Corticobasal degeneration with deep white matter lesion diagnosed by brain biopsy.

Corticobasal degeneration (CBD) is a rare progressive neurodegenerative disorder characterized by asymmetric presentation of cerebral cortex signs, cortical sensory disturbance and extrapyramidal signs. Herein, we report a case of a 66-year-old Japanese woman who presented with apraxia of the right hand. She subsequently developed postural instability and cognitive impairments that rapidly worsened. One and a half years later, the patient was wheelchair-bound and severely demented. Brain magnetic resonance imaging revealed left dominant atrophy of the frontoparietal lobe. There was a hyperintense lesion in the deep white matter expanding toward the subcortical area on fluid-attenuated inversion recovery (FLAIR) images. In order to rule out the possibility of an intracranial tumor such as an astrocytoma or malignant lymphoma, we performed a brain biopsy of the left frontal middle gyrus. The patient became bedridden and showed akinetic mutism 1 year after biopsy. Pathological examination revealed a large amount of 4-repeat tau-immunoreactive neuropil threads scattered predominantly in the corticomedullary junction and tau-immunoreactive structures, consistent with CBD. Immunostaining for p53 showed no positive cells, and there were very few Ki-67-positive cells. On immunoblots of sarkosyl-insoluble brain extracts, a major doublet of 64 and 68 kDa full-length tau with two closely related fragments of approximately 37 kDa were detected. Based on these results, the patient was pathologically diagnosed as having CBD, excluding the possibility of tumor. Taken together with previous similar case reports, our findings indicate that a deep white matter hyperintense lesion on FLAIR images may be a useful clue to CBD, predicting rapid clinical progression with severe dementia based on severe white matter degeneration with a large amount of tau accumulation on pathological examination.

Negative features of sporadic amyotrophic lateral sclerosis: Motor neurons of Onuf's nucleus survive in ADAR2-conditional knockout mice.

Patients with amyotrophic lateral sclerosis (ALS) do not develop oculomotor disturbances and vesicorectal dysfunction until end-stage disease owing to the survival of certain motor neurons (MNs), including oculomotor neurons and MNs within Onuf's nucleus. In sporadic ALS, adenosine deaminase acting on RNA 2 (ADAR2)-mediated editing of GluA2 mRNA at the Q/R site is compromised in lower MNs. We previously developed genetically modified mice with a conditional knockout of ADAR2 in cholinergic neurons (ADAR2flox/flox/VAChT-Cre, Fast; AR2). These mice displayed slow and progressive lower motor neuron death with TAR DNA-binding protein 43 (TDP-43) pathology, attributable to insufficient editing at the GluA2 Q/R site due to ADAR2 deficiency. MN death was more common in fast-fatigable MNs owing to differential vulnerability under conditions of ADAR2 deficiency. Although facial and hypoglossal nerves were impaired in AR2 mice, cell death did not occur within the oculomotor nerve nucleus, as observed in patients with sporadic ALS. Since the basis for avoiding cystorectal damage in ALS is unknown, we compared the features of Onuf's nucleus MNs in 12-month-old AR2 mice with those in age-matched wild-type mice. Although the number of MNs was not significantly lower in AR2 mice, the neurons exhibited a shrunken morphology and TDP-43 pathology. Onuf's nucleus MNs could survive in an ADAR2-deficient state and mainly included fast fatigue-resistant (FR) and slow (S) MNs. In summary, FR and S MNs show increased resilience to ADAR2 deficiency, potentially participating in an important neuronal death avoidance mechanism in ALS.

Morphometric analysis of spinal motor neuron degeneration in sporadic amyotrophic lateral sclerosis.

