Symptomatology and Neuropathology of patients presenting with focal cortical signs.

Here, we describe two patients who presented with focal cortical signs and underwent neuropathological examination. Case 1 was a 73-year-old woman with progressive speech disorder and abnormal behavior. She showed agraphia of the frontal lobe type, featured by the omission of kana letters when writing, other than pyramidal tract signs, pseudobulbar palsy, and frontal lobe dementia. Neuropathological examination, including TAR DNA-binding protein 43 (TDP-43) immunohistochemistry, revealed bilateral frontal and anterior temporal lobe lesions accentuated in the precentral gyrus and posterior part of the middle frontal gyrus. Both upper and lower motor neurons showed pathological changes compatible with amyotrophic lateral sclerosis. Case 2 was a 62-year-old man with progressive speech disorder and hand clumsiness. He had a motor speech disorder, compatible with apraxia of speech, and limb apraxia of the limb-kinetic and ideomotor type. Neuropathological examination revealed degeneration in the left frontal lobe, including the precentral gyrus, anterior temporal, and parietal lobe cortices. Moreover, numerous argyrophilic neuronal intracytoplasmic inclusions (Pick body) and ballooned neurons were observed in these lesions and the limbic system. The pathological diagnosis was Pick disease involving the peri-Rolandic area and parietal lobe. In these two cases, the distribution of neuropathological changes in the cerebral cortices correlated with the clinical symptoms observed.

Late-onset autosomal recessive cerebellar ataxia and neuropathy with a novel splicing mutation in the ATM gene.

Autosomal recessive cerebellar ataxias comprise many types of diseases. The most frequent autosomal recessive cerebellar ataxias are Friedreich ataxia, but other types are relatively rare. We encountered a consanguineous family with two cases of late-onset cerebellar ataxia with neuropathy. We performed whole-exome sequencing in one patient and confirmed by Sanger sequencing in other family members. Neurological examination revealed cerebellar ataxia, hand tremor, and neck dystonia, distal muscle wasting, and diminished tendon reflexes. The patients had no conjunctival telangiectasia or immunodeficiency. Blood examination revealed slightly elevated α-fetoprotein. Brain MRI demonstrated marked cerebellar atrophy and mild brainstem atrophy. The electrophysiologic study and nerve biopsy showed axonal neuropathy. Whole-exome sequencing revealed a novel homozygous missense variant (NM_000051.3: c.496G > C) in the ataxia-telangiectasia mutated gene. This homozygous variant was found in another patient, co-segregated within the family members-this variant results in aberrant splicing (skipping exon 5) on RT-PCR analysis. We identified the ataxia-telangiectasia mutated variant in an adult, late-onset autosomal recessive cerebellar ataxias family. We should consider ataxia-telangiectasia even in late-onset autosomal recessive cerebellar ataxias without telangiectasia or immunodeficiency.

Histopathologic Analysis of Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL): A Report of a New Genetically Confirmed Case and Comparison to 2 Previous Cases.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a nonhypertensive hereditary cerebral small vessel disease that is caused by mutations in a single gene, HTRA1. The HTRA1 protein normally represses transforming growth factor-ß (TGF-ß) signaling and its mutations result in vascular changes. Ten homozygous, 1 compound heterozygous, and 1 homozygous frameshift mutation have been identified in the HTRA1 gene of patients with genetically confirmed CARASIL. However, few studies have compared neuropathologic findings in patients with the same or different mutations in HTRA1. We analyzed histopathologic alterations in 3 autopsied patients with genetically confirmed CARASIL: 2 of them had the HTRA1 p.R302X mutation and 1 had the HTRA1 p.A252T mutation. All 3 had similar cerebral arteriopathy showing myointimal proliferation, multi-layering and splitting of elastic laminae, and marked loss of medial smooth muscle cells. One CARASIL patient with the p.R302X mutation had atherosclerosis-like intimal thickening and arteriolosclerosis in the arteries of visceral organs, indicating that atherosclerotic changes are not confined to the intracranial vasculature but can occur throughout the body. CARASIL is a unique hereditary disease that shows similar neuropathology, systemic vascular pathology, and other TGF-ß1-related pathology associated with HTRA1 mutation.

