Yohsuke Yagi

Spreading of amyotrophic lateral sclerosis lesions—multifocal hits and local propagation?

Objective To investigate whether or not the lesions in sporadic amyotrophic lateral sclerosis (ALS) originate from a single focal onset site and spread contiguously by prion-like cell-to-cell propagation in the rostrocaudal direction along the spinal cord, as has been hypothesised (the ‘single seed and simple propagation’ hypothesis). Methods Subjects included 36 patients with sporadic ALS and initial symptoms in the bulbar, respiratory or upper limb regions. Abnormal spontaneous activities in needle electromyography (nEMG)—that is, fibrillation potentials, positive sharp waves (Fib/PSWs) or fasciculation potentials (FPs)—were compared among the unilateral muscles innervated by different spinal segments, especially between the T10 and L5 paraspinal muscles, and between the vastus medialis and biceps femoris. Axon length and the proportion of muscle fibre types, which are both related to motoneuronal vulnerability in ALS, are similar in the paired muscles. Results Fourteen of 36 patients showed a non-contiguous distribution of nEMG abnormalities from the onset site, with skipping of intermediate segments. In eight of them, the non-contiguous pattern was evident between paired muscles with the same motoneuronal vulnerability. The non-contiguously affected lumbosacral lesions involved motoneuron columns horizontally or radially proximate to one another, appearing to form a cluster in four of the eight patients. FPs, known to precede Fib/PSWs, were shown more frequently than Fib/PSWs in all the lumbosacral segments but L5, suggesting that 2nd hits occur at L5 and then spread to other lumbosacral segments. Conclusions In sporadic ALS, the distribution of lower motoneuron involvement cannot be explained by the ‘single seed and simple propagation’ hypothesis alone. We propose a ‘multifocal hits and local propagation’ hypothesis instead.

Next-generation sequencing-based small RNA profiling of cerebrospinal fluid exosomes

MicroRNAs (miRNAs), particularly those found in human body fluids, have been suggested as potential biomarkers. Among various body fluids, the cerebrospinal fluid (CSF) shows promise as a profiling target for diagnosis and monitoring of neurological diseases. However, relevant genome-scale studies are limited and no studies have profiled exosomal miRNAs in CSF. Therefore, we conducted a next-generation sequencing-based genome-wide survey of small RNAs in the exosomal and non-exosomal (supernatant) fractions of healthy human CSF as well as serum in each donor. We observed miRNA enrichment in the exosomal fractions relative to the supernatant fractions of both CSF and serum. We also observed substantial differences in exosomal miRNA profiles between CSF and serum. Half of the reported brain miRNAs were found in CSF exosomal fractions. In particular, miR-1911-5p, specifically expressed in brain tissue, was detected in CSF but not in serum, as confirmed by digital PCR in three additional donors. Our data suggest that the brain is a major source of CSF exosomal miRNAs. Here we provide the important evidence that exosomal miRNAs in CSF may reflect brain pathophysiology.

Serum amyloid A level is increased in neuromyelitis optica and atypical multiple sclerosis with smaller T2 lesion volume in brain MRI

Serum amyloid A (SAA) is known to promote the development of T helper 17 cells (Th17) and can be a critical mediator of disease pathogenesis. We analyzed SAA levels in 40 patients with multiple sclerosis (MS) and related disorders, and 10 with non-inflammatory neurological disease (NIND) as controls. We found that SAA levels were significantly increased in neuromyelitis optica (NMO) patients and relapsing and remitting MS (RRMS) patients showing atypical phenotype with spinal cord lesions and smaller T2 lesion volume in brain MRI, resembling NMO. Therefore, SAA levels can be associated with clinical phenotypes in MS and NMO.

