Kazuaki Kanai

Autologous peripheral blood stem cell transplantation for POEMS syndrome

Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes syndrome is a rare multisystem disorder. Overproduction of vascular endothelial growth factor (VEGF) by plasmocytoma could be responsible for the symptoms. The authors treated four patients with high-dose chemotherapy and autologous peripheral blood stem cell transplantation. Within 6 months, symptoms associated with rapid normalization of serum VEGF levels improved.

Aldose reductase inhibition alters nodal Na+ currents and nerve conduction in human diabetics

Background: In diabetic nerves, activation of the polyol pathway via an aldose reductase and the resulting impairment of the Na+–K+ pump would lead to a decreased transaxonal Na+ gradient and thereby reduced nodal Na+ currents. Objective: To investigate whether the aldose reductase inhibitor (ARI) epalrestat improves nodal Na+ currents and nerve conduction in human diabetic neuropathy. Methods: The authors conducted a 6-month, open clinical trial with an ARI, epalrestat, in 30 patients with mild-to-moderate diabetic neuropathy. The latent addition technique and measurements of the strength-duration time constant were used to estimate nodal persistent Na+ currents in median motor axons. Excitability testing and extensive nerve conduction studies including F-wave analyses were performed before and 1 and 6 months after the initiation of treatment with oral epalrestat. Results: Within a month of the start of treatment, there was a significant improvement in nerve conduction, particularly in conduction times across the carpal tunnel and F-wave latencies. The results of latent addition (p < 0.05) and strength-duration time constant (p = 0.06) suggested increased nodal persistent Na+ currents. At 6 months, nerve conduction continued to improve. Conclusions: Aldose reductase pathway inhibition could rapidly increase nodal Na+ currents and thereby improve the slowing of nerve conduction, presumably because of a restoration of the membranous Na+ gradient.

Voltage-gated potassium channel antibody-associated encephalitis with basal ganglia lesions

Antibodies reactive with neuronal voltage-gated potassium channels (VGKCs) have been reported in patients with limbic encephalitis, which affects the medial temporal lobes and is characterized by subacute onset of temporal lobe seizures, memory impairment, and personality changes.1–5 MRI of those patients showed only abnormal signal intensity located in the medial temporal lobes.1–5 We describe a patient with encephalitis associated with anti-VGKC antibody who had MRI abnormalities localized in the basal ganglia as well as in the medial temporal lobes that improved dramatically on corticosteroid treatment.nnA previously healthy, 23-year-old woman presented with a generalized seizure and was admitted to a nearby hospital, 2 months after onset of repeated short-term fevers with cervical lymphadenopathy. She showed disorientation and memory loss. Brain CT was negative. A CSF examination showed pleocytosis (12 lymphocytes/mm3) and a normal protein level. Viral encephalitis was diagnosed, and she was prescribed IV acyclovir. She continued to show severe memory loss and childishness. Brain MRI done 17 days after admission showed symmetric abnormal signal intensities localized in the bilateral …

A rapid functional decline type of amyotrophic lateral sclerosis is linked to low expression of TTN

Objective To classify the patterns of functional decline in patients with sporadic amyotrophic lateral sclerosis (ALS) and explore the genetic backgrounds that modified these patterns. Methods We included 465 patients with sporadic ALS in the analysis and clustered the longitudinal functional scores in the registered patients, using a mixture approach of a non-linear mixed-effects model. We conducted a genome-wide analysis of 572u2005983 single nucleotide polymorphisms (SNPs). We then assessed the association between the clusters of longitudinal functional scores and SNPs. Results We identified the following four clusters of longitudinal functional decline in the cases: a rapid decline cluster, an intermediate decline cluster, a sigmoidal decline cluster and a moderate decline cluster. We identified seven SNPs associated with the rapid decline cluster, using a recessive model (p=3.47–8.34×10−8). The OR for the probabilities of the rapid decline cluster ranged from 5.5 to 5.84. Homozygosity for the minor alleles in the seven SNPs, which constituted a linkage disequilibrium (LD) block, was associated with decreased expression of TTN (encoding Titin, a large sarcomere protein) in the expression quantitative trait loci database of a large-scale Japanese genetic variation database (p=8.6×10−10–1.1×10−7). TTN expression in immortalised lymphocyte lines was decreased in patients who were homozygous for the minor alleles compared with those who were homozygous for the major alleles (n=19 in each group, p=0.002). Conclusions We detected an LD block associated with a rapid functional decline in patients with sporadic ALS, which is linked to decreased expression of TTN.

