[A case of hyperammonemia resulting from urinary tract infection caused by urease-producing bacteria in a Parkinson's disease patient with drug-induced urinary retention].

A 71-year-old woman with a 9-year history of Parkinson's disease was admitted to our hospital emergently because of consciousness disturbance. Her consciousness level was 200 on the Japan coma scale (JCS), and she presented with tenderness and distension of the lower abdomen. Brain computed tomography showed normal findings. Blood tests showed an increased ammonia level (209 µg/dl) with normal AST and ALT levels. We catheterized the bladder for urinary retention. Five hours after admission, the blood ammonia level decreased to 38 µg/dl, and her consciousness level improved dramatically. Corynebacterium urearyticum, a bacterial species that produces urease, was detected by urine culture. Therefore, she was diagnosed with hyperammonemic encephalopathy resulting from urinary tract infection caused by urease-producing bacteria. In this case, urologic active agents had been administered to treat neurogenic bladder. We suspect that these drugs caused urinary obstruction and urinary tract infection. It is important to recognize that obstructive urinary tract infection caused by urease-producing bacteria can cause hyperammonemia. Neurological disorders, such as Parkinson's disease, tend to complicate neurogenic bladder. This disease should be considered in elderly patients with Parkinson's disease who are receiving urologic active drugs.

Acute-Onset Severe Occipital Neuralgia Associated With High Cervical Lesion in Patients With Neuromyelitis Optica Spectrum Disorder.

OBJECTIVE: To address occipital neuralgia in patients with neuromyelitis optica spectrum disorder (NMOSD). BACKGROUND: NMOSD is an inflammatory demyelinating disease that commonly presents with pain; however, headache symptoms have received little attention. METHODS: We presented three cases of NMOSD in which the patients experienced acute-onset, severe, and steroid-responsive occipital neuralgia. All patients provided consent to use their demographic and imaging data retrospectively. RESULTS: In all three cases, MRI revealed a new high-intensity area in the cervical cord at the C1-C3 level of the spine, which was diminished in two of the three cases after corticosteroid pulse therapy. CONCLUSION: Our cases support the recognition of NMOSD as a cause of secondary headache. As patients with NMOSD experience severe occipital neuralgia, a relapse should be considered and a cervical MRI should be performed.

Reduction in the numbers of drugs administered to elderly in-patients with polypharmacy by a multidisciplinary review of medication using electronic medical records.

AIM: Polypharmacy is a major problem for elderly patients in developed countries. We investigated whether a multidisciplinary medication review using electronic medical records could reduce the number of drugs administered to elderly patients receiving polypharmacy. METHODS: The present study included 432 elderly patients (188 women, 244 men; 267 patients aged 65-74 years and 165 patients aged ≥75 years) who were admitted to and discharged from the Department of Neurology and Geriatrics, Gifu University Hospital, between 2004 and 2011; those who died at the hospital were excluded. The names, categories, and numbers of orally administered drugs at admission and discharge were examined retrospectively using electronic medical records. The histories of continuous oral immunotherapy use at the hospital, falls during the 2 years before hospital admission and the presence of fall risk factors were also evaluated. P-values <0.05 were considered statistically significant. RESULTS: On average 1.14 ± 3.07 fewer types of drugs were given to patients at discharge than at admission in patients receiving polypharmacy (P < 0.001). However, the number of drugs given to patients undergoing continuous oral immunotherapy increased by 1.67 ± 3.47 (P < 0.001). The number of drugs was reduced in 33.1% of fallers, and 36.3% of non-fallers. In both fallers and non-fallers, there was a reduction in drug categories associated with falls. CONCLUSIONS: Multidisciplinary medication review using electronic medical records could significantly reduce the numbers of drugs taken by elderly inpatients receiving polypharmacy, including drugs associated with falls, in both fallers and non-fallers Geriatr Gerontol Int 2017; 17: 653-658.

Identification of target antigens of naturally occurring autoantibodies in cerebrospinal fluid.