Tacrolimus Monotherapy: A Promising Option for Ocular Myasthenia Gravis

We reviewed the records of patients with ptosis-onset ocular MG at the Tokyo Medical and Dental University Hospital from January 2005 until November 2010. Patients who took other immunosuppressive agents or underwent thymectomy were excluded. The clinical features of 4 MG patients who were treated with a cholinesterase inhibitor and tacrolimus as the only immunosuppressant agent are shown in table 1 . The dose of cholinesterase inhibitor was fixed during the observation. The mean (SD) age of the patients was 74.0 (9.3) years and the male-to-female ratio was 2: 2. All of the patients were Myasthenia Gravis Foundation of America clinical classification class I and had responded well to tacrolimus. We observed these patients for 24 months after starting tacrolimus. The mean anti-acetylcholine receptor antibody titers before and after the treatment with tacrolimus were 26.35 (24.7) and 13.73 (15.6) nmol/l, respectively. The antiacetylcholine receptor antibody titer was reduced in all patients after the treatment, and the posttreatment-to-pretreatment ratio was 0.50 (0.20). Remarkable adverse effects were not observed during tacrolimus administration. All 4 patients responded well to tacrolimus without prednisolone or other immunosuppressive agents and have remained Dear Sir, Myasthenia gravis (MG) is an autoimmune disease that affects the neuromuscular junction. Anticholinesterase agents are the basic symptomatic treatment for MG, which partially compensates for the reduced safety margin at the neuromuscular junction; these agents may be sufficient in rare cases of mild MG with purely ocular involvement. Corticosteroid immunosuppressant drugs are the mainstay of diseasemodifying therapy for MG; however, the adverse effects of corticosteroids include osteoporosis, hypertension, exacerbation or precipitation of diabetes mellitus, gastrointestinal ulcers, cataracts, and opportunistic infection [1] . Therefore, an alternative to corticosteroid therapy is needed, especially in elderly patients. The calcineurin inhibitor tacrolimus is the immunosuppressant agent used for organ transplantation and a variety of immune-mediated disorders including MG. Currently, tacrolimus is recommended only as a third-line therapy for long-term use in patients who are unresponsive to azathioprine, methotrexate, or mycophenolate mofetil [2] . To our knowledge, several preceding reports have documented the efficacy of tacrolimus for MG when combined with corticosteroids [3–5] , but we are not aware of other studies that documented the efficacy of tacrolimus alone for MG. Received: October 30, 2012 Accepted: January 13, 2013 Published online: March 19, 2013