OBJECTIVES: This study aimed to clarify the relationship between 43-kDa TAR DNA-binding protein (TDP-43) pathology and spinal cord anterior horn motor neuron (AHMN) atrophy in sporadic amyotrophic lateral sclerosis (SALS). METHODS: Eight patients with SALS and 12 controls were included in this study. Formalin-fixed specimens of lumbar spinal cord samples were paraffin-embedded and sectioned at the level of the fourth lumbar spinal cord with a 4 µm thickness. Using a microscope, the long diameters of the neurons with nucleoli were measured in spinal AHMNs stained with an anti-SMI-32 antibody. AHMNs were divided into medial and lateral nuclei for statistical analysis. We also used previously reported data to measure the long diameter of AHMNs with initial TDP-43 pathology, in which TDP-43 was present both in the nucleus and cytoplasm. RESULTS: The long diameter of the lumbar spinal AHMNs in patients with SALS was smaller in the medial nucleus (42.54 ± 9.33 µm, n = 24) and the lateral nucleus (49.41 ± 13.86 µm, n = 129) than in controls (medial nucleus: 55.84 ± 13.49 µm, n = 85, p < 0.001; lateral nucleus: 62.39 ± 13.29 µm, n = 756, p < 0.001, Mann-Whitney U test). All 21 motor neurons with initial TDP-43 pathology were in the lateral nucleus, and their long diameter (67.60 ± 18.3 µm, p = 0.352) was not significantly different from that of controls. CONCLUSION: Motor neuron atrophy in SALS does not occur during the initial stages of TDP-43 pathology, and TDP-43 pathology is already advanced in the atrophied motor neurons.

Non-traumatic Rectus Sheath Hematoma During Direct Oral Anticoagulation.

We report a case of anticoagulation therapy complicated by a non-traumatic rectus sheath hematoma (RSH). RSH is a relatively rare occurrence caused by bleeding into the rectus sheath following the rupture of the superior and inferior epigastric vessels combined with a primary tear of the rectus muscle fibers. Herein, we report a rare presentation of RSH in a 73-year-old man taking the direct oral anticoagulant (DOAC) apixaban orally. The patient presented with sudden right abdominal pain after a severe cough, which worsened with cough and movement. The Fothergill and Carnett signs were positive. The platelet count, renal function test, and the prothrombin time/international normalized ratio were within the normal range. The activated partial thromboplastin time was 40.0 s, slightly longer than normal. Computed tomography (CT) of the abdomen and pelvis showed RSH, and DOAC therapy was temporarily discontinued. Subsequently, RSH resolution was confirmed via CT four weeks after the onset. DOACs are safer and more efficacious than warfarin for patients with non-valvular atrial fibrillation. However, RSH is a potential complication of anticoagulant therapy. This case report demonstrates that RSH should be considered in the differential diagnosis of sudden-onset abdominal pain and mass in patients on DOACs.

Pathological features of glial cells and motor neurons in the anterior horn of the spinal cord in sporadic ALS using ADAR2 conditional knockout mice.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective degeneration of motor neurons (MNs). In the MNs of patients with ALS, adenosine deaminase acting on RNA 2 (ADAR2)-mediated RNA editing of GluA2 mRNA at the Q/R site is profoundly deficient. In genetically modified mice (ADAR2flox/flox/VAChT-Cre.Fast; AR2), the selective knockout of ADAR2 in cholinergic neurons induced progressive loss of lower MNs. MNs exhibiting an age-related increase in abnormal TDP-43 localization and reduced ADAR2 immunoreactivity are localized in the lateral areas of the anterior horns (AHs) in aged wild-type mice. However, the patterns in the AHs of AR2 mice remain unknown. In this study, we investigated whether similar degeneration is observed in AR2 mice. We compared the number of astrocytes and MNs in the lateral and medial AHs of the lumbar spinal cord of 12-month-old AR2 mice with age-matched wild-type mice. The number of MNs significantly decreased in both the lateral and medial areas in AR2 mice AHs, particularly in the former. The number of reactive astrocytes increased significantly in the lateral areas of the AHs of AR2 mice. In conclusion, stronger activation of astrocytes with reduction of MNs in the ADAR2 deficiency-related lateral area increases in AR2 mice AHs. Fast fatigable MNs are expected to be present in the lateral area of the AHs. We found that MN death is more common in the lateral area of AHs associated with FF MNs due to differences in vulnerability to MN under ADAR2 deficiency.

