Expanded clinical spectrum of oculopharyngodistal myopathy type 1.

INTRODUCTION/AIMS: Heterozygous CGG repeat expansions in low-density lipoprotein receptor-related protein 12 (LRP12) have recently been identified as a cause of oculopharyngodistal myopathy (OPDM), and the disease is designated as OPDM type 1 (OPDM1). In contrast to broadening of our knowledge on the genetic background of OPDM, what we know of the clinical phenotype of genetically confirmed OPDM1 remains limited. METHODS: This investigation was a single-center case series study of OPDM consisting of ten patients from seven families. Repeat-primed polymerase chain reaction and Southern blot analyses were performed to confirm the CGG repeat expansions in LRP12. Clinical findings were retrospectively reviewed. RESULTS: Seven patients from five families were identified as having CGG repeat expansions in LRP12. We found a high prevalence of axial muscle involvement, such as neck muscle weakness (6/7) and fatty infiltration in the rectus abdominis muscle, as revealed by computed tomography (5/5). We identified patients with very subtle oculopharyngeal symptoms, mimicking isolated distal myopathy. Muscle specimens were collected from the biceps brachii and tibialis anterior muscles of three patients. Myopathic changes were more severe with more atrophic fibers forming clusters in the tibialis anterior than the biceps brachii muscles of these three patients. No rimmed vacuoles were observed in the biceps brachii muscles in two of the three patients. DISCUSSION: This study shows the expanded clinical spectrum of OPDM1, highlighting the importance of axial muscle evaluation in OPDM1. Considering patients with very subtle oculopharyngeal symptoms, genetic analysis of LRP12 should be considered in patients with isolated distal myopathy.

[Facts and Cases of Diseases and Observations Are Described from My Own Experience].

Facts and cases of diseases and observations are described from my own experience. 1) Refer carefully with correct recognition of the levels of the vertebral body and cord segment. 2) The spinal nerve root is defined as the part of the peripheral nerves in the subarachnoid space. 3) The importance of referred pain and its mechanisms of symptoms are described. 4) The technique of straight-leg-raising test is useful for the diagnosis of Guillain-Barre syndrome and the detection of the lumbar narrow canal. 5) Insidious onset and progress of the calf atrophy are described. Although the cause of this case remains unknown, I naming this disease "OMURANAE"and arousing interest around it.

Low back pain due to superior cluneal nerve entrapment: A clinicopathologic study.

INTRODUCTION: We studied the clinical and nerve pathologic features in 6 patients whose low back pain (LBP) was relieved by superior cluneal nerve (SCN) neurectomy to determine whether nerve compression was the mechanism underlying this type of LBP. METHODS: All 6 patients (7 nerves) underwent SCN neurectomy for intractable LBP. Their clinical outcomes and the pathologic features of 7 nerves were reviewed. RESULTS: All patients reported LBP relief immediately after SCN neurectomy. Pathologic study of the 7 resected nerves showed marked enlargement, decreased myelinated fiber density, an increase in thinly myelinated fibers (n = 2), perineurial thickening (n = 5), subperineurial edema (n = 4), and Renaut bodies (n = 4). At the distal end of 1 enlarged nerve, we observed a moderate reduction in the density and marked reduction in the number of large myelinated fibers. DISCUSSION: The pathologic findings and effectiveness of neurectomy suggest that, in our patients, SCN neuropathy likely elicited LBP via nerve compression. Muscle Nerve 57: 777-783, 2018.

Anti-TIF1-γ antibody and cancer-associated myositis: A clinicohistopathologic study.