Naturally occurring autoantibodies have natural physiologic functions related to normal cell processes. However, the repertoire of naturally occurring autoantibodies against neuronal antigens in CSF is unclear. The purpose of this study was to identify naturally occurring autoantibodies against neuronal antigens in CSF from patients with various neurologic diseases by proteomics-based analysis. The CSF samples were collected from 77 patients with various neurologic disorders. The antigen source for 2-dimensional immunoblotting was the SH-SY5Y human neuroblastoma cell line. There were 8 spots recognized in CSF from more than one-fourth of the 77 patients including all patient groups and these spots were recognized in intravenous immunoglobulin preparations. These antigen spots were identified as heat shock 105-kDa/110-kDa protein 1, isoform CRA_b, 78-kDa glucose-regulated protein, heat shock cognate 71-kDa protein, tubulin beta chain, vimentin (2 spots), and 60-kDa heat shock protein, mitochondrial; we could not identify the protein name corresponding to 1 of the 8 spots. In summary, there were 6 proteins identified that were main target antigens that reacted with naturally occurring autoantibodies in CSF from patients with varied neurologic disorders; the functions of autoantibodies against the identified antigens are unknown and may be clarified with further studies. BIOLOGICAL SIGNIFICANCE: Naturally occurring autoantibodies may have important functions in tissue homeostasis. In this study, we identified 6 common target antigens that reacted with autoantibodies in cerebrospinal fluid (CSF) from patients, independent of disease type. These findings may clarify the importance of naturally occurring autoantibodies in CSF and the use of these antibodies potentially may be a novel therapy for various neurologic disorders.

B-cell-activating factor belonging to the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) levels in cerebrospinal fluid of patients with meningoencephalitis.

The B-cell-activating factor belonging to the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) are important factors for the survival of transitional and mature B cells. High levels of BAFF and APRIL are present in adults with several autoimmune diseases. However, there are few reports about BAFF and APRIL levels in the cerebrospinal fluid (CSF) of patients with meningoencephalitis. We evaluated BAFF and APRIL levels in CSF samples from patients with viral meningitis (VM) (28 patients), autoimmune encephalitis (AE) associated with antineuronal antibodies (15 patients), idiopathic normal pressure hydrocephalus (iNPH) (11 patients), herpes simplex encephalitis (HSE) (9 patients), bacterial meningitis (BM) (6 patients), and cryptococcal meningitis (CM) (4 patients). The CSF BAFF levels were significantly higher in patients with HSE, BM, or VM than AE or iNPH, and significantly higher in patients with CM than iNPH. The CSF APRIL levels were significantly higher in patients with HSE or BM than AE, VM, or iNPH. Although this is a preliminary report due to within-group variation and small sample size, the data suggest that CSF BAFF and APRIL levels are increased in HSE and BM, but not AE.

Identification of target antigens of antiendothelial cell antibodies against human brain microvascular endothelial cells in healthy subjects.

Antiendothelial cell antibodies (AECAs) have been detected in patients who have autoimmune and inflammatory diseases. Previous studies showed that AECAs against human umbilical vein endothelial cells were detected in healthy subjects. In the present study, we evaluated AECAs against human brain microvascular endothelial cells (HBMEC) in serum. We detected 250 antigen spots that reacted with AECAs in serum samples from 30 healthy subjects by 2-dimensional immunoblot using primary cultured HBMEC as the antigen source. There were 10 spots that corresponded to common target antigen spots and reacted with AECAs in serum samples from > 25% of the 30 healthy subjects. We identified 7 proteins that corresponded to 8 of the 10 spots by mass spectrometry: 78-kDa glucose-regulated protein, dihydropyrimidinase-related protein 2, heterogeneous nuclear ribonucleoprotein L, vimentin, perilipin 3, alpha-enolase, and annexin A2. The results suggest that these 7 HBMEC proteins are major target antigens of natural AECAs.

[A case of nonsystemic vasculitic neuropathy with spondylosis deformans in an 84-year-old woman].