Effect of Serum Perampanel Concentration on Sporadic Amyotrophic Lateral Sclerosis Progression.

BACKGROUND AND PURPOSE: To clarify the effect of perampanel (PER) on sporadic amyotrophic lateral sclerosis (sALS) progression, the relationship between the changes in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores and serum PER concentrations was investigated. METHODS: 12 patients with sALS from our hospital who agreed to participate and completed the PER for sALS randomized phase 2 study were included. After completing the study, we retrospectively obtained serum PER concentration data from the patients. Based on their mean PER concentrations, we divided the patients who had been taking PER into two groups: four patients with a mean PER concentration of ≥400 ng/mL were assigned to the H group, and three with a mean PER concentration of <400 ng/mL were assigned to the L group. The control group consisted of five patients who had been taking a placebo. We obtained the ALSFRS-R scores of each patient at 36 and 48 weeks after randomization. The differences in ALSFRS-R scores at baseline (0 weeks) and each subsequent week were used in the analysis. RESULTS: At 48 weeks, there were no differences in the degree of deterioration of the bulbar, upper and lower limb, and respiratory ALSFRS-R subscores and total ALSFRS-R score. However, at 36 weeks, the bulbar subscore was significantly lower in the H group than in the control group (p=0.032). CONCLUSIONS: Because high PER concentrations may exacerbate bulbar symptoms in patients with sALS, serum PER measurements may be beneficial when patients with sALS are taking PER.

Profound downregulation of the RNA editing enzyme ADAR2 in ALS spinal motor neurons.

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset fatal motor neuron disease. In spinal motor neurons of patients with sporadic ALS, normal RNA editing of GluA2, a subunit of the L-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, is inefficient. Adenosine deaminase acting on RNA 2 (ADAR2) specifically mediates RNA editing at the glutamine/arginine (Q/R) site of GluA2 and motor neurons expressing Q/R site-unedited GluA2 undergo slow death in conditional ADAR2 knockout mice. Therefore, investigation into whether inefficient ADAR2-mediated GluA2 Q/R site-editing occurs universally in motor neurons of patients with ALS would provide insight into the pathogenesis of ALS. We analyzed the extents of GluA2 Q/R site-editing in an individual laser-captured motor neuron of 29 ALS patients compared with those of normal and disease control subjects. In addition, we analyzed the enzymatic activity of three members of the ADAR family (ADAR1, ADAR2 and ADAR3) in ALS motor neurons expressing unedited GluA2 mRNA and those expressing only edited GluA2 mRNA. Q/R site-unedited GluA2 mRNA was expressed in a significant proportion of motor neurons from all of the ALS cases examined. Conversely, motor neurons of the normal and disease control subjects expressed only edited GluA2 mRNA. ADAR2, but not ADAR1 or ADAR3, was significantly downregulated in all the motor neurons of ALS patients, more extensively in those expressing Q/R site-unedited GluA2 mRNA than those expressing only Q/R site-edited GluA2 mRNA. These results indicate that ADAR2 downregulation is a profound pathological change relevant to death of motor neurons in ALS.

