Keiichi Hokkoku

Decremental responses to repetitive nerve stimulation (RNS) in motor neuron disease.

OBJECTIVE To clarify the features of decremental responses following repetitive nerve stimulation in patients with motor neuron diseases (MNDs), in comparison with myasthenia gravis (MG). METHODS The subjects consisted of 48 MND, 39 generalized MG and 19 ocular MG patients. Six muscles, both proximal and distal muscles, were tested. RESULTS Significant decrements (>5%) in at least one muscle were observed in 83% of the MND patients, and 74% and 47% of the generalized MG and ocular MG patients, respectively. Decrements were more frequently observed in the proximal muscles both in MND and MG patients (deltoid 76% and 62%, and trapezius 71% and 51% for MND and generalized MG, respectively), suggesting lower safety factors in neuromuscular transmission in those muscles. Decrements in the nasalis were rare in MND (8%) in comparison with generalized MG (54%). CONCLUSIONS Decremental responses were frequently observed in MND patients. There were small differences between MND and MG regarding the distribution and other features of decrements, such as the degree of the U-shape or the responses to different stimulus frequencies and to brief exercise. SIGNIFICANCE These results imply that the underlying mechanism regulating the decrements is common to MND and MG.

Electromyographs of the flexor digitorum profundus muscle are useful for the diagnosis of inclusion body myositis

Introduction: The frequent observation of high‐amplitude and long‐duration motor unit potentials (MUPs) in inclusion body myositis (IBM) is problematic, because it may lead to a misdiagnosis of amyotrophic lateral sclerosis (ALS). Objective: To document the diagnostic utility of EMG from the flexor digitorum profundus (FDP) muscle for IBM. Methods: Quantitative analyses of MUP parameters were performed in the FDP and biceps brachii (BB) muscles from 7 biopsy‐confirmed IBM patients. Results: In the FDP muscle, all MUP parameters were significantly decreased in IBM patients, which indicated the predominance of low‐amplitude and short‐duration MUPs in this muscle. In the BB muscle, most parameters were increased, suggesting the frequent contamination of high‐amplitude and long‐duration MUPs. Conclusions: Low‐amplitude MUPs in the FDP muscle indicate the presence of an advanced myopathy in this muscle that was extremely weak for all subjects. Examining the FDP muscle would reduce the chance of misdiagnosing IBM as ALS. Muscle Nerve 46: 181–186, 2012

Spread to the dorsal ulnar cutaneous branch: A pitfall during the routine antidromic sensory nerve conduction study of the ulnar nerve

OBJECTIVE To document the incidence and effects of a previously unreported pitfall during routine antidromic sensory nerve conduction study (SCS) of the ulnar nerve: the spread of the wrist stimulation to the dorsal ulnar cutaneous (DUC) branch. METHODS The subjects consisted of 20 healthy volunteers. An antidromic sensory nerve action potential (SNAP) was recorded over the proximal interphalangeal joint of the little finger, and the DUC response was monitored over the dorsum of hand to check for the occurrence of this spread. RESULTS The spread occurred in all subjects, which caused a 4-87% increase in the SNAP amplitude. The likelihood that this spread may occur during routine SCS varied among the subjects, and also within an individual subject depending on minute shifts of the stimulating site. Selective stimulation of the ulnar main trunk up to maximal intensity without spread to the DUC was not achieved despite every effort in two subjects. CONCLUSIONS This spread phenomenon may occur frequently during routine antidromic SCS, but would not be recognized without monitoring the DUC response. SIGNIFICANCE This pitfall may interfere with the reproducibility of the SNAP amplitude, and also with the diagnosis of ulnar neuropathy at the wrist.

Adult-onset vanishing white matter disease with novel missense mutations in a subunit of translational regulator, EIF2B4