Subacute autonomic and sensory neuropathy closely related to cytomegalovirus infection preceded by frequent syncopal attacks.

A 73-year-old woman who had hypertension developed a slight fever and general malaise with laboratory-proven hepatic dysfunction as well as frequent syncopal attacks 3 months before admission to our hospital. One month later, she developed urinary retention and distal limb numbness. Upon admission, her neurological examination showed reduced limb tendon reflexes, glove and stocking-type numbness, and diminished senses of touch, temperature, pain, and distal leg vibration and position. Serum cytomegalovirus (CMV) IgM antibody and CMV IgG antibody were elevated on admission, and both decreased thereafter, confirming CMV infection. No serum anti-ganglioside antibody was detected. Cerebrospinal fluid revealed a mild pleocytosis and elevated proteins. Compound muscle action potential (CMAP) amplitudes of the tibial and peroneal nerve were slightly reduced. Sensory nerve action potential (SNAP) amplitudes of the median and ulnar nerves were reduced, and sural SNAP was not evoked. Systolic blood pressure dropped 48 mmHg when the patient assumed a standing position from a supine one, demonstrating orthostatic hypotension, and a cold pressor test was abnormal, both indicating an obvious hypofunction of the sympathetic nerve. The postganglionic autonomic nerve appeared to be damaged because the accumulation of [(123)I] meta-iodobenzylguanidine was reduced on myocardial scintigraphy. These findings combined together led us to make a diagnosis of subacute autonomic and sensory neuropathy associated with CMV infection in this case. Following an eventless administration of oral fludrocortisones, intravenous immuno-globulin (IVIg) was given after one month of the hospitalization with a remarkable reduction of the syncope. This case is instructive in two points. One is that there may be a couple of months with syncope alone before the sensory disturbance appearance, and the other is that IVIg may be considerably effective for the patient-annoying syncopes. To our knowledge, this is the first report of subacute autonomic and sensory neuropathy caused by CMV infection.

ALS patients with ability to communicate after long-term mechanical ventilation have confined degeneration to the motor neuron system.

OBJECTIVE: To clarify the position in the amyotrophic lateral sclerosis (ALS) spectrum, of a subgroup of patients who maintained the ability to communicate after long-term mechanical ventilation (LTMV) by tracheostomy. METHODS: We undertook a clinicopathological investigation of sporadic ALS in three patients who maintained the ability to communicate after approximately 30-year survival on LTMV by tracheostomy. RESULTS: The age of onset and duration of disease was 48 years and 31 years in patient 1, 55 years and 29 years in patient 2, and 31 years and 33 years in patient 3, respectively. Each patient displayed slow disease progression. In all patients, both upper and lower motor neurons were markedly degenerated, while other neuronal systems and the brainstem tegmentum were spared. A few normal-looking motor neurons remained in the anterior horn of the spinal cord. There were no TAR DNA-binding protein 43-immunoreactive inclusions in the lower motor neurons in any patient and only occasional inclusions in the cerebral cortex of one patient. CONCLUSION: The clinicopathological findings of these three patients suggest that there is a distinct subgroup of ALS patients characterized by the above-mentioned features.

Predictive factors for prognosis following unsedated percutaneous endoscopic gastrostomy in ALS patients.