We report an 84-year-old woman with left lower limb muscle weakness and numbness who also had weakness in her right lower limb, which showed spontaneous partial improvement. Neurological examination revealed lower extremity weakness and sensory disturbance in all modalities, predominantly distally on the left side. Laboratory studies yielded normal results, except for a slightly high erythrocyte sedimentation rate. Nerve conduction studies showed axonal neuropathy in the right tibial nerve, and loss of action potentials in other lower limb nerves. Histological study of the left sural nerve revealed mainly loss of axons and differences in the density of fascicules in the axons. In addition, inflammatory cells infiltrated around small blood vessels. Therefore, we diagnosed nonsystemic vasculitic neuropathy. Magnetic resonance imaging revealed that she also had spondylosis deformans and radiculopathy, which was more difficult to differentiate. Neural biopsy was important for diagnosis.

Cardiac sympathetic function in the patients with amyotrophic lateral sclerosis: analysis using cardiac [123I] MIBG scintigraphy.

Amyotrophic lateral sclerosis (ALS), which is the most serious form of degenerative motor neuron disease in adults, is characterized by upper and lower motor neuron degeneration, skeletal muscle atrophy, paralysis, and death. Some patients with respiratory-dependent ALS die of sudden cardiac arrest or anoxic encephalopathy following circulatory collapse, which may be associated with sympathetic hyperactivity. Cardiac [(123)I] MIBG scintigraphy is a diagnostic method of cardiac sympathetic function. However, few reports have addressed cardiac sympathetic function in ALS patients using this technique. We investigated cardiac sympathetic function in 63 ALS patients and 10 healthy volunteers using cardiac [(123)I] metaiodobenzylguanidine (MIBG) scintigraphy [heart/mediastinum ratio (H/M ratio) in the early phase and washout ratio (WR)] at the time of diagnosis. The WR of cardiac [(123)I] MIBG scintigraphy, which indicates cardiac sympathetic activity, was significantly increased in ALS patients compared with controls. ALS patients with an increased WR exhibited a significantly higher progression rate compared with those with normal WR. Moreover, the survival of ALS patients with increased WR was significantly decreased compared with those with normal WR. These results suggested that some patients with ALS have sympathetic hyperactivity at the time of diagnosis. ALS patients may suffer from chronic cardiac sympathetic hyperactivity, which is associated with sudden cardiac death and stress induced cardiomyopathy. Increased WR in cardiac [(123)I] MIBG scintigraphy may be a predictive factor in ALS patients.

Is there a difference in gastric emptying between myotonic dystrophy type 1 patients with and without gastrointestinal symptoms?

Gastrointestinal symptoms are frequent complaints in patients with myotonic dystrophy type 1 (MyD1) and may be associated with reduced gastrointestinal motility caused by smooth muscle dysfunction. Although previous studies have found delayed gastric emptying (GE) in MyD1 patients, the relationship between GE and symptoms has been unclear. We investigated GE in 23 MyD1 patients and 20 healthy volunteers using the 13C-acetate breath test. The MyD1 patients were divided into two groups: those with gastrointestinal symptoms (n = 9) and those without gastrointestinal symptoms (n = 14). The GE function was estimated using the 13C-acetate breath test as half-emptying time (HET) and peak time of the 13C-%-dose-excess curve (T max). GE (HET and T max) was more significantly delayed in patients with MyD1 than in the controls. The GE in MyD1 patients with gastrointestinal symptoms was significantly delayed compared to those without gastrointestinal symptoms. The GE in MyD1 patients with gastrointestinal symptoms was more significantly delayed than in the controls. The GE was significantly delayed in MyD1 patients with gastrointestinal symptoms for >5 years as compared to those with the disease for <5 years, while GE of MyD1 patients without gastrointestinal symptoms did not correlate with the duration of the disease. The GE in MyD1 patients did not correlate with the muscular disability rating scale. These findings suggest that impairment of GE evolves over time and that the progression of delayed GE and skeletal muscle impairment are independent. Smooth muscle impairment may be affected at an earlier stage in MyD1.