To the Editor: Vanishing white matter disease (VWM) is one of the most prevalent inherited leucoencephalopathies with autosomal recessive inheritance. The clinical features of VWM are episodes of rapid neurological deterioration provoked by stresses, such as fever and minor head trauma, during a chronic progressive course (1). Magnetic resonance imaging (MRI) findings that exhibit leukoencephalopathy, with lesions having cerebrospinal fluid (CSF)-like signals, are very characteristic. The phenotypic variation is broad – most cases of VWM develop in early childhood though adult-onset cases have also been reported occasionally. Severe forms start in the prenatal or early infantile period and lead to early death (2). In contrast, much milder variants start in adolescence or adulthood and are characterized by slow disease progression. VWM is caused by mutations in the genes EIF2B1-5 encoding the subunits of eukaryotic translation initiation factor 2B (eIF2B). Among them, mutations in EIF2B5 are the most common, accounting for 60–70% of all cases of VWM (3). On the other hand, mutations in EIF2B4 are 4–14% (4, 5). Here, we describe a patient with adult-onset VWM who carries novel missense mutations in EIF2B4. A 59-year-old Japanese woman presented to our hospital. She noticed gait unsteadiness and forgetfulness at the age of 56, which exacerbated slowly. She had experienced no episodes of rapid neurological symptoms evoked by stresses. Her birth and development during childhood were normal, and she had no ovarian failure. The family history was unremarkable. Her parents did not have a consanguineous marriage. Neurological examinations showed spastic paraparesis, increased bilateral patellar tendon reflexes, and bilateral extensor Babinski signs. Mini-Mental State Examination score was 16. Wechsler Adult Intelligence Scale-third edition (WAIS-III) revealed a low intelligence quotient (verbal IQ of 66, performance IQ of 59, full-scale IQ of 60). Brain MRI showed symmetric diffuse high-intensity lesions in the deep white matter on T2-weighted images. The lesions in the deep frontal white matter had CSF-like signals on fluid-attenuated inversion recovery (FLAIR) images (Fig. 1a,b). The results of routine laboratory tests were normal. CSF examination showed elevation of protein at 54 mg/dl (normal <40) and increased glycine concentrations at 11.6 μmol/l (normal 7.7± 3.5); the latter is considered a biochemical marker for VWM (6). The clinical course and MRI findings characteristic of VWM prompted us to perform genetic analyses. Sanger sequencing of all exons of the VWM causative genes, EIF2B1-5, revealed novel heterozygous missense mutations, c.617T>C (p.Met206Thr) and c.952A>G (p.Ile318Val) in EIF2B4. Furthermore, direct nucleotide sequence analysis of the plasmids, in which genomic segments containing c.617T>C and c.952A>G in EIF2B4 were cloned, revealed that the mutations, c.617T>C (p.Met206Thr) and c.952A>G (p.Ile318Val), were located on different alleles (Fig. 1c). As shown in Fig. 1d, the amino acid Ile318 of EIF2B4 is highly conserved among species, and p.Ile318Val mutation is predicted to be probably damaging and disease causing by Polyphen-2, SIFT, and Mutation Taster. On the other hand, the amino acid Met206 is highly conserved among mammals. By SIFT and Mutation Taster, p.Met206Thr is predicted to be damaging and disease causing (Fig. 1d). These mutations were not present in 276 unrelated Japanese control subjects, and not registered in the Human Genetic Variation Database (HGVD), a database of the exome sequencing of 1208 Japanese individuals. This is the second reported case of adult-onset VWM with mutations in EIF2B4 (4). The age of 56, when our case developed symptoms, is the oldest among patients with EIF2B4 mutation thus reported (5). So far, the influence of genotype on the phenotype in EIF2B4 mutation has not yet been clarified. Revealing the genotype–phenotype relationship is important as it enables clinicians and genetic counselors to provide appropriate information to patients and families. Our case indicates that the heterozygous c.617T>C (p.Met206Thr) and c.952A>G (p.Ile318Val) mutations in EIF2B4 might be related to the late-onset milder form of VWM.

Origin of far-field potentials in the ulnar compound muscle action potential

The compound muscle action potential (CMAP) following ulnar nerve stimulation receives a considerable contribution from far‐field potentials (FFPs), although their origin is not entirely clear. We investigated this issue using voluntary contractions.

Molecular epidemiological study of familial amyotrophic lateral sclerosis in Japanese population by whole-exome sequencing and identification of novel HNRNPA1 mutation

To elucidate the genetic epidemiology of familial amyotrophic lateral sclerosis (FALS) in the Japanese population, we conducted whole-exome sequencing analysis of 30 FALS families in whom causative mutations have not been identified in previous studies. Consequently, whole-exome sequencing analysis revealed novel mutations in HNRNPA1, TBK1, and VCP. Taken together with our previous results of mutational analyses by direct nucleotide sequencing analysis, a microarray-based resequencing method, or repeat-primed PCR analysis, causative mutations were identified in 41 of the 68 families (60.3%) with SOD1 being the most frequent cause of FALS (39.7%). Of the mutations identified in this study, a novel c.862/1018C>G (p.P288A/340A) mutation in HNRNPA1 located in the nuclear localization signal domain of hnRNPA1, enhances the recruitment of mutant hnRNPA1 into stress granules, indicating that an altered nuclear localization signal activity plays an essential role in amyotrophic lateral sclerosis pathogenesis.