INTRODUCTION: This study aimed to determine the prognostic factors and the values that predict survival after percutaneous endoscopic gastrostomy (PEG) tube placement in patients with amyotrophic lateral sclerosis (ALS). METHODS: We retrospectively analyzed the correlations for 97 consecutive patients with ALS between clinical parameters and survival following PEG tube placement using the log-rank test and Cox proportional-hazards models. RESULTS: The log-rank test showed that an arterial carbon dioxide pressure (PaCO2 ) of ≤ 40 mmHg (P = 0.0054), a forced vital capacity (FVC) of ≥ 38% of predicted (P = 0.0003), and bulbar-onset (P = 0.0121) were significantly associated with better post-PEG survival. Multivariate analysis showed that the FVC and PaCO2 were associated with better post-PEG survival (P = 0.0081 and P = 0.0265, respectively). CONCLUSIONS: PEG tube placement in ALS is recommended when FVC is ≥ 38% of predicted and when PaCO2 is normal. Muscle Nerve 54: 277-283, 2016.

A lethal intracranial Rosai-Dorfman disease of the brainstem diagnosed at autopsy.

Rosai-Dorfman disease (RDD) is a benign histiocytic proliferative disorder characterized by the accumulation of histiocytes in lymph nodes and various other organs. RDD seldom involves the central nervous system, and cases of purely intracranial RDD are particularly rare. We report a case of purely intracranial RDD involving the brainstem that was diagnosed at autopsy. A 68-year-old woman visited our hospital because of visual disturbances and loss of energy. Magnetic resonance imaging revealed an obscure mass in the brainstem. Despite exhaustive work-ups, the etiology of the intracranial mass remained unclear. The patient died of respiratory depression, and an autopsy was performed for pathological investigation. Macroscopically, a pink pale mass 2.5 cm in diameter was found in the brainstem, with no attachment to the dura. Histologically, it was composed of histiocytic cells with incorporation of small lymphocytes (emperipolesis). Immunohistochemical staining revealed that the cells were positive for CD68 and S100 and negative for CD1a, consistent with a diagnosis of RDD. Purely intracranial RDD is extremely rare and considered benign. To date, nine cases (including ours) have been reported. To our knowledge, this is the first case of intracranial RDD with autopsy. Although generally considered benign, RDD involving the brainstem might be lethal.

Predictors of impaired communication in amyotrophic lateral sclerosis patients with tracheostomy-invasive ventilation.

Predictors of communication impairment in patients with amyotrophic lateral sclerosis (ALS) using tracheostomy-invasive ventilation (TIV) were investigated. Seventy-six ALS patients using TIV were enrolled and classified into three subgroups of communication ability: patients who could communicate with communication devices (Stage I), patients who had difficulty with communication (Stage II, III, or IV), and patients who could not communicate by any means (Stage V). Predictors of communication impairment were analysed by the Cox proportional hazard model. Results demonstrated that there were no significant differences in disease duration between subgroups. Within 24 months after disease onset, patients who needed TIV and tube feeding, developed oculomotor impairment or became totally quadriplegic and progressed from Stage I to II and V significantly earlier. Multivariate analyses revealed that within 24 months from onset, the need for TIV and progression to total quadriplegia were significant events in patients who progressed to Stage II, whereas the development of oculomotor limitation was significant in patients who progressed to Stage V. In conclusion, TIV, impaired oculomotor movement and total quadriplegia are predictors of severe communication impairment. Rapid disease progression might indicate future communication impairment after the use of TIV. We highly recommend early detection of impaired communication and identification of the best methods of communication.

[A case of encephalitis with hyperfamiliarity for faces].

A 21-year-old right-handed woman was admitted to our hospital with fever, headache, and seizures. On admission, she showed anterograde and retrograde amnesia. These features, together with mild pleocytosis in the cerebrospinal fluid, led to the diagnosis of encephalitis. Brain MRI was normal. EEG revealed small spike waves in the left temporal lobe. There were no recurrent convulsions. Five days later, she stated she had hyperfamiliarity for faces of people she had never met before. She reported that many people appeared familiar regardless of age, sex, and profession; however, feelings of likes and dislikes did not accompany these symptoms. This symptom lasted for 20 days. Her ability to recognize known faces was normal, and prosopagnosia was not present. Neuropsychological tests indicated that her verbal memory was impaired. The retrograde amnesia remained until discharge. Considering the psychological findings attributable to left temporal lobe dysfunction, as well as previous reports on similar cases, our case suggests a possible relationship between lesions of the left temporal lobe and hyperfamiliarity for faces.