OBJECTIVE: We aimed to analyze the clinical and histopathologic features of cancer-associated myositis (CAM) in relation to anti-transcriptional intermediary factor 1 γ antibody (anti-TIF1-γ-Ab), a marker of cancer association. METHODS: We retrospectively studied 349 patients with idiopathic inflammatory myopathies (IIMs), including 284 patients with pretreatment biopsy samples available. For the classification of IIMs, the European Neuromuscular Center criteria were applied. Patients with CAM with (anti-TIF1-γ-Ab[+] CAM) and without anti-TIF1-γ-Ab (anti-TIF1-γ-Ab[-] CAM) were compared with patients with IIM without cancers within and beyond 3 years of myositis diagnosis. RESULTS: Cancer was detected in 75 patients, of whom 36 (48%) were positive for anti-TIF1-γ-Ab. In anti-TIF1-γ-Ab(+) patients with CAM, cancers were detected within 1 year of myositis diagnosis in 35 (97%) and before 1 year of myositis diagnosis in 1. All the anti-TIF1-γ-Ab(+) patients with CAM satisfied the dermatomyositis (DM) criteria, including 2 possible DM sine dermatitis cases, and were characterized histologically by the presence of perifascicular atrophy, vacuolated fibers (VFs), and dense C5b-9 deposits on capillaries (dC5b-9). In contrast, 39 anti-TIF1-γ-Ab(-) patients with CAM were classified into various subgroups, and characterized by a higher frequency of necrotizing autoimmune myopathy (NAM). Notably, all 7 patients with CAM classified into the NAM subgroup were anti-TIF1-γ-Ab(-) and exhibited no dC5b-9 or VFs. CONCLUSIONS: CAM includes clinicohistopathologically heterogeneous disease entities. Among CAM entities, anti-TIF1-γ-Ab(+) CAM has characteristically shown a close temporal association with cancer detection and the histopathologic findings of dC5b-9 and VFs, and CAM with NAM is a subset of anti-TIF1-γ-Ab(-) CAM.

[Visual tracking with/without passive whole-body rotation in Parkinson's disease (PD): Dissociation of smooth-pursuit and cancellation of vestibulo-ocular reflex (VOR)].

Although impaired smooth-pursuit in Parkinson's disease (PD) is well known, reports are conflicting on the ability to cancel vestibulo-ocular reflex (VOR) when the target moves with head, requiring gaze-pursuit. To compare visual tracking performance with or without passive whole-body rotation, we examined eye movements of 10 PD patients and 6 age-matched controls during sinusoidal horizontal smooth-pursuit and passive whole-body rotation (0.3 Hz, ± 10°). Three tasks were tested: smooth-pursuit, VOR cancellation, and VORx1 while subjects fixated an earth-stationary spot during whole-body rotation. Mean ± SD eye velocity gains (eye velocities/stimulus velocities) of PD patients during the 3 tasks were 0.32 ± 0.24 0.25 ± 0.22, 0.85 ± 0.20, whereas those of controls were 0.91 ± 0.06, 0.14 ± 0.07, 0.94 ± 0.05, respectively. Difference was significant between the two subject groups only during smooth-pursuit. Plotting eye-velocity gains of individual subjects during VOR cancellation against those during smooth-pursuit revealed significant negative linear correlation between the two parameters in the controls, but no correlation was found in PD patients. Based on the regression equation of the controls, we estimated expected eye velocity gains of individual subjects during VOR cancellation from their smooth-pursuit gains. Estimated gains of PD patients during VOR cancellation were significantly different from their actual gains, suggesting that different neural mechanisms operate during VOR cancellation in the controls and PD.

Treatment of low back pain in patients with vertebral compression fractures and superior cluneal nerve entrapment neuropathies.

BACKGROUND: Superior cluneal nerve entrapment neuropathy (SCN-EN) may contribute to low back pain (LBP). However, it is often misdiagnosed as lumbar spine disorder and poorly understood. METHODS: Between April 2012 and September 2013, we treated 27 patients (3 men, 24 women; mean age 75.0 years) with LBP due to SCN-EN elicited by vertebral compression fractures. Symptoms were unilateral in 4 patients and bilateral in 23 patients. The interval between symptom onset and treatment averaged 10.8 months; the mean postoperative follow-up period was 19.0 months. The clinical outcomes were assessed utilizing the numeric rating scale (NRS) for LBP, the Japanese Orthopedic Association (JOA) score, and the Roland-Morris Disability Questionnaire (RDQ) before and after treatment (e.g., until the latest follow-up). RESULTS: LBP in 17 patients was immediately improved by SCN block only. The remaining 10 patients required surgery (involving 18 sites) as SCN blocks were only transiently effective. Operative intervention resulted in the immediate and continued improvement of their LBP. Notably, their NRS decreased from 7.4 to 1.5, their RDQ scores from 19.6 to 7.0, and their JOA scores increased from 10.7 to 20.3. CONCLUSIONS: In this series, 27 patients with LBP due to SCN-EN responded either to SCN blocks (17 patients) or surgical release of SCN entrapment (10 patients at 18 sites).