Paraneoplastic neuromyotonia due to lung carcinoma and invisible muscle cramps evaluated using ultrasonography

lateralis, tibialis anterior, and gastrocnemius muscles, similar to a previous report [2]. It revealed persistent and involuntary contractions in the hypodermal muscles of the trapezius (left), deltoid (right and left), tibialis anterior (right), and gastrocnemius (right) (Video 1). Regarding malignancy survey, the levels of carcinoembryonic antigen, soluble cytokeratin 19 fragment, and progastrin-releasing peptide in the peripheral blood were elevated to 8.0 ng/mL (normal <5.0), 6.2 ng/mL (normal <3.5), and 159 pg/mL (normal <80.9), respectively. Chest computed tomography (CT) revealed a tumor in the right lung (Fig. 1b). We assessed the antibodies related to paraneoplastic syndrome, using a commercially available immunoblot assay, EUROLineScan (Euroimmun, Luebeck, Germany). The intensity of the antigen band of anti-titin antibodies was borderline + [0, negative; (+), borderline; +, ++, and +++, representing three degrees of positive test]. The IgG anti-voltage-gated potassium channels complex antibody level was 19 pM (normal <72.0 pM). Following surgical removal of the tumor, the pathological diagnosis was also LCNEC, at the disease stage of T2aN1M0, stage IIA. Three months post-surgery, the symptoms of muscle cramps and pain were improved. The patient was prescribed pregabalin at 100 mg/day and remained under good condition regarding his neurological symptoms. Eight months post-surgery, he received radiological therapy (gamma knife) owing to brain metastasis. Chest CT revealed no tumor relapses. He claimed that invisible muscle cramps continuously remained on the bilateral deltoid, trapezius, pectoralis major, and gastrocnemius. Pregabalin was needed continuously to ameliorate his muscle pain. Needle EMG indicated continuous neuromyotonic discharge on the first dorsal interossei on the right side. Muscle ultrasonography revealed muscle cramps in the deltoid (right and left) and trapezius (left) (Video 1), not observed in the tibialis anterior and gastrocnemius. To the Editor,

Demyelinating Peripheral Neuropathy Due to Renal Cell Carcinoma

Renal cell carcinoma (RCC) patients who develop a paraneoplastic syndrome may present with neuromuscular disorders. We herein report the case of a 50-year-old man who suffered from progressive gait disturbance and muscle weakness. The results of a nerve conduction study fulfilled the criteria of chronic inflammatory demyelinating polyneuropathy. An abdominal CT scan detected RCC, the pathological diagnosis of which was clear cell type. After tumor resection and a single course of intravenous immunoglobulin therapy, the patients symptoms drastically improved over the course of one year. The patients neurological symptoms preceded the detection of cancer. A proper diagnosis and the initiation of suitable therapies resulted in a favorable outcome.

COQ2 variants in Parkinson’s disease and multiple system atrophy

Coenzyme Q2, polyprenyltransferase (COQ2) variants have been reported to be associated with multiple system atrophy (MSA). However, the relationship between COQ2 variants and familial Parkinson’s disease (PD) remains unclear. We investigated the frequency of COQ2 variants and clinical symptoms among familial PD and MSA. We screened COQ2 using the Sanger method in 123 patients with familial PD, 52 patients with sporadic PD, and 39 patients with clinically diagnosed MSA. Clinical information was collected from medical records for the patients with COQ2 variants. Allele frequencies of detected rare non-synonymous variants were compared by public database of the Exome Aggregation Consortium (ExAC) and Japanese genetic variation database, using Fisher’s exact test. We detected two probands with rare variants in COQ2, the p.P157S from Family A, whose patient was clinically diagnosed as having juvenile PD, and the p.H15xa0N/p.G331S from Family B, whose patients shared common symptoms of PD. Furthermore, in an association study comparing these familial PD and MSA cases with a public variant database, eight non synonymous variants were detected in COQ2. Three of these were very rare variants, namely, p.P157S, p.L261Qfs*4, and p.G331S, and one variant, p.G21S, was found to show a significant association with familial PD. COQ2 variants rarely may associate with the disease onset of familial PD. Our findings contribute to an understanding of COQ2 variants in neurodegenerative disorders.

Myalgia caused by chronic myositis associated with plasmacytosis: a case report

BackgroundCutaneous and systemic plasmacytosis are skin disorders characterized by cutaneous polyclonal plasma cell infiltration accompanied by polyclonal hypergammaglobulinemia. Cutaneous plasmacytosis involvement is limited to the skin, mainly on the face and trunk, while systemic plasmacytosis also involves 2 or more organ systems. However, there have been no reports of inflammatory myositis due to plasmacytosis. Here, we report a patient with plasmacytosis who developed myalgia and easy fatigability due to inflammatory myositis.Case presentationA 54-year-old man with cutaneous plasmacytosis on the face, chest, and back complained of a history of atypical facial and lower leg pain and easy fatigability since the age of 45xa0years. Muscle-strength tests revealed bilateral trivial gastrocnemius weakness with myalgia. The results of routine blood analysis, including creatine kinase and thyroid function, were normal, but levels of several inflammation markers and autoantibodies were elevated. Additionally, lower leg magnetic resonance imaging and gastrocnemius muscle biopsy revealed inflammatory myositis mimicking polymyositis. His plasmacytosis, myalgia, and lower leg weakness were ameliorated by prednisolone.ConclusionThe patient was diagnosed with inflammatory myositis due to plasmacytosis. Given that plasmacytosis has previously been reported to disrupt the immune status, myositis in this patient might have been associated with abnormal autoimmune inflammation. Neurologists and physicians should thus be aware that plasmacytosis might be associated with inflammatory myositis accompanied by myalgia.