Isolated shoulder palsy diagnosed from needle EMG and an associated movement.

Cerebral infarction at the precentral gyrus may cause localized paresis of the upper limb such as isolated hand or finger paresis [1]. Clinical diagnosis of such cases may be difficult because they mimic paresis of peripheral origin, as documented by the term of ‘‘pseudoperipheral’’ palsy [1]. Rare isolated shoulder palsy due to stroke has also been reported [2]. Such cases may well be misdiagnosed as shoulder or cervical problems, especially the proximal type of cervical spondylotic amyotrophy (CSA), which often develops weakness acutely [3]. This point has not been stressed in previous reports of isolated shoulder palsy, although shoulder images performed prior to brain magnetic resonance imaging (MRI) in some cases may suggest such an initial confusion [4]. Herein, we describe a patient who was initially diagnosed with proximal type of CSA, but the coordination synkinesis and the recruitment pattern in needle electromyography (EMG) led to the correct diagnosis. A 65-year-old man came to our clinic complaining of sudden onset difficulty in elevating the left upper limb. He was also aware of pain around the shoulder. He had been treated for hypertension, hyperlipidemia, and diabetes mellitus. Neurological examinations on the day of onset revealed weakness of 4/5 (Medical Research Council scale) in the left lateral deltoid, anterior deltoid, and infraspinatus muscles. Other muscles in the left upper limb as well as in the lower limb had normal power. The sensory examinations were completely normal. Limb and truncal ataxia was not observed. Deep tendon reflexes were normal. Proximal type of CSA was suspected based on the C5 distribution of muscle weakness and needle EMG was planned. Needle EMG in the left anterior deltoid muscle on the third day revealed no spontaneous activities and a normal recruitment pattern of motor unit potentials of normal shape, although their firing frequency did not increase to maximum when this weak muscle maximally contracted. These findings indicated a poor activation of central origin. Furthermore, when the manual muscle testing of the serratus anterior muscle was conducted with the elbow flexed, a spontaneous extension of the elbow joint was observed only on the affected side, which was considered to be coordination synkinesis (Fig. 1a, b). Central weakness was suspected from these findings, and brain MRI was performed, which revealed a small fresh infarction at the right precentral gyrus (Fig. 1c, d). He was immediately admitted and urgent carotid artery stenting was performed because his symptoms showed fluctuation and marked stenosis of the right internal carotid & Takamichi Kanbayashi ta_kanba@yahoo.co.jp

Primary central nervous system methotrexate associated lymphoproliferative disorders in a patient with rheumatoid arthritis

We report on a 52-year-old woman with rheumatoid arthritis (RA) who developed methotrexate associated lymphoproliferative disorders (MTX-LPD) in the central nervous system (CNS) in the course of immunosuppressive therapy for RA. The patient was admitted because of monoplegia in her left hand. She had been receiving methotrexate (MTX) for her RA for several years and etanercept had also been introduced because of a worsening of the arthritis six months before admission. Brain MRI revealed multiple lesions with enhancement scattered throughout both hemispheres. 18F-fluorodeoxyglucose-positron emission tomography/computed tomography showed abnormal accumulation suggesting malignancy in the right frontal lobe where abnormal enhancement was observed on the MRI. A brain biopsy was performed at the identified site and it confirmed diffuse large B-cell lymphoma (DLBCL). We therefore diagnosed her as MTX-LPD. According to previous reports, most MTX-LPD cases tend to show regression after the cessation of MTX. However, our case showed no regression and even needed chemotherapy. The patient had a poorer prognosis than previous cases and died 17 months after the onset. Although it is an uncommon complication, particularly in the CNS, MTX-LPD should be considered as a critical differential diagnosis if a patient receiving MTX develops central nervous system lesions. Immediate medical intervention including brain biopsy is required.