Surgery for amygdala enlargement with mesial temporal lobe epilepsy: pathological findings and seizure outcome.

OBJECTIVE: Amygdala enlargement (AE) has been suggested to be a subtype of mesial temporal lobe epilepsy (MTLE). However, most reports related to AE have referred to imaging studies, and there have been few reports regarding surgical and pathological findings. The present study was performed to clarify the surgical outcomes and pathology of AE. METHODS: Eighty patients with drug-resistant MTLE were treated surgically at the Tokyo Metropolitan Neurological Hospital between April 2010 and July 2013. Of these patients, 11 were diagnosed as AE based on presurgical MRI. Nine patients with AE underwent selective amygdalohippocampectomy, while the remaining two patients underwent selective amygdalotomy with hippocampal transection. Intraoperative EEG was routinely performed. The histopathology of the resected amygdala tissue was evaluated and compared with the amygdala tissue of patients with hippocampal sclerosis. RESULTS: Pathological findings indicated that 10 of 11 specimens had closely clustering hypertrophic neurons with vacuolisation of the background matrix. Slight gliosis was seen in nine specimens, while the remaining two showed no gliotic changes. Intraoperative EEG showed abnormal sharp waves that seemed to originate not from the amygdala but from the hippocampus in all cases. Ten patients became seizure-free during the postoperative follow-up period. CONCLUSIONS: Histopathologically, clustering hypertrophic neurons and vacuolation with slight gliosis or without gliosis were considered to be pathological characteristics of AE. Amygdalohippocampectomy or hippocampal transection with amygdalotomy is effective for seizure control in patients with AE.

Factors affecting longitudinal functional decline and survival in amyotrophic lateral sclerosis patients.

Our objective was to elucidate the clinical factors affecting functional decline and survival in Japanese amyotrophic lateral sclerosis (ALS) patients. We constructed a multicenter prospective ALS cohort that included 451 sporadic ALS patients in the analysis. We longitudinally utilized the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) as the functional scale, and determined the timing of introduction of a tracheostomy for positive-pressure ventilation and death. A joint modelling approach was employed to identify prognostic factors for functional decline and survival. Age at onset was a common prognostic factor for both functional decline and survival (p < 0.001, p < 0.001, respectively). Female gender (p = 0.019) and initial symptoms, including upper limb weakness (p = 0.010), lower limb weakness (p = 0.008) or bulbar symptoms (p = 0.005), were related to early functional decline, whereas neck weakness as an initial symptom (p = 0.018), non-use of riluzole (p = 0.030) and proximal dominant muscle weakness in the upper extremities (p = 0.01) were related to a shorter survival time. A decline in the ALSFRS-R score was correlated with a shortened survival time (p < 0.001). In conclusion, the factors affecting functional decline and survival in ALS were common in part but different to some extent. This difference has not been previously well recognized but is informative in clinical practice and for conducting trials.

The El Escorial criteria: strengths and weaknesses.

The El Escorial criteria for the diagnosis of amyotrophic lateral sclerosis (ALS) were established 20 years ago and have been used as inclusion criteria for clinical trials. However, concerns have been raised concerning their use as diagnostic criteria in clinical practice. Moreover, as modern genetics have shed new light on the heterogeneity of ALS and the close relationship between ALS and frontotemporal dementia (FTD) recognized, the World Federation of Neurology Research Group on ALS/MND has initiated discussions to amend and update the criteria, while preserving the essential components for clinical trial enrolment purposes.

Prevalence and incidence of amyotrophic lateral sclerosis in Japan.