Parkinsonism in a patient with valosin-containing protein gene mutation showing: a case report

The valosin-containing protein (VCP) gene has been identified as being responsible for hereditary inclusion body myopathy (IBM) with Paget’s disease of the bones and frontotemporal dementia (IBMPFD) [1] as well as familial amyotrophic lateral sclerosis [2]. Pathologically, phosphorylated TDP-43 accumulates in various tissues, such as motor neurons in the anterior horn, cerebral cortex, bone, muscle, and substantia nigra [2–4]. Recently, a family with a VCP mutation showed diverse clinical manifestations, including parkinsonism; thus, the concept of multisystem proteinopathy was proposed [3]. Here we report a case of a patient with a VCP mutation who presented with limb-girdle muscle weakness/atrophy and Ldopa-unresponsive parkinsonism related to a progressive supranuclear palsy (PSP)-like symptoms. A 51-year-old woman visited our hospital because of postural abnormality and gait instability that had developed 7 years previously and had progressed gradually. Neurological examination revealed proximal weakness in her upper limbs, as indicated by aMedical ResearchCouncil scale grade of 4/5 for the deltoid and biceps brachii muscles, and in her trunk, as evidenced by a waddling gait. She had muscle atrophy of the upper-limb girdle, bilateral scapular winging (Fig. 1a), and lumbar hyperlordosis. However, facial, distal upper-limb, and lower-limb weakness were not observed. In addition, mild but significant parkinsonism (e.g., slight limitation of vertical eye movement compensated by doll’s eye phenomenon, loss of postural reflexes, cervical dystonic features, difficulty rising from a chair, mild bilateral rigidity, limited facial expression, and mild bradykinesia; Suppl Video) was observed. Generalized hyperreflexia without sensory loss, ataxia, and autonomic disturbances was not observed. No obvious dementia was noted, and her MiniMental State Examination scores were 29/30. A detailed past history suggested that she had gradually developed emotional blunting and showed a decline in personal grooming. She had a family history of muscle and neurological diseases: her father and uncle had similar symptoms of waddling gait and muscle weakness, and her uncle’s muscle biopsy revealed rimmed vacuolarmyopathy. In addition, her grandmother had been diagnosed with Parkinson’s disease. Brain magnetic resonance (MR) imaging revealed frontoparietal cortical atrophy (Fig. 2a), but the midbrain/ pons ratio (M/P ratio) [5] and MR parkinsonism index (MRPI) [6] were 0.257 and 10.55, respectively; this indicated that significant atrophies of the midbrain, pons, and superior/middle cerebellar peduncle were absent (Fig. 2b– d). Brain single-photon emission computed tomography (SPECT) showed significantly decreased blood flow in the frontotemporal cortex (Fig. 2e). Biopsy of the right biceps brachii muscle revealed IBM with rimmed vacuoles (Fig. 1b), and nuclear and cytoplasmic aggregates showed abnormal phosphorylated TDP-43 staining (data not shown). Genetic analysis revealed a p.R191Q mutation (c.572G[A) in VCP (Fig. 1c); thus, IBMPFD was diagnosed. She was started on levodopa/carbidopa therapy (300 mg/day), but her parkinsonism did not improve. Electronic supplementary material The online version of this article (doi:10.1007/s00415-017-8467-2) contains supplementary material, which is available to authorized users.

3-2-01. Decreased motor axonal potassium currents in peripheral nerve hyperexcitability syndrome with negativity for anti-VGKC antibody and positivity for anti-CRMP5 antibody

Peripheral nerve hyperexcitability (PNH) syndromes are caused by spontaneous discharges originating from motor axons. Antibodies against voltage-gated potassium channels (VGKC) are detected in some patients with PNH syndrome, but the cause in the remaining patients has not yet been clarified. The index patient was a 46-year-old female with recurred thymoma and myasthenia gravis. Six month after the start of chemotherapy, she developed myokymia, fasciculations and muscle cramps in both her lower limbs. A nerve conduction studies revealed mild axonal polyneuropathy and a motor F-wave examination showed marked after-discharges. Needle electromyography showed fasciculation potentials and myokymic discharges. From these results, the patient was diagnosed with PNH syndrome. Nerve excitability study showed extremely greater supernormality in the recovery cycle and greater changes in depolarizing threshold electrotonus than control, suggesting decreased slow potassium currents in the motor axons. Serological tests revealed the absence of anti-VGKC antibody and the presence of anti-collapsin response mediator protein 5 (CRMP5) antibody. A recent study reported that CRMP5 plays an important role in axon–Schwann cell cooperation during development and nerve regeneration. The coexistence of nerve regeneration and anti-CRMP5 antibody may cause abnormal axon–Schwann cell interaction, which would result in slow potassium channel dysfunction and associated symptoms such as myokymia.