Reversible cerebral vasoconstriction syndrome accompanied by hypomagnesemia

Dear Editor-in-Chief: Reversible cerebral vasoconstriction syndrome (RCVS) is a clinical and radiological syndrome characterized by hyperacute, severe headaches with or without other neurological symptoms and reversible cerebral artery vasoconstriction [1, 2]. Posterior reversible encephalopathy syndrome (PRES) is also a clinical and radiographic syndrome characterized by vasogenic cerebral edema that most often affects the occipital and posterior parietal lobes and is accompanied by a headache, visual symptoms, seizures, and other neurological symptoms. RCVS and PRES have several clinical features in common and are frequently encountered concurrently [1]. Recently, it has been suggested that these two entities are part of the same disease spectrum based on the common pathology of vasoconstriction and endothelial dysfunction in the cerebral arteries [1]. Several studies have revealed that magnesium works as a vasodilator in the cerebral arteries and hypomagnesemia contributes to the development of PRES by the loss of this mechanism [2–4]. Since vasoconstriction and endothelial dysfunction are pathological features of both PRES and RCVS, it has been postulated that hypomagnesemia is a possible cause of RCVS [1]. However, to the best of our knowledge, there have been no reports describing a patient with RCVS due to hypomagnesemia. Here, we report a case of RCVS accompanied by hypomagnesemia induced by cisplatin therapy. Informed consent was obtained from the patient for publication of this case report and the accompanying images. A 57-year-old woman with a history of cervical cancer was admitted to our hospital for general convulsions. She had been receiving chemotherapy with cisplatin for the past month. She complained of severe, intermittent headaches, suggestive of thunderclap headaches, occurring over several days prior to admission. On admission, she was in status epilepticus. Her blood pressure and heart rate were 108/82 mmHg and 118 beats/min, respectively. She was immediately treated with anticonvulsant therapy, intubation, and mechanical ventilation. Brain computed tomography images revealed no abnormalities. Diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) of the brain revealed a high-intensity area in the left occipital lobe (Fig. 1a). The intensity of the lesion was higher on the DWI than on the FLAIR images, suggesting that the lesion was ischemic rather than due to vasogenic edema. Magnetic resonance angiography (MRA) showed multifocal segmental narrowing and dilatation of the cerebral arteries, suggesting vasoconstriction (Fig. 1b). Hematological investigation showed mild anemia and neutropenia. Blood urea nitrogen and serum creatinine increased to 23.1 mg/dL (normal, 8.0 to 20.0 mg/dL) and 1.61 mg/dL (normal, 0.46 to 0.79 mg/ dL), respectively, suggesting renal dysfunction due to cisplatin. Measurement of serum electrolytes revealed moderate hypomagnesemia (1.2 mEq/L; normal, 1.8 to 2.4 mEq/L) and mild hypocalcemia (8.4 mg/dl, normal, 8.6 to 10.2 mg/dl). The serum total cholesterol level was normal (156 mg/dl; normal, 142 to 220 mg/dl). She was diagnosed with RCVS with cerebral infarction in the left occipital lobe. We considered hypomagnesemia to be the cause of her RCVS because we could find no other possible pathogenesis for RCVS, such as vasoactive drugs, electrolyte abnormalities like hypercalcemia, or metabolic abnormalities like hypercholesterolemia [1]. Furthermore, we believe that the tubular injury due to cisplatin and the following urinary loss of magnesium gave rise to her hypomagnesemia. Replacement of her magnesium with intravenous (IV) magnesium sulfate was initiated. We also anticipated that the magnesium sulfate would help relieve the vasoconstriction because it is effective for RCVS caused by eclampsia [1]. In addition to magnesium sulfate, verapamil was administered * Keiichi Hokkoku k1-hokkoku@hotmail.co.jp

Emery-Dreifuss Muscular Dystrophy-Related Myopathy with TMEM43 Mutations: TMEM43 EDMD-Related Myopathy

TMEM43 is a protein found within the inner nuclear membrane that is associated with the linker of the nucleoskeleton and cytoskeleton (LINC) complex. Mutations in the TMEM43 gene reportedly result in the autosomal dominant condition known as Emery-Dreifuss muscular dystrophy (EDMD) -related myopathy, but clinical data are limited. We identified a filioparental case of EDMD-related myopathy in which the father and son were carriers of TMEM43 mutations.