Takamichi Kanbayashi

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.

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

Isolated Shoulder Palsy due to Intracerebral Hemorrhage

A small cortical infarction confined to the medial location of the precentral knob on the precentral gyrus may cause isolated shoulder palsy. However, there are no reports indicating intracerebral hemorrhage as a cause of isolated shoulder palsy. We herein report the case of a 48-year-old man who presented with isolated shoulder palsy as an initial symptom of subcortical hemorrhage at the precentral gyrus. Such cases may be easily misdiagnosed as shoulder or cervical spine problems. The distribution of muscle weakness is the key to an accurate diagnosis.

Fasciculation potentials and decremental responses in amyotrophic lateral sclerosis

OBJECTIVE The positive correlation between fasciculation potentials (FPs) and decremental responses in repetitive nerve stimulation test (RNS) in amyotrophic lateral sclerosis (ALS) patients has been described based on only one past study. We revisited this issue. METHODS Subjects consisted of 30 prospectively-enrolled ALS patients on whom both needle EMG and RNS were conducted in the same trapezius muscle. Fasciculation potentials (FPs) were identified off-line from the restored 3-min signal. Firing rate of FPs (FR-FP) per minute was calculated from the total count of FPs of different origins. Correlations between FR-FP, decremental percentage (Decr%) and the amplitude of the initial compound muscle action potential (CMAPamp) in RNS were investigated. RESULTS There was no correlation between FR-FP and Decr% (r = 0.03) or between FR-FP and CMAPamp (r = 0.04). A significant negative correlation was observed between CMAPamp and Decr% (r = -0.56, P < .005). CONCLUSION FPs are not correlated with the decremental response in RNS. SIGNIFICANCE The underlying mechanism for FPs and decremental responses in ALS must be different and unrelated to each other.

F97. Interaction of cathodal and anodal stimulations in nerve conduction studies

Introduction In nerve conduction studies (NCS), it has long been believed that the phenomenon of anodal block occurs under the anode during bipolar stimulation. However, recent studies demonstrated that anodal block hardly occurs, whereas anodal stimulation actually occurs instead, i.e. the action potential is generated from the anode itself. During our previous investigation on anodal stimulation, we unexpectedly discovered a phenomenon that the anodal stimulation was easy to occur when the cathode was placed away from the nerve trunk. Furthermore, careful observation in ordinary NCS reveals that the cathodal stimulation becomes difficult to elicit when the anode is moved away from the nerve during the effort to make the baseline flat. These findings suggest that the cathodal stimulation and anodal stimulation may interact with each other. In this study, we aimed to investigate the interaction of cathodal and anodal stimulations. Methods Subjects were 7 healthy volunteers. The ulnar nerve was stimulated at the wrist using two bipolar surface electrodes. Both stimulating electrodes were placed perpendicular to the nerve course. The cathode of one electrode was placed distally, whereas the anode of the other electrode was placed proximally separated by the inter-electrode distance of 23 mm. In this way, we reproduced the setting of ordinary NCS. Furthermore, we were able to change the stimulus intensity at cathode and anode independently. The ascending volley from the anode was evaluated by the antidromic mixed nerve action potential (MNAP) at the elbow, and the descending volley from the cathode was evaluated by the compound muscle action potential (CMAP) from the abductor digiti minimi muscle. In this study, we performed two experiments. In Experiment 1, we variously changed the stimulus intensity at the cathode, and investigated how the current required for the anodal stimulation changes. In Experiment 2, we variously changed the stimulus intensity at the anode, and investigated how the current required for the cathodal stimulation changes. Results In Experiment 1, when the stimulus intensity at the distal cathode was set at 0, 5, 10, 15, and 20 mA, the threshold of MNAP by anodal stimulation was 8.8 ± 2.0, 10.2 ± 1.8, 11.5 ± 2.3, 12.6 ± 2.8, and 13.6 ± 3.0 mA, respectively. In Experiment 2, when the stimulus intensity at the proximal anode was set at 0, 2, 4, 6, and 8 mA, the threshold of CMAP by cathodal stimulation was 2.9 ± 0.3, 2.8 ± 0.3, 2.6 ± 0.3, 2.5 ± 0.3, and 2.3 ± 0.3 mA, respectively. Conclusion During bipolar stimulation, the cathodal stimulation suppresses the anodal stimulation, whereas the anodal stimulation assists the cathodal stimulation. As a mechanism of such inter-electrode interaction, we postulated that the hyperpolarized zone formed around the depolarized cathode suppresses the anodal stimulation, whereas the depolarized zone formed around the hyperpolarized anode assists the cathodal stimulation.

Investigation of anodal stimulation and its implications for F-wave examinations

Introduction: Recent studies have shown that stimulation occurs at the anode of stimulating electrodes instead of anodal block. This phenomenon may be a pitfall in F‐wave examinations. Methods: Subjects included 10 healthy volunteers. Their ulnar nerve was stimulated at the wrist with the cathode placed distally. Antidromic impulses were evaluated using mixed nerve action potential (MNAP) at the elbow. Results: Anodal stimulation occurred for both sensory and motor fibers at 22 mm proximal to the anode, on average, which may theoretically shorten the F‐wave latency by about 0.8 ms. Displacement of the anode away from the nerve made anodal stimulation less likely. In contrast, displacement of the cathode away from the nerve lowered the threshold for anodal stimulation, a newly found interaction between cathode and anode. Conclusions: In this work we identified detailed features of anodal stimulation and potential influence on F‐wave examinations. Muscle Nerve 56: 51–56, 2017.

