Gaku Murakami

Low CSF hypocretin-1/orexin-A associated with hypersomnia secondary to hypothalamic lesion in a case of multiple sclerosis

Sirs: Hypocretins/orexins are hypothalamic neuropeptides that are related to sleep-wake regulation [1, 10]. It has been reported that cerebrospinal fluid (CSF) hypocretin1/orexin-A level is dramatically decreased in narcolepsy-cataplexy [4, 8, 9, 11]. Narcolepsy is also known to occur secondary to hypothalamic lesions caused by tumors, stroke, multiple sclerosis (MS) or acute disseminated encephalomyelitis, and the CSF hypocretin-1 level is decreased in some of them [5–7, 12]. However, it remains unclear whether CSF hypocretin level correlates with the severity of hypersomnia and the REM pathology. We reported the MRI finding of bilateral hypothalamic lesions in a case of MS presenting with hypersomnia [3]. We further examined details of sleep investigations and correlated them with CSF hypocretin-1 level and the MRI findings. A 22-year-old woman was admitted to our hospital one week after the acute onset of hypersomnia. She had developed diplopia as an initial symptom of MS one year before the onset of hypersomnia. She also complained of numbness of the lower extremities and polyuria. She did not experience any narcolepsy-related symptoms such as cataplexy, sleep paralysis and hypnagogic hallucination. MRI revealed bilateral FLAIR hyperintensity in the hypothalamus [3]. CSF showed increased myelin basic protein (242 pg/mL; normal < 100 pg/mL). CSF hypocretin-1 level was measured using radioimmunoassay kit (Phenix Pharmaceuticals, USA). HLA was positive for DR-4 and DR-6 but negative for DR-2. Sleep investigations including polysomnography (PSG) followed by multiple sleep latency test (MSLT) were performed 11days after the onset of hypersomnia. Methylprednisolone (1000 mg/day for 3 days) was started on the following day which was followed by oral prednisolone therapy, and her clinical symptom resolved within two weeks after methylprednisolone therapy was started. CSF hypocretin-1 level was undetectable (< 40 pg/mL; normal 200–350 pg/mL) on the first evaluation (Table 1). PSG showed sleep onset REM period (SOREMP), and confirmed the absence of any other sleep disorders. MSLT showed a mean sleep latency of 2.8 minutes and five SOREMPs out of five sessions. On the second evaluation two months later, the patient had no complaint of hypersomnia. Hypothalamic lesions were diminished. MSLT showed a mean sleep latency of 17.4 minutes and SOREMP appeared only once. CSF hypocretin-1 level was 167 pg/mL. On the third evaluation four months after the first one, MSLT showed a mean sleep latency of 14.8 minutes and no SOREMP. CSF hypocretin level was normal (211 pg/mL). This patient showed acute onset of hypersomnia but did not show cataplexy or any other narcolepsyrelated symptoms. Our case does not fulfill the diagnostic criteria of narcolepsy because the diagnosis of narcolepsy requires either cataplexy or other narcolepsy-related LETTER TO THE EDITORS

Heidenhain Variant of Creutzfeldtjakob Disease: Diffusion‐Weighted MRI and PET Characteristics

Creutzfeldt‐Jakob disease (CJD) is characterized by rapidly progressive dementia with a variety of neurological disorders and a fatal outcome. The authors present a case with visual disturbance as a leading symptom and rapid deterioration in global cognitive functions. The cerebrospinal fluid was positive for 14‐3‐3 protein, and diffusion‐weighted magnetic resonance imaging (MRI) showed marked hyperintensity in the parieto‐occipital cortices, where hypometabolism was clearly detected on positron emission tomography (PET). Pattern‐reversal visual evoked potentials showed prolonged P100 latencies and increased N75/P100 amplitudes. All these findings supported a diagnosis of the Heidenhain variant of CJD, whereas a long clinical course, a lack of myoclonus, and an absence of periodic synchronous discharges on electroencephalography were atypical. Diffusion‐weighted MRI and PET in combination with visual evoked potential recording and 14‐3‐3 protein detection may be useful for the early diagnosis of CJD.