Anti-endothelial cell antibodies in patients with cerebral small vessel disease.

The pathogenesis of cerebral small vessel disease (CSVD) in the elderly is poorly understood. Endothelial cell activation and dysfunction may play a causal role in the pathogenesis of CSVD. It was reported that anti-endothelial cell antibodies (AECAs) are associated with endothelial cell dysfunction and inflammation. We hypothesized that AECAs may be associated with the pathogenesis of CSVD. We examined AECAs in sera from 12 elderly subjects with CSVD, 12 elderly subjects without CSVD, and 18 healthy volunteers by 2-dimensional immunoblotting using primary cultured human brain microvascular endothelial cells as the antigen source. We identified 4 AECAs that were detected in sera from more than one-half of the elderly subjects with CSVD. Subsequently, we analyzed the target antigens of these 4 antibodies by liquid chromatography-tandem mass spectrometry. The target antigens of these 4 antibodies were tropomyosin alpha-4 chain (TPM4), vimentin, alpha-enolase, and annexin A2. Among these 4 antibodies, the anti-TPM4 antibody was significantly more frequently detected in sera from the elderly subjects with CSVD than the other subjects. We determined the anti-TPM4 antibody level in sera from 21 elderly subjects with CSVD and 25 subjects without CSVD by enzyme-linked immunosorbent assay. The anti-TPM4 antibody level was significantly higher in the subjects with than without CSVD. Therefore, an autoimmune, inflammatory process with high levels of anti-TPM4 antibody may contribute to the development of CSVD in the elderly.

Late-onset patients with sporadic amyotrophic lateral sclerosis in Japan have a higher progression rate of ALSFRS-R at the time of diagnosis.

OBJECTIVE: The population in Japan is aging at a faster rate than in other countries in the world. It is speculated that the number of patients with late-onset amyotrophic lateral sclerosis (ALS) will increase even more in the future. However, few studies have been undertaken on the characteristics of patients with late-onset ALS in Japan. This study sought to investigate the clinical features of patients with late-onset ALS compared with those with early-onset ALS using the progression rate (ΔFS). METHODS: Forty-five patients with sporadic ALS were divided into 2 groups: 23 patients with early-onset of ALS (<65 years; early onset) and 22 patients with late-onset ALS (≥65 years; late onset). Every patient was followed up from the time of initial diagnosis to the primary endpoint (death or time culminating in death without tracheostomy or ventilation assistance including noninvasive positive pressure ventilation) or for at least 48 months after initial diagnosis. RESULTS: ΔFS in the patient group with late onset was significantly higher than that of the group with early onset (p=0.010). Survival of patients with late onset was significantly decreased compared to that of patients with early onset (p=0.031). CONCLUSION: Our finding suggested that patients with late-onset ALS showed more rapid disease progression than those with early-onset ALS using ΔFS.

Antibodies against the tom40 subunit of the translocase of the outer mitochondrial membrane complex and cognitive impairment in Alzheimer's disease.

Recent studies suggest that microvascular abnormalities are involved in pathology and progression of Alzheimer's disease. The purpose of this study was to examine the presence of antibodies against cerebral microvascular endothelial cells specific for Alzheimer's disease, and to evaluate the association of these antibodies with cognitive impairment. The study included patients with Alzheimer's disease (age ≥60 years; 24 patients), control subjects without neurological diseases (age ≥60 years; 19 subjects), patients with multiple sclerosis (all ages; 17 patients), and healthy control subjects (age <40 years; 18 subjects). Serum was analyzed with 2-dimensional electrophoresis and Western blot, with cultured human brain microvascular endothelial cells as the antigen source. The anti-Tom40 antibody was identified significantly more frequently in patients with Alzheimer's disease than control subjects or patients with multiple sclerosis. In patients with Alzheimer's disease, the mean scores for the Mini-Mental State Examination were significantly lower for patients who were positive for anti-Tom40 antibody than those who were negative for anti-Tom40 antibody. In summary, the anti-Tom40 antibody is significantly associated with cognitive impairment in patients with Alzheimer's disease.