Impaired smooth-pursuit in Parkinson's disease: normal cue-information memory, but dysfunction of extra-retinal mechanisms for pursuit preparation and execution.

While retinal image motion is the primary input for smooth-pursuit, its efficiency depends on cognitive processes including prediction. Reports are conflicting on impaired prediction during pursuit in Parkinson's disease. By separating two major components of prediction (image motion direction memory and movement preparation) using a memory-based pursuit task, and by comparing tracking eye movements with those during a simple ramp-pursuit task that did not require visual memory, we examined smooth-pursuit in 25 patients with Parkinson's disease and compared the results with 14 age-matched controls. In the memory-based pursuit task, cue 1 indicated visual motion direction, whereas cue 2 instructed the subjects to prepare to pursue or not to pursue. Based on the cue-information memory, subjects were asked to pursue the correct spot from two oppositely moving spots or not to pursue. In 24/25 patients, the cue-information memory was normal, but movement preparation and execution were impaired. Specifically, unlike controls, most of the patients (18/24 = 75%) lacked initial pursuit during the memory task and started tracking the correct spot by saccades. Conversely, during simple ramp-pursuit, most patients (83%) exhibited initial pursuit. Popping-out of the correct spot motion during memory-based pursuit was ineffective for enhancing initial pursuit. The results were similar irrespective of levodopa/dopamine agonist medication. Our results indicate that the extra-retinal mechanisms of most patients are dysfunctional in initiating memory-based (not simple ramp) pursuit. A dysfunctional pursuit loop between frontal eye fields (FEF) and basal ganglia may contribute to the impairment of extra-retinal mechanisms, resulting in deficient pursuit commands from the FEF to brainstem.

Multifocal conduction block in a patient with sarcoid neuropathy: successful treatment with intravenous immunoglobulin.

A 54-year-old-woman with sarcoidosis presented with progressive symmetric, predominantly distal weakness and sensory dysfunction with areflexia in all four limbs. Nerve conduction studies showed multifocal conduction blocks in several nerves. Oral steroids were ineffective; however, intravenous immunoglobulin (IVIG) therapy rapidly and repeatedly improved the patient's neurologic symptoms with a resolution of the conduction blocks. Multifocal conduction blocks are not frequently reported in patients with sarcoid neuropathy, but they may respond to early treatment with IVIG.

[Cerebellum and eye movement control -- neuronal mechanisms of memory-based smooth-pursuit and their early clinical application].

Recent studies implicate the cerebellum in cognitive functions in addition to its well-established roles in motor control and learning. Using a memory-based smooth-pursuit task that separates visual working memory from motor preparation and execution, monkeys were trained to pursue (i.e., go) or not pursue (i.e., no-go), a cued direction, based on the working memory of visual motion-direction and a go/no-go instruction. Task-related neuronal activity was examined in cerebral and cerebellar major smooth-pursuit pathways. Different cerebral and cerebellar areas carried distinctly different signals during memory-based smooth-pursuit. In the cerebellum, prediction-related signals (visual working memory, pursuit selection and movement preparation) were represented in the vermal lobules VI-VII and caudal fastigial nucleus, whereas the floccular region (flocculus and ventral paraflocculus) contained predominantly execution-related signals. This task was applied to patients with cerebellar degeneration and idiopathic Parkinson's disease (PD). None of the PD patients tested exhibited impaired working memory of motion-direction and/or go/no-go selection, but they did show task-specific difficulty in generating an initial smooth-pursuit component, suggesting difficulty in smooth-pursuit preparation. In contrast, most cerebellar patients exhibited impaired visual working memory in addition to difficulty in preparing for and executing smooth-pursuit. These results suggest different roles for the basal ganglia and cerebellum in smooth-pursuit planning.

Fasciculation potentials in amyotrophic lateral sclerosis and the diagnostic yield of the Awaji algorithm.