Taste impairment in Miller Fisher syndrome

Miller Fisher syndrome (MFS) was first described by Charles Miller Fisher in 1956 [1]; its cardinal clinical features are external ophthalmoplegia, ataxia, and areflexia. Taste impairment is considered to be an extremely rare clinical feature of MFS [2]. Here, we report a case of MFS with taste impairment and review the previously reported similar cases. A 53-year-old male was referred to our department because of taste impairment, diplopia, and gait disturbance. About 1 month before these symptoms emerged, he had experienced symptoms of an upper respiratory infection which spontaneously resolved. On admission, he was fully alert, his body temperature was 36.5 C and his blood pressure was 171/113 mmHg. He complained of diplopia, but neurological examination did not reveal obvious ocular movement abnormalities. He also complained of dysesthesia around his mouth and taste impairment, but did not have facial nerve palsy. He did not recognize sourness well, especially on his palate. He did not complain of lacrimal hyposecretion. He had no weakness in his extremities, but deep tendon reflexes were absent. He had ataxia in his extremities and trunk, and performed tandem gait with difficulty. Immunoglobulin (Ig) G anti-GQ1b antibodies were detected in the patient’s serum. Cerebrospinal fluid examination revealed a mild elevation of protein without pleocytosis: cell 1.3/ll, protein 50.2 mg/ dl, glucose 59 mg/dl, and oligoclonal bands were present. Brain magnetic resonance imaging operated on days 2 and 5 after disease onset revealed no abnormalities which could explain his neurological symptoms. Nerve conduction studies of his upper and lower extremities were normal. Electrogustometry revealed elevated thresholds in his right and left soft palates, but normal thresholds in the anterior two-thirds and posterior one-third of his tongue, suggesting dysfunction of the bilateral greater petrosal nerves. Four days after admission, neurological examination revealed obvious ocular movement abnormalities, impairment of abduction, adduction and supraduction of both eyes, resulting in a diagnosis of MFS. Intravenous immunoglobulin (0.4 g/kg/day) was immediately administered and his symptoms, including taste impairment, gradually improved. On day 35 after disease onset, electrogustometry revealed normal thresholds in his right and left soft palates. The frequency of taste impairment in patients with Guillain–Barré syndrome has been reported to be 0.6–2 % [3, 4]. Since only two other cases with MFS presenting with taste impairment have been reported in the literature [2, 5], taste impairment is a very rare clinical feature of MFS. Clinical features of these two patients and the present case are summarized in Table 1. Taste impairment in MFS could independently occur without facial nerve palsy and could be an initial symptom of MFS. Uchibori et al. [2] postulated that the presence of specific antibodies, including anti-GQ1b antibodies, might affect peripheral nerves associated with taste and taste buds in MFS patients with taste impairment. Since taste disturbance emerged without facial nerve palsy, a similar mechanism might be associated with the symptom in the present case. Because a continuous spectrum was suggested to exist between MFS Y. Yagi (&) H. Yokote Y. Watanabe T. Amino T. Kamata Department of Neurology, Musashino Red Cross Hospital, Kyonancho 1-26-1, Musashino, Tokyo 180-8610, Japan e-mail: yyagi-tmd@umin.ac.jp

Cervical dystonia in an Alzheimer's disease patient treated with donepezil.

The cholinesterase inhibitor donepezil is a safe, effective, and widely used drug for the long-term symptomatic treatment of Alzheimer’s disease (AD) [1]. Dystonia is a rare complication of donepezil treatment, and some authors have reported dystonia, including Pisa syndrome, in patients treated with this drug [2]. Here, we report an AD patient treated with donepezil who developed cervical dystonia. A woman in her late 70s was referred to our department because of progressive forgetfulness. She had impaired episodic memory for recent events and her mini-mental state examination score was 12. Eye movement was normal, and she did not have akinesia or rigidity in her extremities that would suggest parkinsonism. Brain magnetic resonance imaging showed mild brain atrophy, and 99mTc-ECD single-photon emission computed tomography showed diminished blood flow in both temporal and parietal lobes, but this was more severe in the left hemisphere. She was diagnosed with AD and was started on a 5-mg dose of donepezil. Within 1 month of beginning the donepezil regimen, she developed severe torticollis and complained of difficulty in walking and eating. Physical examination revealed no abnormality other than torticollis to the left side. Physical examination and imaging studies did not provide any evidence of Parkinson’s disease or dementia with Lewy bodies, and she did not take other dopaminergic or psychotropic drugs. Therefore, we suspected that her torticollis was a side effect of donepezil. Treatment with memantine did not affect her torticollis, and we decided to discontinue donepezil treatment. Several weeks later, she experienced relief of her torticollis. She was then treated with memantine alone and had a good outcome. Dystonia is considered a rare complication of treatment with donepezil, and previous case reports and the present findings provide evidence that this complication can be due to drugs that act on the cholinergic system. Kwak et al. [2] previously reported Pisa syndrome in an AD patient treated with donepezil, and Huvent-Grelle et al. [3] reviewed Pisa syndrome in AD patients treated with 3 cholinesterase inhibitors: donepezil, rivastigmine, and galantamine. Villarejo et al. [4] suggested that cholinergic excess may induce Pisa syndrome. Although dystonia is a rare complication of cholinesterase inhibitors, clinicians must be aware of this phenomenon because of the increasing number of dementia patients and the growing use of cholinesterase inhibitors to treat them. Because cholinergic excess induced by cholinesterase inhibitors seems to be a cause of dystonia, treatment with the noncompetitive N-methyl-D-aspartate receptor antagonist memantine [5] is an alternative for AD patients who experience side effects on cholinesterase inhibitors.