BACKGROUND: Previous studies have reported a high incidence of amyotrophic lateral sclerosis (ALS) in endemic foci in the Kii Peninsula, Japan. However, little is known about the ALS frequency in the whole country. Furthermore, the presence of ethnic variation in the incidence of ALS remains unknown. METHODS: We conducted a nationwide survey of ALS frequency in 2013 to estimate its annual prevalence and incidence. ALS was diagnosed based on the El Escorial Criteria. The study period was the 2009 fiscal year, from April 2009 to March 2010. To compare the incidence of ALS among prefectures, standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated under the assumption of Poisson distribution. RESULTS: The annual crude prevalence and incidence rates per 100 000 people per year were 9.9 (95% CI 9.7-10.1) and 2.2 (95% CI 2.1-2.3), respectively. The age group with the highest prevalence as well as incidence was 70-79 years, and the male-female ratio was approximately 1.5. The annual incidence rate adjusted for age and sex using the 2000 U.S. standard population was 2.3 (95% CI 2.2-2.4) per 100 000 people. Some prefectures had significantly high SIRs: Okinawa, Nara and Wakayama in the Kii Peninsula, and Niigata for males; Kumamoto for females. CONCLUSIONS: This is the first report on the annual prevalence and incidence of ALS in the representative population of Japan. We identified some prefectures with a high incidence of ALS. However, the incidence of ALS in the Japanese population was much lower than in the Caucasian populations of Europe and North America.

Prognostic role of "prion-like propagation" in SOD1-linked familial ALS: an alternative view.

"Prion-like propagation" has recently been proposed for disease spread in Cu/Zn superoxide dismutase 1 (SOD1)-linked familial amyotrophic lateral sclerosis (ALS). Pathological SOD1 conformers are presumed to propagate via cell-to-cell transmission. In this model, the risk-based kinetics of neuronal cell loss over time appears to be represented by a sigmoidal function that reflects the kinetics of intercellular transmission. Here, we describe an alternative view of prion-like propagation in SOD1-linked ALS - its relation to disease prognosis under the protective-aggregation hypothesis. Nucleation-dependent polymerization has been widely accepted as the molecular mechanism of prion propagation. If toxic species of misfolded SOD1, as soluble oligomers, are formed as on-pathway intermediates of nucleation-dependent polymerization, further fibril extension via sequential addition of monomeric mutant SOD1 would be protective against neurodegeneration. This is because the concentration of unfolded mutant SOD1 monomers, which serve as precursor of nucleation and toxic species of mutant SOD1, would decline in proportion to the extent of aggregation. The nucleation process requires that native conformers exist in an unfolded state that may result from escaping the cellular protein quality control machinery. However, prion-like propagation-SOD1 aggregated form self-propagates by imposing its altered conformation on normal SOD1-appears to antagonize the protective role of aggregate growth. The cross-seeding reaction with normal SOD1 would lead to a failure to reduce the concentration of unfolded mutant SOD1 monomers, resulting in continuous nucleation and subsequent generation of toxic species, and influence disease prognosis. In this alternative view, the kinetics of neuronal loss appears to be represented by an exponential function, with decreasing risk reflecting the protective role of aggregate and the potential for cross-seeding reactions between mutant SOD1 and normal SOD1.

Prevalence and Incidence of Amyotrophic Lateral Sclerosis in Japan.