Prolyl Isomerase Pin1 Expression in the Spinal Motor Neurons of Patients With Sporadic Amyotrophic Lateral Sclerosis.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease. Selective deficiency of edited adenosine deaminase acting on RNA 2 (ADAR2), a key molecule in the acquisition of Ca2+ resistance in motor neurons, has been reported in sporadic ALS (sALS) spinal motor neurons. Since ADAR2 activity is positively regulated by prolyl isomerase Protein never in mitosis gene A interacting-1 (Pin1), a known phosphorylation-dependent peptidyl-prolyl cis/trans isomerase, we investigated Pin1 expression in spinal motor neurons in sALS. METHODS: Specimens of the spinal cord were obtained from the lumbar region in eight sALS patients and age-matched five controls after postmortem examinations. The specimens were double stained with anti-Pin1 and anti-TAR DNA-binding protein of 43 kDa (TDP-43) antibodies, and examined under a fluorescence microscope. RESULTS: This study analyzed 254 and 422 spinal motor neurons from 8 sALS patients and 5 control subjects, respectively. The frequency of motor neurons with high cytoplasmic Pin1 expression from the spinal cord did not differ significantly between sALS specimens without cytoplasmic TDP-43 inclusions and control specimens. However, in sALS specimens, neurons for which the Pin1 immunoluminescence intensity in the cytoplasm was at least twice that in the background were more common in specimens with cytoplasmic TDP-43 inclusions (p<0.05 in χ² test). CONCLUSIONS: In sALS, neurons with higher expression levels of Pin1 levels had more TDP-43 inclusions. Despite the feedback mechanism between Pin1 and ADAR2 being unclear, since Pin1 positively regulates ADAR2, our results suggest that higher Pin1 expression levels in motor neurons with TDP-43 pathology from sALS patients represent a compensatory mechanism.

Induced loss of ADAR2 engenders slow death of motor neurons from Q/R site-unedited GluR2.

GluR2 is a subunit of the AMPA receptor, and the adenosine for the Q/R site of its pre-mRNA is converted to inosine (A-to-I conversion) by the enzyme called adenosine deaminase acting on RNA 2 (ADAR2). Failure of A-to-I conversion at this site affects multiple AMPA receptor properties, including the Ca(2+) permeability of the receptor-coupled ion channel, thereby inducing fatal epilepsy in mice (Brusa et al., 1995; Feldmeyer et al., 1999). In addition, inefficient GluR2 Q/R site editing is a disease-specific molecular dysfunction found in the motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients (Kawahara et al., 2004). Here, we generated genetically modified mice (designated as AR2) in which the ADAR2 gene was conditionally targeted in motor neurons using the Cre/loxP system. These AR2 mice showed a decline in motor function commensurate with the slow death of ADAR2-deficient motor neurons in the spinal cord and cranial motor nerve nuclei. Notably, neurons in nuclei of oculomotor nerves, which often escape degeneration in ALS, were not decreased in number despite a significant decrease in GluR2 Q/R site editing. All cellular and phenotypic changes in AR2 mice were prevented when the mice carried endogenous GluR2 alleles engineered to express edited GluR2 without ADAR2 activity (Higuchi et al., 2000). Thus, loss of ADAR2 activity causes AMPA receptor-mediated death of motor neurons.

Clinicopathologic Features of Oculopharyngodistal Myopathy With LRP12 CGG Repeat Expansions Compared With Other Oculopharyngodistal Myopathy Subtypes.