Is there delayed gastric emptying in patients with multiple system atrophy? An analysis using the (13)C-acetate breath test.

Autonomic failure is one of the criteria according to the second consensus statement for the diagnosis of multiple system atrophy (MSA). Gastrointestinal symptoms are frequent complaints in patients with MSA and may be associated with reduced gastrointestinal motility due to autonomic nervous system dysfunction. However, there are few reports on gastric emptying in patients with MSA. We investigated gastric emptying in 25 patients with MSA, 20 patients with sporadic adult-onset ataxia of unknown etiology (SAOA), and 20 healthy volunteers using the (13)C-acetate breath test. Gastric emptying function is estimated by this test as the half-emptying time (HET) and peak time of the (13)C-%-dose-excess curve (T (max)), with expirations collected for 4 h after a test meal and determination of (13)CO(2) content using an infrared (IR) spectrophotometer. The HET and T (max) of gastric emptying were significantly delayed in patients with MSA as compared to those in SAOA and controls (p < 0.01). The HET and T (max) were not significantly different between SAOA and controls. No correlation existed between the HET or T (max) and the duration or severity of the disease in MSA patients. These results suggested that gastric emptying was significantly delayed in patients with MSA, and the delay already appeared in the early stage of the disease. Delayed gastric emptying is one of the autonomic failures and may be a clinical marker of MSA.

Elevated anti-heat shock protein 60 antibody titer is related to white matter hyperintensities.

BACKGROUND: There are many reports that the antibody against heat shock protein 60 (Hsp60) is present in most patients with coronary artery disease and atherosclerosis, and that its titer correlates with disease severity. However, few reports have described the association between anti-Hsp60 antibody and cerebrovascular disease. METHODS: We determined the anti-Hsp60 antibody titer in patients with neurologic diseases and healthy subjects using enzyme-linked immunosorbent assay (ELISA) and evaluated their findings of brain magnetic resonance imaging (MRI) of the white matter. White matter hyperintensities (WMHs) on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images were classified into 2 categories: periventricular hyperintensity (PVH) and deep white matter hyperintensity (DWMH). The lesions in each category were then divided into 4 grades (grades 0-3) according to the Fazekas rating scale. RESULTS: There were no significant differences in the titer between patients with neurologic diseases and healthy subjects. The mean grade of DWMHs (mean ± SD, 1.56 ± 0.70) was significantly higher in 18 subjects in the high-titer group (≥39.8 ng/mL; mean titer + 2 SD in sera from 23 healthy subjects) than in 86 subjects (mean ± SD, 0.09 ± 0.76) in the normal-titer group (<39.8 ng/mL; P < .003). The mean grade of PVHs (mean ± SD, 1.50 ± 0.71) was also significantly higher in the high-titer group than in the normal-titer group (mean ± SD, 1.17 ± 0.62; P < .02). CONCLUSIONS: A significant correlation was noted between anti-Hsp60 antibody titer and the severity of WMHs on brain MR images. We suggest that an elevated titer of the anti-Hsp60 antibody could be a risk factor for cerebral small-vessel disease.

Neuromyelitis optica in Japanese sisters.

We report cases of Japanese sisters with neuromyelitis optica (NMO). The elder sister was 25, when she was diagnosed with right optic neuritis. After 3 months, she developed left optic neuritis and myelitis. At age 27, she had the second relapse, but she has been free from episodes thereafter. The younger sister was 26, when she was diagnosed with optic neuritis. Thus far, she has 9 relapses, comprising both myelitis and optic neuritis. Both sisters had normal brain MRI scans, longitudinally extensive transverse myelitis over 3 vertebral segments, and positive results for anti-aquaporin-4 antibody (AQAP4Ab). They fulfilled the Wingerchuk criteria for definite NMO. Both sisters shared some immunogenetic factors, but they were not exposed to the same environmental factors after their early twenties. The final disability status was almost the same in both cases, and both showed a very benign course. These data suggest that genetic factors affect the age at onset and environmental factors may affect the frequency of relapse.