Amyotrophic lateral sclerosis with a sudden-onset history

Highlights • We reported on two patients with ALS with a sudden-onset history.• Marked weakness of the extensor digitorum with relatively mild weakness of the other muscles was characteristic.• The risk of initial misdiagnosis is high for such patients.

Cerebral air embolism likely due to pulmonary Mycobacterium avium complex disease.

The entry of air into vascular structures can cause cerebral air embolism (CAE) that results in severe neurological deficits or even death [1–5]. Well-known causes of CAE include iatrogenic complications of several procedures, including central venous catheterization, pulmonary barotrauma, and decompression sickness [1–3]. In contrast, to the best of our knowledge, only three reports have investigated CAE associated with infectious lung disease. According to these reports, staphylococcal pneumoniae with pneumatoceles [4], continuous drainage of infected lung bullae [5], and pneumothorax following pneumonia [1] resulted in CAE. The authors insisted that damaged pulmonary vessels and emphysematous lesions following infectious lung disease allowed air to enter the cerebral arterial circulation [1,4,5]. Here we report a case of CAE where a damaged lung with pulmonary Mycobacterium avium complex (MAC) disease in a patient presenting with a chronic severe cough was regarded as the cause of CAE. An 83-year-old man with a history of pulmonary MAC disease was admitted to our hospital for dehydration. He had been diagnosed with pulmonary MAC disease approximately 3 years ago, and presented with a chronic severe cough. However, he had never received medication. He received fluid therapy for the dehydration, recovered, and was about to be discharged. However, he suddenly became unconscious and developed general convulsions. Neurological examination revealed conjugate gaze deviation to the left, right hemiparesis, and bilateral positive Babinskis sign. Brain computed tomography (CT) scans obtained 30 min after onset revealed small air density areas in the left frontal lobe, and the patient was diagnosed with cerebral air embolism (Fig. 1A). Curiously, no catheter, even a peripheral venous catheter, urethral catheter, or nasogastric catheter, was placed on the patient prior to onset. Moreover, no procedures that could result in air embolism such as neurosurgical, cardiac, or thoracic procedures [3] had been performed. This suggested that the air must have originated from the patients own body. Transthoracic echocardiography was performed, but no abnormalities were found, including air bubbles. Because of the intermittent convulsive seizures, hyperbaric oxygen therapy was not feasible. Intravenous fluids, 100% oxygen, and anticonvulsant therapy were given

Restless legs syndrome heralding an acute exacerbation of multiple sclerosis

Restless legs syndrome (RLS) is a neurological movement disorder characterized by a distressing urge to move the legs, usually accompanied by unpleasant sensations, paresthesia, and motor restlessness. These symptoms increase or appear during rest periods, mostly at night, with partial or total relief by movement. Several medical and neurological conditions have been reported to be related to RLS, such as iron deficiency, renal failure, pregnancy, diabetes, rheumatoid arthritis, neuropathies, myelopathies, and Parkinson’s disease. Increased incidence of RLS in patients with multiple sclerosis (MS) has also been reported [1], although there have been no reports of RLS development as an initial symptom of an acute attack of MS. Here, we describe a patient who presented with RLS as a prodromal symptom preceding an acute exacerbation of MS. A 40-year-old woman suffered from right optic neuritis, which was successfully treated with an oral corticosteroid. Brain, cervical spine and thoracic spine MRI at that time revealed no apparent lesions. Three months later, she presented at our clinic complaining of discomfort in both legs associated with an urge to move the legs, which had persisted for 1 week and was mainly felt while lying down in the night. Neurological examinations showed no abnormalities. Her symptoms were consistent with the diagnostic criteria of RLS [2]. Following the diagnosis of idiopathic RLS, a dopamine agonist was administered, with no effect. One week later, difficulty in walking developed and she was admitted to our hospital. Neurological examinations revealed weakness of the left lower limb, increased left patellar and Achilles tendon reflexes, and the positive left Babinski sign. She noticed paresthesia in the left distal forearm and right lower limb, and pain and temperature sensations were lost on the right side below the T11 level. Urination became difficult, although the symptoms of RLS remained the same. Routine laboratory tests showed no abnormalities, including serum iron and ferritin. Autoantibodies such as anti-nuclear antibody and anti-SSA/SSB antibodies were negative. Cerebrospinal fluid cell count, protein, and IgG index were normal, and oligoclonal band was negative, whereas myelin basic protein was elevated at 416 pg/ml (normal \109). Aquaporin-4 (AQP4) antibody, which was measured by a cell-based assay using HEK-293 cells stably transfected with the M23 isoform of AQP4, was negative. Cervical and thoracic spine MRI at the time of admission revealed T2 high-intensity lesions in the dorsal medulla, C1–2, left T1–2, and left T10 levels of the spinal cord (Fig. 1), of which those at C1–2 and T1–2 levels were enhanced by Gadolinium. Gadolinium enhancement was not performed in the thoracic spine MRI. Brain MRI showed a very small T2 high-intensity lesion compatible with a demyelinating plaque in the right periventricular while matter. Visual-evoked potentials (VEPs) at the time of admission revealed a prolonged latency of the right P100 T. Kanbayashi H. Kamiya K. Hokkoku Y. Hatanaka M. Sonoo (&) Department of Neurology, Teikyo University School of Medicine, Kaga 2-11-1, Itabashi-ku, Tokyo 1738605, Japan e-mail: sonoom@med.teikyo-u.ac.jp