Importance: Repeat expansion of CGG in LRP12 has been identified as the causative variation of oculopharyngodistal myopathy (OPDM). However, to our knowledge, the clinicopathologic features of OPDM with CGG repeat expansion in LRP12 (hereafter referred to as OPDM_LRP12) remain unknown. Objective: To identify and characterize the clinicopathologic features of patients with OPDM_LRP12. Design, Setting, and Participants: This case series included 208 patients with a clinical or clinicopathologic diagnosis of oculopharyngeal muscular dystrophy (OPDM) from January 1, 1978, to December 31, 2020. Patients with GCN repeat expansions in PABPN1 were excluded from the study. Repeat expansions of CGG in LRP12 were screened by repeat primed polymerase chain reaction and/or Southern blot. Main Outcomes and Measures: Clinical information, muscle imaging data obtained by either computed tomography or magnetic resonance imaging, and muscle pathologic characteristics. Results: Sixty-five Japanese patients with OPDM (40 men [62%]; mean [SD] age at onset, 41.0 [10.1] years) from 59 families with CGG repeat expansions in LRP12 were identified. This represents the most common OPDM subtype among all patients in Japan with genetically diagnosed OPDM. The expansions ranged from 85 to 289 repeats. A negative correlation was observed between the repeat size and the age at onset (r2 = 0.188, P = .001). The most common initial symptoms were ptosis and muscle weakness, present in 24 patients (37%). Limb muscle weakness was predominantly distal in 53 of 64 patients (83%), but 2 of 64 patients (3%) had predominantly proximal muscle weakness. Ptosis was observed in 62 of 64 patients (97%), and dysphagia or dysarthria was observed in 63 of 64 patients (98%). A total of 21 of 64 patients (33%) had asymmetric muscle weakness. Aspiration pneumonia was seen in 11 of 64 patients (17%), and 5 of 64 patients (8%) required mechanical ventilation. Seven of 64 patients (11%) developed cardiac abnormalities, and 5 of 64 patients (8%) developed neurologic abnormalities. Asymmetric muscle involvement was detected on computed tomography scans in 6 of 27 patients (22%) and on magnetic resonance imaging scans in 4 of 15 patients (27%), with the soleus and the medial head of the gastrocnemius being the worst affected. All 42 muscle biopsy samples showed rimmed vacuoles. Intranuclear tubulofilamentous inclusions were observed in only 1 of 5 patients. Conclusions and Relevance: This study suggests that OPDM_LRP12 is the most frequent OPDM subtype in Japan and is characterized by oculopharyngeal weakness, distal myopathy that especially affects the soleus and gastrocnemius muscles, and rimmed vacuoles in muscle biopsy.

TDP-43 pathology in sporadic ALS occurs in motor neurons lacking the RNA editing enzyme ADAR2.

Both the appearance of cytoplasmic inclusions containing phosphorylated TAR DNA-binding protein (TDP-43) and inefficient RNA editing at the GluR2 Q/R site are molecular abnormalities observed specifically in motor neurons of patients with sporadic amyotrophic lateral sclerosis (ALS). The purpose of this study is to determine whether a link exists between these two specific molecular changes in ALS spinal motor neurons. We immunohistochemically examined the expression of adenosine deaminase acting on RNA 2 (ADAR2), the enzyme that specifically catalyzes GluR2 Q/R site-editing, and the expression of phosphorylated and non-phosphorylated TDP-43 in the spinal motor neurons of patients with sporadic ALS. We found that all motor neurons were ADAR2-positive in the control cases, whereas more than half of them were ADAR2-negative in the ALS cases. All ADAR2-negative neurons had cytoplasmic inclusions that were immunoreactive to phosphorylated TDP-43, but lacked non-phosphorylated TDP-43 in the nucleus. Our results suggest a molecular link between reduced ADAR2 activity and TDP-43 pathology.

Novel etiological and therapeutic strategies for neurodiseases: RNA editing enzyme abnormality in sporadic amyotrophic lateral sclerosis.

The motor neurons of patients with sporadic amyotrophic lateral sclerosis (ALS) express abundant Q/R site-unedited GluR2 mRNA, whereas those of patients with other motor neuron diseases including familial ALS associated with mutated SOD1 (ALS1) and those of normal subjects express only Q/R site-edited GluR2 mRNA. Because adenosine deaminase acting on RNA type 2 (ADAR2) specifically catalyzes GluR2 Q/R site-editing, it is likely that ADAR2 activity is not sufficient to edit this site completely in motor neurons of patients with sporadic ALS. Because these molecular abnormalities occur in disease- and motor neuron-specific fashion and induce fatal epilepsy in mice, we have hypothesized that GluR2 Q/R site-underediting due to ADAR2 underactivity is a cause of neuronal death in sporadic ALS. We found that cytoplasmic fragile X mental retardation protein interacting protein 2 (CYFIP2) mRNA had an ADAR2-mediated editing position using RNA interference knockdown. Our review will include a discussion of new ADAR2 substrates that may be useful for research on sporadic ALS.

