history of dry eyes presented with chronic progressive disturbance of her right finger extension, bilateral foot drops, and dysesthesia in the left lower leg. On admission, neurological examination revealed decreased tendon reflex in the right upper limb and bilateral lower limbs, and dysesthesia in the distal outer portions of the bilateral lower legs. Her vibration sensation was moderately diminished in both lower legs. Weakness ranging from moderate to severe was predominantly found in the muscles innervated by the radial (r > l), medial (r > l), ulnar (r > l), deep peroneal (r ≒ l), tibial (r < l), and medial planter nerves (r < l). Nerve conduction study showed asymmetrical axonal neuropathy, while chronic neurogenic changes were observed on needle electromyography. Cerebrospinal fluid analysis results were unremarkable, except for an elevated IgG index (1.53) and the presence of oligoclonal IgG bands. Seropositive anti-SS-A antibody and histological findings of the biopsied minor salivary gland, as well as the lack of other connective tissue disorders, indicated primary Sjögren syndrome (SjS). A left sural nerve biopsy showed inhomogeneous reductions in the myelinated fibers within fascicules, mild infiltration of CD8-positive T lymphocytes around small vessels, and no fibrinoid necrosis in the arteries. From these findings, the diagnosis of motor-dominant multiple mononeuritis associated with primary SjS was made. Therapy that comprised a single course of intravenous (IV) methylprednisolone (1 g for 3 days), followed by oral prednisolone (60 mg/day) with gradual tapering, resulted in no amelioration of her symptoms. She then received IV immunoglobulin (0.4 mg/kg/day for 5 days), which resulted in moderate improvement in the strength of several muscles and a reduction of CSF IgG index (0.89). A wide variety of peripheral nerve complications are documented in primary SjS. However, the present case is unique in the symptoms of chronic progressive, motor-dominant, multiple mononeuritic phenotype.

[MRI comparison between hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and primary progressive multiple sclerosis (PPMS)].

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is an autosomal dominant inherited leukoencephalopathy characterized by numerous cerebral neuroaxonal spheroids. To date, detection of colony stimulating factor 1 receptor (CSF-1R) gene mutation in HDLS gave us hint to think its pathophysiology as a microglial dysfunction, so called "primary microgliopathy". Clinical features of HDLS are variable. Typically, psychiatric symptoms and cognitive decline are initial features of HDLS. However, in some cases, when motor symptoms precede cognitive decline, HDLS may mimic primary progressive multiple sclerosis (PPMS). Herein we tried to clarify MRI features of HDLS (2 women, age 22-28 years, average 25.0 years, EDSS 7.00) in comparison with PPMS (6 men and 10 women, age 29-64 years, average 33.7 years, EDSS 6.03). In consequence, our MRI findings suggesting HDLS rather than PPMS are as follows: restricted diffusivity, severe corpus callosum atrophy, and preferential involvement of deep white matter lesion compared with periventricular white matter. In contrast, characteristic features suggesting PPMS are as follows: prevailing periventricular white matter lesion, cerebellar lesions, optic neuritis, and cervical spinal cord lesion. Sagittal fluid-attenuated inversion recovery (FLAIR) images of brain and cervical cord are highly useful to discriminate these two diseases.

A case of hereditary diffuse leukoencephalopathy with axonal spheroids caused by a de novo mutation in CSF1R masquerading as primary progressive multiple sclerosis.

We report a sporadic case of hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) confirmed by biopsy and colony-stimulating factor 1 receptor (CSF1R) sequencing. A 28-year-old woman developed progressive spastic gait and dysarthria. Brain T2/FLAIR-weighted magnetic resonance imaging showed bilateral high signal intensity lesions in the parietal deep white matter, which subsequently extended anteriorly. Biopsied brain specimens demonstrated demyelinated white matter tissue with axonal spheroids infiltrated with foamy macrophages, and CD8(+) and CD4(+) T cells. She had a heterozygous mutation, c.2381T>C (p.782 Ile>Thr), in CSF1R. This is the first genetically proven case of HDLS mimicking primary progressive multiple sclerosis.