Unexpected postmortem diagnoses in cases of clinically diagnosed amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that is clinically and pathologically characterized by impairment of the upper and lower motor neurons. The clinical diagnosis of ALS is not always straightforward because of the lack of specific biomarkers and clinical heterogeneity. This review presents the clinical and pathological findings of four autopsied cases that had been diagnosed with ALS before death. These cases had demonstrated definite and progressive motor neuron signs and symptoms, whereas postmortem assessment revealed miscellaneous disorders, including fungal infection, paraneoplastic syndrome, and amyloidosis. Importantly, nonmotor neuron signs and symptoms, including seizures, extra-pyramidal signs, ocular movement disorders, sensory disturbance, and dysautonomia, had also been documented during the disease course of the cases in the present study. The ALS-unlike symptoms were indicative of the "true" diagnosis in each case when those symptoms were isolated from motor neuron signs/symptoms.

[Epiconus Syndrome and Conus Syndrome].

The most caudal part of the spinal cord shows special anatomical characteristics and it contains epiconus (L4-S2 segments), the conus medullaris (S3-S5 segments), and surrounding nerve roots. Lesions of the thoracolumbar junction cause epiconus or conus syndrome. Epiconus syndrome is characterized by segmental muscular weakness and atrophy of one or both lower extremities, often accompanied by foot drop. It may manifest as motor neuron disease in the absence of sensory loss. Ossification of the ligamentum flavum is an important cause of epiconus syndrome. Conus syndrome is characterized by urinary and rectal disturbances, usually accompanied by some motor and sensory symptoms involving the lower extremities. Both syndromes are often misdiagnosed as lumbar radiculopathy or cauda equina lesions. A thorough understanding of the anatomical features and pathophysiology is important for early and accurate diagnosis of epiconus or conus syndrome.

[A case of Fisher syndrome presented by rapidly progressing bilateral palatoplegia after cytomegalovirus infection].

A 35-year-old male developed sensory abnormality of peripheral limbs and oral cavity after prior infection with diarrhea and cold symptoms. Hyperrhinolalia, nasopharyngeal reflux, double vision, and wobbling in walking rapidly progressed. Neurological examination revealed palatoplegia, omnidirectional ophthalmoplegia, hyperreflexia, sensory disturbance of extremities, and truncal and limb ataxia due to decreased deep sensation. A peripheral nerve conduction study found a slight decrease in sensory nerve action potential of the median nerve and a decrease in F wave frequency of the median nerve. Serum IgM-CMV antibody was positive on admission. After IVIg therapy, palatoplegia and ataxia markedly improved. In this case, GalNAc-GD1a and GM2 antibodies, which are often detected after CMV infection, were positive in addition to the GT1a and GQ1b antibodies, and it was assumed that these findings were associated with the palatoplegia, which is included in cranial nerve palsy. Pathophysiologically, the present case is considered to be an overlap with acute oropharyngeal palsy (AOP), which is a rare subtype of Guillain-Barre syndrome, and Fisher syndrome (FS). The clinical aspects of the present case suggest a continuous spectrum between AOP and FS.

[Spinal Disorders in the Oldest-Old].

Adult spinal deformity causing thoracolumbar hyperkyphosis is prevalent among the aging population, and is associated with impaired ADL and QOL. Corrective spine surgery is now developing for this common condition. Old patients with Parkinson's disease frequently have osteoporosis and vertebral compression fractures, which affect spinal deformity and postural abnormality. Diffuse idiopathic skeletal hyperostosis and cervical spinal cord injury without bone injury are important spinal disorders in the aged. Neurologists should be aware of locomotive syndrome, including spinal disorders, for appropriate management of motor dysfunction in super-old patients.

Higher Levels of Cystatin C Are Associated with Extracranial Carotid Artery Steno-Occlusive Disease in Patients with Noncardioembolic Ischemic Stroke.