Background: Previous studies have reported a high incidence of amyotrophic lateral sclerosis (ALS) in endemic foci in the Kii Peninsula, Japan. However, little is known about the ALS frequency in the whole country. Furthermore, the presence of ethnic variation in the incidence of ALS remains unknown.Methods: We conducted a nationwide survey of ALS frequency in 2013 to estimate its annual prevalence and incidence. ALS was diagnosed based on the El Escorial Criteria. The study period was the 2009 fiscal year, from April 2009 to March 2010. To compare the incidence of ALS among prefectures, standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated under the assumption of Poisson distribution.Results: The annual crude prevalence and incidence rates per 100 000 people per year were 9.9 (95% CI 9.7-10.1) and 2.2 (95% CI 2.1-2.3), respectively. The age group with the highest prevalence as well as incidence was 70-79 years, and the male-female ratio was approximately 1.5. The annual incidence rate adjusted for age and sex using the 2000 U.S. standard population was 2.3 (95% CI 2.2-2.4) per 100 000 people. Some prefectures had significantly high SIRs: Okinawa, Nara and Wakayama in the Kii Peninsula, and Niigata for males; Kumamoto for females.Conclusions: This is the first report on the annual prevalence and incidence of ALS in the representative population of Japan. We identified some prefectures with a high incidence of ALS. However, the incidence of ALS in the Japanese population was much lower than in the Caucasian populations of Europe and North America.

A novel WDR45 mutation in a patient with static encephalopathy of childhood with neurodegeneration in adulthood (SENDA).

Static encephalopathy of childhood with neurodegeneration in adulthood (SENDA) is an X-linked dominant neurodegenerative disorder, and is classified as a subtype of neurodegeneration with brain iron accumulation. Recently, de novo heterozygous mutations in WDR45 at Xp11.23 have been reported in patients with SENDA. We report the clinical and neuroradiological findings of a patient with SENDA with a novel c.322del mutation in WDR45. In this patient, characteristic MRI findings were useful for diagnosis.

[Familial progressive external opthalmoplegia, parkinsonism and polyneuropathy associated with POLG1 mutation].

Multiple mitochondrial DNA (mtDNA) deletions usually occur secondarily to a mutation in one of the enzymes involved in mtDNA maintenance, such as polymerase γ, which is encoded by the nuclear polymerase γ1 gene (POLG1) and POLG2. Patients with multiple mtDNA deletion disorders show clinical heterogeneity of symptoms, in addition to usually seen progressive external ophthalmoplegia (PEO). We conducted clinical, histological and genetic analyses of two affected sisters in a family with the autosomal dominant inheritance pattern of PEO. A 73-year-old woman (patient 1) with congenital hypogonadism and PEO developed L-dopa responsive parkinsonism about the age of 60. Neurological examination revealed mild proximal muscle weakness and polyneuropathy too. Her 69-year-old sister (patient 2) also showed PEO, parkinsonism and polyneuropathy. Histopathological studies of biopsied muscle specimens from patient 1 revealed numerous ragged red fibers as well as fibers with increased succinate dehydrogenase activity and decreased cytochrome c oxidase activity. Multiple mtDNA deletions were detected, both by Southern blot and long-range PCR assays of total DNA from the biopsied muscle specimens. A systemic mutational analysis in both sisters revealed a heterozygous p.Y955C (c.2864A>G) mutation in POLG1. This is the first Japanese family identified with this mutation. We reviewed cases with this mutation highlighting a wide phenotypic spectrum of this disorder.

The Card Placing Test: a new test for evaluating the function of the retrosplenial and posterior cingulate cortices.

BACKGROUND/AIM: We developed a test named the Card Placing Test (CPT), which is potentially useful for evaluating a function of the retrosplenial and posterior cingulate cortices (RSC/PCC). Part A of the test assesses the ability of a subject to retain information on spatial locations of cards placed on the floor around the subject. Part B examines the subject's ability to integrate information on the spatial locations of similarly arranged cards and information on changes in body direction. The aim of this study is to identify brain regions involved in the CPT performance. SUBJECTS AND METHODS: Twenty-five subjects were recruited from our memory clinic. We analyzed the correlation between the CPT scores and resting state regional cerebral blood flow (rCBF) determined by single-photon emission tomography. RESULTS: The scores for part A correlated with rCBF in the right inferior parietal lobule. The scores for part B were associated with rCBF in the RSC/PCC. CONCLUSIONS: The right inferior parietal lobule seems to play a pivotal role in performing part A of the CPT, whereas the RSC/PCC appears to be involved in accomplishing part B of the CPT.