AMPA receptor-mediated neuronal death in sporadic ALS.

alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor-mediated excitotoxicity has been proposed to play a role in death of motor neurons in amyotrophic lateral sclerosis (ALS). We demonstrated that RNA editing of GluR2 mRNA at the glutamine/arginine (Q/R) site was decreased in autopsy-obtained spinal motor neurons, but not in cerebellar Purkinje cells, of patients with sporadic ALS. This molecular change occurs in motor neurons of sporadic ALS cases with various phenotypes, but not in degenerating neurons of patients with other neurodegenerative diseases, including SOD1-associated familial ALS. Because GluR2 Q/R site-editing is specifically catalyzed by adenosine deaminase acting on RNA 2 (ADAR2), it is likely that regulatory mechanism of ADAR2 activity does not work well in the motor neurons of sporadic ALS. Indeed, ADAR2 expression level was significantly decreased in the spinal ventral gray matter of sporadic ALS as compared to normal control subjects. It is likely that ADAR2 underactivity selective in motor neurons induced deficient GluR2 Q/R site-editing, which results in the neuronal death of sporadic ALS. Thus, among multiple different molecular mechanisms underlying death of motor neurons, it is likely that an increase of the proportion of Q/R site-unedited GluR2-containing Ca(2+)-permeable AMPA receptors initiates the death of motor neurons in sporadic ALS. To this end, normalization of ADAR2 activity in motor neurons may become a therapeutic strategy for sporadic ALS.

Spontaneous Intracranial Hypotension with a Reversible Splenial Lesion after Swimming.

Spontaneous intracranial hypotension (SIH) is an important cause of headache mainly associated with spinal cerebrospinal fluid leakage. We herein report the case of a 51-year-old man who developed SIH after swimming. Brain magnetic resonance imaging (MRI) showed a transient high-intensity lesion in the splenium of the corpus callosum (SCC), in addition to bilateral subdural hematomas (SDH) and pseudo-subarachnoid hemorrhage on brain computed tomography. The splenial lesion disappeared and SDH improved after an epidural blood patch. This case emphasizes that transient SCC lesions could coexist with SIH and that SIH should be considered in the differential diagnosis of SCC lesions.

A central nervous system metastasis of melanoma with stroke-like onset of left-lower quadrantanopsia.

"Stroke mimics" mean diseases presenting with acute neurological impairments that are taken for stroke. Discriminating them is crucial to avoid improper treatment or delayed correct treatment. We describe a 48-year-old woman presenting with a sudden onset of scintillating scotoma and left-lower quadrantanopsia. Hyperacute cerebral infarction was suspected. However, brain magnetic resonance imaging (MRI) revealed a mass at the cortico-medullary junction in the right occipital lobe. We diagnosed her as metastatic melanoma. We suspected that neurological deficits can be attributed to seizure, and therefore introduced levetiracetam. She showed neurological improvement immediately. Our case demonstrated the importance of considering brain tumor as a differential diagnosis in patients presenting with acute-onset neurological deficits. In addition to appropriate treatment of tumor, the use of newer antiepileptic drugs resulted in good neurological prognosis in metastatic brain tumors.

Tumefactive multiple sclerosis which initially presented with brainstem encephalitis with a long-term follow-up.

Tumefactive demyelinating lesions (TDLs) are rare in multiple sclerosis (MS). We herein report a case of tumefactive MS which initially presented with brainstem encephalitis with a long-term follow-up. The patient had experienced relapse mostly in the brainstem in the first twenty years, and then in the periventricular white matter afterwards. The patient responded well to steroid treatment recovered without sequalae. However, immunodeficiency due to the long-term use of oral prednisolone made aggressive therapy during the relapse impossible, so recovery after steroid therapy is incomplete. Our case is different from classical MS in clinical course and response to treatment. Our report offers rare information on long-term outcome of tumefactive MS.