INTRODUCTION: The role of fasciculation potentials (FPs) in the diagnosis of amyotrophic lateral sclerosis (ALS) has been underrated. The Awaji algorithm has restored the value of FPs. Our aim was to test the diagnostic yield of the Awaji algorithm, with consideration of FPs. METHODS: Subjects consisted of 139 consecutive ALS patients retrospectively enrolled over 5 years. At presentation we evaluated the diagnostic categories using the revised El Escorial Criteria (R-EEC) and the Awaji algorithm. RESULTS: The percentage of patients classified as confirmed ALS, clinically probable (laboratory-supported), or higher was 43% using the R-EEC and 37% using the Awaji algorithm. Thirteen patients with upper motor neuron signs only in one body region showed a decrease in their category using the Awaji algorithm. FPs were observed in 89% of ALS patients and were frequent in proximal muscles. CONCLUSION: The sensitivity of the Awaji algorithm is lower than that of the R-EEC.

Spinal cord biopsy findings of anti-aquaporin-4 antibody-negative recurrent longitudinal myelitis in a patient with sicca symptoms and hepatitis C viral infection.

We describe the pathological features of a spinal cord biopsy from a 69-year-old woman with anti-aquaporin-4 antibody-negative recurrent longitudinal myelitis. Spinal cord MRI showed T2 high-intensity lesions with strong gadolinium enhancement, when episodes of sensory-motor impairment were repeated. The radiological abnormality was corrected by corticosteroid administration, but improvement of the symptoms was minimal. Although the patient had sicca symptoms and fulfilled four of the diagnostic criteria for Sjögren syndrome, the diagnosis was excluded, because of infection with hepatitis C virus, an exclusion criterion of Sjögren syndrome. In the spinal cord lesions, necrotic changes affected both myelin and axons. Infiltrating lymphocytes were predominantly T-cells. The proliferation of small vessels with hyalinization and concomitant occlusive change was remarkable. These pathological findings resembled those previously reported in Sjögren syndrome. Ultrastructurally, the endothelial cells of the small vessels showed features of activated cells and contained vesiculo-tubular structures in the cytoplasm, indicating that increased blood-brain barrier (BBB) permeability might contribute to pathogenesis. We speculated that increased BBB permeability and T-cell entry in the spinal parenchyma triggered pathological reactions resulting in necrotic changes in the spinal cord. Obstruction of small vessels might add ischemic damage to the lesions. The clinical course and pathological findings indicated that damage progressed rapidly in the spinal cord and was irreversible. The lesions apparently differed from typical demyelination plaques. Faced with such spinal cord lesions, a preventive therapeutic approach is necessary to avoid attack-associated disability.

Immune-mediated myositis in Crohn's disease.

We report a patient with uncontrolled Crohn's disease who presented with progressive weakness of proximal muscles and a marked elevation of serum creatine kinase. Muscle biopsy from the left deltoid exhibited myositic changes with inflammatory infiltrates in the perimysium, endomysium, and perivascular locations. Most were stained as CD68-positive macrophages, whereas some were CD4- and CD8-positive T lymphocytes. Due to uncontrolled bowel inflammation, several fistulae were found in the descending colon, and partial colectomy was performed. An examination of the resected colon exhibited inflammation of the bowel structure surrounded mainly by CD68-positive macrophages. The histopathological findings of the descending colon were analogous to those of the muscle. After an increased dose of mesalazine and partial colectomy, her muscle symptoms improved. These findings suggest that the myositis in Crohn's disease is immune-mediated and that treatment of bowel inflammation should be emphasized as opposed to steroid or other immunosuppressive therapy.

Incidence and extent of Lewy body-related alpha-synucleinopathy in aging human olfactory bulb.