BACKGROUND: Large artery atherosclerosis is a major cause of ischemic stroke worldwide. Differential biomarker profiles associated with extra- and intracranial atherosclerosis are a topic of considerable interest. Cystatin C (CysC), a marker of renal function, is a risk factor for cardiovascular disease. AIM: We sought to determine whether CysC levels were associated with extra- and intracranial large artery stenosis (LAS) in patients with acute ischemic stroke. METHODS: We retrospectively analyzed data of acute noncardioembolic ischemic stroke patients who were admitted to our stroke center within 5 days from symptom onset. Serum CysC levels were measured using latex agglutination turbidimetric immunoassay. Extra- and intracranial LAS were defined as ≥ 50% diameter stenosis or occlusion of the relevant internal carotid artery (ICA) and/or middle cerebral artery (MCA) using carotid echography and volume rendering on magnetic resonance angiography. Multivariate logistic analyses were used to assess the association between CysC levels and LAS after adjustment for potential confounders. RESULTS: Of 205 patients (mean age 70.2 years), 76 (37.1%) had LAS. The distribution of LAS was 29 extracranial ICA, 34 intracranial ICA/MCA (8 ICA only, 25 MCA only, 1 ICA+MCA) and 13 tandem stenosis (both extracranial ICA and intracranial ICA/MCA). Levels of CysC were higher in patients with extracranial ICA stenosis than in those with intracranial ICA/MCA stenosis (1.23 ± 0.33 vs. 0.97 ± 0.21 mg/l, p < 0.001). In multivariate analysis, the highest CysC tertile (>1.04 mg/l) was significantly associated with extracranial ICA stenosis (adjusted odds ratio [OR] 5.01, 95% confidence interval [CI] 1.51-16.63, p = 0.009) after adjustment for age, sex, diabetes, chronic kidney disease, current smoking, systolic blood pressure, HDL cholesterol, high-sensitivity C-reactive protein (hs-CRP) and premorbid lipid-lowering drugs use. When CysC was considered as a continuous variable, 1 SD increase in CysC was significantly associated with extracranial ICA stenosis (adjusted OR 3.01, 95% CI 1.58-5.72, p = 0.001). However, there were no significant associations between CysC levels and intracranial ICA/MCA stenosis. In addition, CysC levels showed a weak but statistically significant correlation with hs-CRP levels (r = 0.195, p = 0.021). Using receiver operating characteristic curve analysis, CysC value displayed good performance in discriminating extracranial ICA stenosis (c-statistic 0.79, 95% CI 0.69-0.89, p < 0.001). CONCLUSIONS: This preliminary study suggests that higher levels of CysC were independently associated with symptomatic extracranial ICA stenosis, but not with intracranial ICA/MCA stenosis in patients with noncardioembolic stroke. Our findings provide new insights into the link between serum CysC and carotid atherosclerosis.

Genetic factors for obesity.

The purpose of the present study was to identify gene polymorphisms for the reliable assessment of genetic factors for obesity. The study population comprised 3906 unrelated Japanese individuals (2286 men, 1620 women), including 1196 subjects (677 men, 519 women) with obesity (body mass index of > or = 25 kg/m2) and 2710 controls (1609 men, 1101 women). The genotypes for 147 polymorphisms of 124 candidate genes were determined with a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of smoking revealed that the -30Gright curved arrow A polymorphism of GCK, the -240Aright curved arrow T polymorphism of ACE, and the -482Cright curved arrow T polymorphism of APOC3 were significantly (P < 0.01) associated with the prevalence of obesity, and the -1989Tright curved arrow G polymorphism of ESR1 was almost significantly associated. A stepwise forward selection procedure demonstrated that ACE, GCK, and ESR1 genotypes significantly (P < 0.01) and independently affected the prevalence of obesity. Combined genotype analysis for these three polymorphisms yielded a lowest odds ratio of 0.45 for the combined genotypes of AT or TT for ACE, GG for GCK, and GG for ESR1 in comparison with the combined genotypes of AA for ACE, GG for GCK, and TT or TG for ESR1. Genotypes for ACE, GCK, and ESR1 may prove reliable for the assessment of genetic factors for obesity. Determination of the combined genotypes for these genes may contribute to the personalized prevention of this condition.

Genetic risk for atherothrombotic cerebral infarction in individuals stratified by sex or conventional risk factors for atherosclerosis.

The aim of the present study was to assess the genetic risk for atherothrombotic cerebral infarction (ACI) in men and women separately as well as in individuals with or without conventional risk factors for atherosclerosis and thereby to contribute to the personalized prevention of ACI. The study population comprised 2705 unrelated Japanese individuals (1244 men, 1461 women), including 636 subjects (372 men, 264 women) with ACI. Subjects with ACI and controls either had or did not have conventional risk factors for atherosclerosis, including hypertension, hypercholesterolemia, and diabetes mellitus. The genotypes for 202 polymorphisms of 152 candidate genes were determined by a method that combines polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Multivariable logistic regression analysis and a stepwise forward selection procedure revealed that 11 different polymorphisms were significantly (P < 0.005) associated with ACI in women or men or in individuals with or without hyper-tension, hypercholesterolemia, or diabetes mellitus: the 584C-->T polymorphism of LIPG, 5665G-->T of EDN1, and G-->A of CCL11 in women; 677C-->T of MTHFR, 1323C-->T of ITGB2, 3932T-->C of APOE, and -231A-->G of EDNRA in men; -572 G -->C of IL6 in hypertensive individuals; -403G-->A of CCL5 and G-->A of COMT in individuals with hypercholesterolemia; and 3932T--> C of APOE and A-->G of TNFSF4 in diabetic individuals. Polymorphisms associated with ACI may thus differ between women and men as well as among individuals with different risk factors. Stratification of subjects on the basis of sex or conventional risk factors for atherosclerosis may therefore be important in order to achieve the personalized prevention of ACI with the use of genetic information.

Assessment of genetic factors for type 2 diabetes mellitus.