Determination of editors at the novel A-to-I editing positions.

A-to-I RNA editing modifies a variety of biologically important mRNAs, and is specifically catalyzed by either adenosine deaminase acting on RNA type 1 (ADAR1) or type 2 (ADAR2) in mammals including human. Recently several novel A-to-I editing sites were identified in mRNAs abundantly expressed in mammalian organs by means of computational genomic analysis, but which enzyme catalyzes these editing sites has not been determined. Using RNA interference (RNAi) knockdowns, we found that cytoplasmic fragile X mental retardation protein interacting protein 2 (CYFIP2) mRNA had an ADAR2-mediated editing position and bladder cancer associated protein (BLCAP) mRNA had an ADAR1-mediated editing position. In addition, we found that ADAR2 forms a complex with mRNAs with ADAR2-mediated editing positions including GluR2, kv1.1 and CYFIP2 mRNAs, particularly when the editing sites were edited in human cerebellum by means of immunoprecipitation (IP) method. CYFIP2 mRNA was ubiquitously expressed in human tissues with variable extents of K/E site editing. Because ADAR2 underactivity may be a causative molecular change of death of motor neurons in sporadic amyotrophic lateral sclerosis (ALS), this newly identified ADAR2-mediated editing position may become a useful tool for ALS research.

[Case of primary intraocular central nervous system lymphoma with high interleukin 10 level and positive cytology in cerebrospinal fluid].

A 73-year-old woman was admitted to the surgical department of our hospital for endoscopic resection of a colonic polyp. The day after endoscopic resection, she became drowsy and dysphasic. Two days later, left hemiparesis and gait difficulty developed. The next day, hemiparesis progressed bilaterally and dyspnea developed due to upper airway stenosis. The most prominent signs were those of bulbar palsy. Blood analysis revealed mild inflammatory responses and hyponatremia. T2-weighted magnetic resonance imaging showed high-intensity lesions in the swollen medulla and cervical spinal cord. Those areas and the meninges of the posterior fossa were enhanced by gadolinium. Steroid pulse therapy was administered, resulting in rapid recovery of bulbar and paretic symptoms with decreased enhanced area. At this point, concentration of cerebrospinal fluid interleukin (IL)-10 was markedly elevated at 146 pg/ml (normal,< 5 pg/ml), suggesting malignant lymphoma. Cytology of the cerebrospinal fluid was repeatedly examined, eventually revealing atypical lymphocytes with hyperlobulated nuclei and clear nucleoli. Lymphocytes stained with anti-CD20 antibody. These findings strongly suggested a diagnosis of primary intraocular and central nervous system lymphoma. In the present case, repeated cytology of cerebrospinal fluid was highly important for diagnosis in this case of high IL-10 level in cerebrospinal fluid.

[Anti-Hu antibody positive sensory neuronopathy causing painful legs and moving toes (PLMT) in a 75-year-old female with small cell lung cancer (SCLC)].

The case is a 75-year-old female. She had dysesthesia in the distal extremities and truncal ataxia, and they had progressed in two months. Neurological examination revealed the findings of segmental dysesthesia in the distal extremities, impaired deep sensations in the trunk and four limbs, and painful legs and moving toes (PLMT). After workup, she was diagnosed with small cell lung cancer and her blood sample was positive for anti-Hu antibody. We concluded that her neurological symptoms were attributable to sensory neuronopathy associated with paraneoplastic syndrome. No cases with PLMT caused by paraneoplastic syndrome have been reported so far. She had chemotherapy to lung cancer and Duloxetine without improvement of PLMT. On the other hand, intravenous immunoglobulin treatment improved lightening pain in the toes without improvement of moving toes.