We investigated the incidence and extent of Lewy body (LB)-related alpha-synucleinopathy (LBAS) in the olfactory bulb (OB) in 320 consecutive autopsy patients from a general geriatric hospital (mean age, 81.5 +/- 8.5 years). Paraffin sections were immunostained with anti-phosphorylated alpha-synuclein, tyrosine hydroxylase, phosphorylated tau, and amyloid beta antibodies. LBAS was found in 102 patients (31.9%) in the central nervous system, including the spinal cord; the OB was involved in 85 (26.6%). Among these 85 patients, 2 had LBAS only in the anterior olfactory nucleus, 14 in the peripheral OB only, and 69 in both areas. In 5 patients, Lewy bodies were found only in the OB by hematoxylin and eosin stain; 3 of these patients had Alzheimer disease, and all had LBAS. Very few tyrosine hydroxylase-immunoreactive periglomerular cells exhibited LBAS. All 35 LBAS patients with pigmentation loss in the substantia nigra had LBAS in the OB. LBAS in the amygdala was more strongly correlated with LBAS in the anterior olfactory nucleus than with that in the OB periphery. LBAS did not correlate with systemic tauopathy or amyloid beta amyloidosis. These results indicate a high incidence of LBAS in the aging human OB; they also suggest that LBAS extends from the periphery to the anterior olfactory nucleus and results in clinical manifestations of LB disease.

[Nationwide questionnaire study in "the Model Core Curriculum" and current status for the undergraduate education in neurology].

To investigate the current state of education for undergraduates, the subcommittee of the Japanese Society of Neurology for undergraduate education sent a questionnaire on the 2001-version of Model Core Curriculum to the department of neurology in 80 medical universities and their 7 associate medical institutes throughout Japan. Answers were obtained from 56 out of those 87 institutes (64.4%). According to the answers, the Core Curriculum was introduced to the program of undergraduate education in 93% of those 56 universities. For the revision of neurology part in the current Core Curriculum, there are number of requests for improving the description on the neurological examination, list of common symptoms and disorders, and addition of therapeutics. Despite application of the Model Core Curriculum in medical education, the present study disclosed that there were considerable difference in the number and content of the lectures, and the duration of clinical clerkship in neurology ward. These differences of the curriculum and training program depends on not only the number of staffs, but also whether they are working as staffs in a department of neurology or as a small group of neurologists within a department other than neurology.

Presynaptic and postsynaptic nigrostriatal dopaminergic functions in multiple system atrophy.

A simultaneous evaluation of presynaptic and postsynaptic dopaminergic positron emission tomography markers, the dopamine transporters and the dopamine D2-like receptors, was performed in eight patients with parkinsonian phenotype of multiple system atrophy. Both presynaptic and postsynaptic markers were revealed to have declined in such a manner that they kept strong positive correlation throughout the striatum of all patients, suggesting that the degeneration process in the striatum may involve the entire structure of the dopaminergic synapse. In two L-3,4,dihydroxyphenyl-alanine-responsive cases, the balance of decline in two markers was relatively shifted to presynaptic dominant side. Correlative positron emission tomography study of presynaptic and postsynaptic dopaminergic function may be useful for the diagnosis of multiple system atrophy and to understand the mechanisms of its temporal L-3,4,dihydroxyphenyl-alanine responsiveness.

Pramipexole-induced antecollis in Parkinson's disease.

We report a case of antecollis, or dropped head with Parkinson's disease (PD) induced by pramipexole, a nonergot dopamine agonist. An 80-year-old woman presented with progressively severe neck flexion, which developed within a few weeks of taking pramipexole at 3 mg/day. She had a disturbed gait and complained of difficulty in daily activity because of restricted visual field and severe stooped posture. Surface EMG showed disproportionate tonus of the neck muscles but needle EMG of the neck muscles was normal. Withdrawal of pramipexole resulted in immediate improvement; the patient could keep the head in natural position and walk normally. Pramipexole-induced antecollis may be serious, but is a reversible dystonia in patients with PD. Clinicians should be aware of such complication.

Characteristics of orthostatic hypotension in Parkinson's disease.