Sialidosis type I with neoplasms in siblings: the first clinical cases.

In a family where three of four siblings expressed mutants of NEU1, compound heterozygosity of 649G-to-A and 727G-to-A in the lysosomal neuraminidase (sialidase) gene, responsible for decreased sialidase activity [1], was linked not only to the sialidosis type I phenotype, but also to the occurrence of neoplasms of different origins. This is the first clinical observation that suggests a possible link between the decreased activity of lysosomal sialidase and the development of a variety of neoplasms. The pedigree tree of this family is shown in Fig. 1. Except for patients 1–3, no other family members had sialidosis, and except for patients 1–3, no other family members had any kind of malignancy. There are no known environmental conditions that may facilitate the neoplasm development in their birthplace. In lymphocytes, sialidase activity was significantly decreased in patient 1 (6.8% of control mean), patient 2 (12.5% of control mean) and patient 3 (17.0% of control mean). Their mother had sialidase activity 55.8% of control mean [2]. The activities of b-galactosidase and b-hexosaminidase were within the normal range in these patients. The clinical features of patients, including the neurologic symptoms are shown in Table 1. Four different mammalian sialidases have been identified: Neu1, Neu2, Neu3, and Neu4 [3]. Some mutations in the sialidase gene NEU1 lead to a decrease in the activity of sialidase; however, homozygous or, more frequently, compound heterozygous mutations are necessary for the expression of a phenotype recognized as sialidosis type I, which has autosomal recessive inheritance and is characterized by a progressive lysosomal storage of sialylated glycopeptides and oligosaccharides [4]. The current communication includes the findings obtained from an autopsied patient (patient 2) with sialidosis type I, who died due to intractable lymphoma at the age of 32 years [5]. Because the emergence of neoplasm in this sialidosis patient is the first and the only one in literature, this comorbitidy was initially considered coincidental. Subsequent development of other kinds of neoplasms in his siblings (patients 1 and 3), however, could not be attributed to only coincidence, considering the extreme rarity of sialidosis. The occurrence of neoplasms in these cases raised the possibility that either biallelic mutations in the relevant gene or the resultant decrease in the sialidase activity is linked to the development of these neoplasms. Indeed, it has been reported that a decreased expression of the Neu1 protein is associated with an enhanced metastatic ability of mouse colon adenocarcinoma cells [6]. The expression level of NEU1 mRNA in human colon cancer tissue is lesser than that in the adjacent non-cancerous mucosa [7]. Because the heterozygous mutation of the genes encoding the proteins of this family leads to a decrease in sialidase activity, this underlying condition might have facilitated the development of neoplasm in these siblings; the development of neoplasms may not necessarily be associated with lysosomal catabolism, but rather linked to cell differentiation, cell growth, and apoptosis [8]. It may also be considered that decreased sialidase activity, which is also detected in galactosialidosis, may also be associated with the development of Y. Yagi (&) A. Machida S. Toru T. Kobayashi Department of Neurology, Nakano General Hospital, Chuo 4-59-16 Nakano, Tokyo 164-8607, Japan e-mail: yyagi-tmd@umin.ac.jp

Transient Charles Bonnet syndrome in a patient with reversible cerebral vasoconstriction syndrome