Diffuse skeletal muscles uptake of [18F] fluorodeoxyglucose on positron emission tomography in primary muscle peripheral T-cell lymphoma.

A 40-year-old man presented with weakness of neck extensor muscles. Cervical magnetic resonance imaging showed high-intensity areas in muscles of the left lateral cervical region on T2-weighted images. Fluorodeoxyglucose-positron emission tomography scan demonstrated striking fluorodeoxyglucose uptake by multiple skeletal muscles of the neck, chest, and abdominal region. Muscle biopsy demonstrated peripheral T-cell lymphoma, unspecified. The diagnosis was primary skeletal muscle peripheral T-cell lymphoma. Primary skeletal muscle non-Hodgkin's lymphoma of T-cell immunophenotype is extremely rare and fluorodeoxyglucose-positron emission tomography demonstrated striking fluorodeoxyglucose uptake in multiple skeletal muscles and served as a quite useful modality for the diagnosis of this patient.

Fasudil and ozagrel in combination show neuroprotective effects on cerebral infarction after murine middle cerebral artery occlusion.

Rho kinase (ROCK), one of the serine/threonine kinases, is involved in pathologic conditions, and its activation causes neuronal cell death. Fasudil, a selective ROCK inhibitor, has been reported to cause increased cerebral blood flow (CBF) in the ischemic brain and protect against neuronal cell death by inhibiting ROCK. Ozagrel, a thromboxane A(2) synthase inhibitor, inhibits platelet aggregation and causes vasodilatation, thereby increasing CBF in cerebral thrombosis. The present study evaluates the combination therapy of fasudil and ozagrel on focal brain ischemia induced by middle cerebral artery occlusion (MCAO) in mice. Each monotherapy of fasudil at 10 mg/kg i.p. and ozagrel at 30 mg/kg i.p. significantly reduced cerebral infarction. The combination therapy of fasudil (3 mg/kg i.p.) and ozagrel (10 mg/kg i.p.), which are noneffective doses, resulted in reduction of cerebral infarction, and the protective effect was observed up to 5 min, but not 3 h, after reperfusion. Regional CBF after MCAO and phosphorylation of endothelial nitric-oxide synthase (NOS) significantly increased in response to the combination therapy, whereas these effects were not observed with monotherapy of either drug. The protective effect of combination treatment was antagonized by the treatment of a NOS inhibitor, nitro-l-arginine methyl ester hydrochloride. These findings indicate that the combination treatment of fasudil and ozagrel exhibits additive effects for neuroprotection after MCAO. These findings indicate that the combination treatment of fasudil and ozagrel may be useful as a potential therapeutic strategy for the treatment of stroke.

Patterns of levels of biological metals in CSF differ among neurodegenerative diseases.

We measured the levels of some biological metals: copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), and zinc (Zn) in the cerebrospinal fluid (CSF) in patients with neurodegenerative diseases (52 patients with amyotrophic lateral sclerosis (ALS)), 21 patients with Alzheimer's disease (AD), and 20 patients with Parkinson's disease (PD) by inductively coupled plasma mass spectrometry (ICP-MS). The diagnoses were additionally supported by neuroimaging techniques for AD and PD. In ALS, the levels of Mg (p<0.01 significant difference), Fe, Cu (p<0.05), and Zn (p<0.10) in CSF were higher than those in controls. Some patients showed very high levels of Cu and Zn before the critical deterioration of the disease. In AD, the levels of Cu and Zn in CSF were significantly higher in patients with late-onset AD (p<0.01). In PD, we found significantly increased levels of especially Cu and Zn in particular (p<0.01) and Mn (p<0.05) in CSF. A multiple comparison test suggested that the increased level of Mg in ALS and that of Mn in PD were the pathognomonic features. These findings suggest that Cu and Zn in particular play important roles in the onset and/or progression of ALS, AD, and PD. Therefore, Cu-chelating agents and modulators of Cu and Zn such as metallothionein (MT) can be new candidates for the treatment of ALS, AD, and PD.