Clinical symptoms of Parkinson's disease (PD) include not only motor distress but also autonomic dysfunction. Orthostatic hypotension (OH) occurs in one-fifth to one-half of all patients with PD. We examined the relation of this type of hypotension to clinical features and cardiovascular parameters such as cardiac 123I-meta-iodobenzylguanidine (MIBG) uptake, changes on the Valsalva maneuver, and plasma norepinephrine concentrations on head-up tilt-table testing (HUT). We performed HUT in 55 patients with PD and divided them into two groups according to the presence or absence of OH, defined as a drop in systolic blood pressure (SBP mmHg) by 20 mmHg or more on standing. We evaluated cardiac sympathetic function by 123I-MIBG scintigraphy and assessed cardiovascular autonomic function by using the Valsalva maneuver in all subjects. We also performed HUT, 123I-MIBG scintigraphy and assessed cardiovascular autonomic function by using the Valsalva maneuver in 20 controls. The results of HUT showed that 20 patients had OH and 35 did not. The hypotension was associated with gender, older age, longer disease duration, posture and gait instability phenotype, low mini-mental state examination scores and visual hallucinations. Cardiac 123I-MIBG uptakes were lower in patients with OH. SBP fell further during early second phase in patients with OH than in patients without the condition and their increase in SBP during the late second phase and the overshoot of SBP during the fourth phase were lower. The blood pressure recovery time during the fourth phase on the Valsalva maneuver was longer in patients with OH than in those without OH. There was, however, no association between the fall in SBP on HUT and baroreflex sensitivity or the plasma norepinephrine concentrations, adjusted by age, disease duration, disease severity and dopaminergic medication using multiple regression analyses. Patients without OH already had impaired cardiac sympathetic and baroreceptor reflex functions as early abnormalities of cardiovascular autonomic control. Our results suggest that pronounced vasomotor and cardiac sympathetic dysfunction is the primary cause of OH in PD, although baroreceptor reflex failure may also make a minor contribution. It was unclear whether vasomotor and cardiac sympathetic dysfunction in patients with PD was caused primarily by the impairment of preganglionic or postganglionic lesions.

Impaired cardiovascular autonomic function in Parkinson's disease with visual hallucinations.

We assessed the relations of visual hallucinations (VH) to cardiovascular autonomic dysfunction in patients with Parkinson's disease (PD). The subjects were 37 patients without VH (VH(-)) and 31 with VH (VH(+)). Autonomic function was evaluated on the basis of cardiac 123-radioiodinated metaiodobenzylguanidine (123I-MIBG) uptake and hemodynamic testing with Valsalva maneuver. Systolic blood pressure (SBP) and plasma norepinephrine concentrations (NE) were measured by tilt-table testing. 123I-MIBG uptake was lower in VH(+) than VH(-). Hemodynamic studies showed that VH(-) had only cardiac sympathetic and parasympathetic dysfunction, while VH(+) additionally had reduced vasomotor sympathetic functions. The fall in SBP during tilt-table testing was greater in VH(+) than VH(-). NE and its difference in the supine and upright positions were decreased in VH(+). We conclude that cardiac and vasomotor sympathetic dysfunction is more severe in VH(+) than in VH(-). Severe dysfunction in PD with VH is probably attributed to Lewy-body lesions or neuronal loss in sympathetic ganglia, the central autonomic system, or both.

Facilitation of spontaneous glycine release by anoxia potentiates NMDA receptor current in the hypoglossal motor neurons of the rat.

Deficiency in energy supply, such as occurs during hypoxia, anoxia, metabolic stress and mitochondrial failure, strongly affects the excitability of central neurons. Such lowered energy supply evokes various changes in spontaneous synaptic input to the hippocampal and cortical neurons. However, how this energy deprivation affects synaptic input to motor neurons, which are also vulnerable to energy deprivation, has never been addressed. Here we report for the first time the effect of metabolic stress on synaptic input to motor neurons by recording postsynaptic currents in the hypoglossal nucleus. Chemical anoxia with NaCN (1 mm) and anoxia with 95% N(2) induced a persistent inward current and a marked and robust increase in action potential-independent synaptic input. This increase was abolished by strychnine, but not by picrotoxin, CNQX or MK-801, indicating glycine release facilitation. Blockade of voltage-dependent Ca(2+) channels and extracellular Ca(2+) deprivation strongly attenuated this facilitation. The amplitude of inward currents evoked by local application of NMDA to the motor neurons in the presence of strychnine was significantly increased during NaCN application. A saturating concentration of d-serine occluded this potentiation, suggesting that released glycine activated the glycine-binding sites of NMDA receptors. By contrast, neurons in the dorsal motor nucleus of the vagus showed no detectable change in synaptic input in response to NaCN. These data suggest that increase in synaptically released glycine in response to metabolic stress may play an exacerbating role in NMDA receptor-mediated excitotoxicity in motor neurons.