Charles Bonnet syndrome (CBS) was first described by a Swiss philosopher named Charles Bonnet in 1760. For a long time, this syndrome was considered to be rare; however, in 1996, Teunisse et al. [1] reported psychopathological characteristics of 60 patients with CBS and questioned the rarity of CBS. CBS is diagnosed if the following criteria are fulfilled: (a) the presence of formed and complex, persistent, or repetitive visual hallucinations; (b) full or partial retention of insight; (c) the absence of delusions; (d) and the absence of hallucinations in other modalities [2]. Reversible cerebral vasoconstriction syndrome (RCVS) is a disorder characterized with reversible segmental and multifocal vasoconstriction of cerebral arteries and severe headaches with or without focal neurological deficits or seizures. Calabrese et al. described the following features for RCVS: (a) transfemoral angiography or indirect [computed tomography (CT) or magnetic resonance (MR)) angiography showing segmental cerebral artery vasoconstriction; (b) no evidence for aneurysmal subarachnoid hemorrhage; (c) normal or near-normal findings for cerebrospinal fluid analysis (protein level \80 mg/dL, white blood cell count\10 cells/lL, normal glucose level); (d) severe, acute headache with or without additional neurological signs or symptoms; and (e) the diagnosis cannot be confirmed until reversibility of the angiographic abnormalities is documented within 12 weeks after onset and if death occurs before the follow-up examinations are completed, the autopsy rules out conditions such as vasculitis, intracranial atherosclerosis, and aneurysmal subarachnoid hemorrhage, which can also manifest with headache and stroke [3]. Here, we report transient visual hallucinations resembling the ones in CBS in a patient with RCVS. A 64-year-old woman experienced severe thunderclap headache when she was skiing. CT and MR imaging (MRI) of her brain performed at that time revealed no abnormality. MRI and magnetic resonance angiography (MRA) conducted about 3 weeks later revealed convexity subarachnoid hemorrhage in the right frontal lobe and multiple segmental cerebral artery vasoconstrictions (Fig. 1). Her blood pressure was 130/96 mmHg, her body temperature was 36.2 C, and she was alert. She had no visual loss but experienced formed and complex visual hallucination such as ‘‘people walking down the street’’ or ‘‘people acting in a theater’’ only when she closed her eyes, and she had full retention of insight. Her visual hallucinations began about 3 weeks after the onset of headache, and lasted for about a week. 99mTc-ECD single-photon emission computed tomography showed diminished blood flow in both the occipital lobes (Fig. 2). Her headache eventually resolved without any neurological deficit. MRA performed at about 5 weeks after the onset of headache showed more cerebral artery vasoconstrictions, but the vasoconstrictions resolved 2 weeks after that, and the patient was diagnosed with RCVS. Y. Yagi (&) Y. Watanabe H. Yokote T. Amino T. Kamata Department of Neurology, Musashino Red Cross Hospital, Kyonancho 1-26-1, Musashino, Tokyo 180-8610, Japan e-mail: yyagi-tmd@umin.ac.jp

Lacunar thalamic infarction with isolated dysesthesia in contralateral fingers

Cerebral infarctions in the thalamus cause various neurological symptoms. Of these, the cheiro-oral syndrome is a pure sensory stroke (PSS) in which sensory disturbance is observed around the corner of the mouth and in the palm on the same side of the body [1]. Here, we report a case of thalamic infarction with sensory disturbance restricted to the thumb and index that mimicked an incomplete form of the cheiro-oral syndrome. A man in his 70s was referred to our department because of a 2-month history of sensory disturbance in his right thumb and index. His symptom developed suddenly and did not improve for 2 months. Neurological examination revealed dysesthesia restricted to the distal phalangeal region on the palmar side of his right thumb and index (Fig. 1a). He had no weakness or sensory disturbance in his face or lower extremities. Motor and sensory nerve conduction studies of his bilateral median nerves yielded normal results. Magnetic resonance imaging (MRI) of the cervical spine revealed only mild cervical spondylosis and no stenosis in the spinal canal or the intervertebral foramen. Brain MRI revealed a small T2-weighted hyperintense lesion in his left thalamus (Fig. 1b). Based on these findings, we concluded that the patient had cerebral infarction in the contralateral thalamus. PSS accounts for 17.4 % of the cases of lacunar syndromes; the thalamus is responsible for the symptoms in