The purpose of the present study was to identify gene polymorphisms for reliable assessment of genetic factors for type 2 diabetes mellitus. The study population comprised 4853 unrelated Japanese individuals (2688 men, 2165 women), including 1489 subjects with type 2 diabetes mellitus (969 men, 520 women) and 3364 controls (1719 men, 1645 women). The genotypes for 148 polymorphisms of 124 candidate genes were determined with a method that combines polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Sixteen polymorphisms were related (p<0.05) to the prevalence of type 2 diabetes mellitus as determined by the chi-square test. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of smoking revealed that, among these polymorphisms, the -603A --> G polymorphism of the gene for coagulation factor III (F3) was significantly (p<0.001) associated with the prevalence of type 2 diabetes mellitus, with the -603G allele representing a risk factor for this condition. A stepwise forward selection procedure demonstrated that F3 genotype (GG versus AA + AG) significantly (p<0.001) and independently affected the prevalence of type 2 diabetes mellitus. Genotype for F3 may prove reliable for assessment of genetic factors for type 2 diabetes mellitus. Determination of the genotype for this gene may contribute to personalized prevention of this condition.

Genetic risk for ischemic and hemorrhagic stroke.

OBJECTIVE: We performed an association study to identify gene polymorphisms for assessing the genetic risk of ischemic or hemorrhagic stroke. METHODS AND RESULTS: The study population comprised 3151 unrelated Japanese individuals: 1141 stroke patients (636 with atherothrombotic cerebral infarction, 282 with intracerebral hemorrhage, and 223 with subarachnoid hemorrhage) and 2010 controls. The genotypes for 202 polymorphisms of 152 genes were determined by suspension array technology. Multivariable logistic regression analysis with adjustment for conventional risk factors revealed that the -572G-->C polymorphism of the interleukin-6 (IL-6) gene (IL6) was significantly (P<0.001) associated with both atherothrombotic cerebral infarction and intracerebral hemorrhage and that the -55C-->T polymorphism of the uncoupling protein 3 gene (UCP3), the -863C-->A polymorphism of the tumor necrosis factor (TNF) gene (TNF), and the G-->A (Gly243Asp) polymorphism of the polycystic kidney disease 1-like gene (PKD1-like) were significantly associated with subarachnoid hemorrhage. CONCLUSIONS: IL6 genotype may be useful in assessing the genetic risk for atherothrombotic cerebral infarction and intracerebral hemorrhage, and genotypes for UCP3, TNF, and PKD1-like may be similarly beneficial in assessment of the risk for subarachnoid hemorrhage. Validation of our findings will require additional studies with independent subject panels.

Charles Bonnet syndrome associated with a first attack of multiple sclerosis.

BACKGROUND: We treated a rare case of Charles Bonnet syndrome (CBS) manifested during temporary blindness in both eyes caused by optic neuritis associated with a first attack of multiple sclerosis (MS). CASE: A 66-year-old Japanese woman became completely blind for 3 months due to optic neuritis after a first attack of MS. During the blind period, she experienced vivid visual hallucinations for about 2 weeks. OBSERVATIONS: The patient had no psychiatric disorders or cognitive impairments; therefore, the visual hallucinations during the period of blindness were indicative of CBS. Unexpectedly, the hallucinations disappeared without treatment following her recovery of vision. CONCLUSIONS: Although rare, visual impairment during a first attack of MS can be associated with visual hallucinations indicative of CBS. The hallucinations can disappear spontaneously with the recovery of vision without treatment.

Cervical myelopathy due to OPLL: clinical evaluation by MRI and intraoperative spinal sonography.

BACKGROUND: Concerning the relationship between morphology and clinical outcome, there have been many reports using computed tomography/myelography but not so many using axial magnetic resonance imaging (MRI) of the spinal cord. This is the first report to correlate axial cord image, intensity changes in MRI, and cord expansion pattern using intraoperative ultrasonography. OBJECTIVE: The objectives were to correlate MRI studies, axial cord images/expansion, and changes in MRI intensity to see if there is a direct prognostic significance to these changes and to determine whether preoperative axial MRI images of the spinal cord predict recovery from compressive myelopathy. METHODS: Posterior cervical decompressions with laminoplasty were performed in 44 patients with cervical myelopathy due to ossification of the posterior longitudinal ligament. On T2-weighted MR images, the cross-sectional shape of the cord at the level of maximal compression was categorized as boomerang, teardrop, or triangle. Additionally, with use of intraoperative ultrasonography, the expansion pattern of the cord that occurred intraoperatively was contrasted with that seen on postoperative MR images. RESULTS: Clinical recovery rates were the worst for those with triangular, intermediate for those with boomerang, and the best for those with teardrop shape. Preoperative low T1 and high T2 signals were found in most cases with triangular cord configurations. Triangular cord configurations showed the least expansion among the three categorized spinal cords. CONCLUSION: Patients with triangular deformity of the cord have atrophy as confirmed on MR studies where there is a low T1 and high T2 signal in the cord. Poor postoperative clinical recovery correlates with the lack of postoperative cord expansion on either MR or ultrasound evaluations. Those with either teardrop or boomerang deformities demonstrate a relatively good recovery rate.