Chemical Library Screening Identifies a Small Molecule That Downregulates SOD1 Transcription for Drugs to Treat Amyotrophic Lateral Sclerosis

Familial amyotrophic lateral sclerosis (fALS) accounts for 10% of ALS cases, and about 25% of fALS cases are due to mutations in superoxide dismutase 1 (SOD1). Mutant SOD1-mediated ALS is caused by a gain of toxic function of the mutant protein, and the SOD1 level in nonneuronal neighbors, including astrocytes, determines the progression of ALS (non-cell-autonomous toxicity). Therefore, the authors hypothesized that small molecules that reduce SOD1 protein levels in astrocytes might slow the progression of mutant SOD1-mediated ALS. They developed and optimized a cell-based, high-throughput assay to identify low molecular weight compounds that decrease SOD1 expression transcriptionally in human astrocyte-derived cells. Screening of a chemical library of 9600 compounds with the assay identified two hit compounds that selectively and partially downregulate SOD1 expression in a dose-dependent manner, without any detectable cellular toxicity. Western blot analysis showed that one hit compound significantly decreased the level of endogenous SOD1 protein in H4 cells, with no reduction in expression of β-actin. The assay developed here provides a powerful strategy for discovering novel lead molecules for treating familial SOD1-mediated ALS.

Similarities of serum anti-ganglioside antibodies in first and third episodes of recurrent Guillain–Barre syndrome: case report

Dear Sirs, Patients with recurrent Guillain–Barre syndrome (RGBS) could show similar symptoms even with different types of preceding infections, thus genetic and immunological host factors are thought to partly determine the clinical phenotype irrespective of the preceding infection [1]. Although a previous study reported that the same antiganglioside antibodies were positive in sera obtained from the third and fourth recurrences of an RGBS patient with similar types of preceding infections [2], anti-ganglioside antibodies in RGBS cases with different types of preceding infections have not been reported. We treated a 37-year-old previously healthy man who developed weakness in the lower limbs 10 days after diarrhea development. On neurological examination, his limbs were moderately weak and deep tendon reflexes were abolished. Senses of temperature, pain, touch, position or vibration were not impaired. Nerve conduction studies (NCS) showed decreased amplitudes of compound muscle action potentials (CMAPs) (Table 1). Cerebrospinal fluid (CSF) analysis revealed elevated total protein (92 mg/dL), normal cell count (1/lL), and glucose level (72 mg/dL). Intravenous injection of immunoglobulin (IVIg) (400 mg/kg/day for 5 days) was performed and the patient was discharged 2 weeks later with a full recovery. At 54 days after onset of the first episode, exacerbation of lower limbs weakness occurred and he was readmitted. Diarrhea preceded the exacerbation of symptoms. IVIg (400 mg/kg/day for 5 days) was administered again, and the patient fully recovered after 2 weeks. Three years later, the patient was presented with weakness in the lower limbs again 1 week after development of a cough. NCS performed on day 3 showed prolonged distal latencies and decreased amplitudes of CMAPs and decreased amplitudes of sensory nerve action potentials, though those of day 1 were within normal ranges (Table 1). His limbs were moderately weak and deep tendon reflexes were abolished. There was no sensory impairment. CSF analysis revealed elevated total protein (51 mg/dL), normal cell count (1/lL), and glucose level (59 mg/dL). Stool culture showed no growth of Campylobacter jejuni. The symptoms deteriorated and he required respiratory support. IVIg (400 mg/kg/day for 5 days) was given twice and the weakness gradually improved, then 2 months later he was discharged with full recovery. Anti-ganglioside antibody assays of sera obtained during the first and third episodes were performed, and similar anti-ganglioside antibodies were positive. These anti-ganglioside antibodies became negative or declined during the recovery phase (Table 2). We found out two important clinical issues from this case. First, results of anti-ganglioside antibody assays indicate that similar antiganglioside antibodies can be positive despite different types of preceding infections. Thus, we speculate that genetic and immunological host factors may determine not only the clinical phenotype, but also reacted anti-ganglioside antibodies. Second, since the second episode occurred within 2 months after the first episode onset, at that time we considered it to be treatment-related fluctuation & Jumpei Togawa togawa-kyt@umin.org

Improvement of pontine perfusion with steroid therapy in a patient with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids: A case report

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory disease in the central nervous system characterized by brainstem symptoms and distinctive radiological features, and responds favorably to steroid therapy. To date, only a few case reports pertaining to this condition have been published, and thus single‐photon emission computed tomography findings of CLIPPERS have not been reported. Here, we document our experiences with an 86‐year‐old patient who we diagnosed with CLIPPERS according to her clinical presentation, radiological findings and favorable response to steroid therapy. N‐isopropyl‐p‐[123I]iodoamphetamine single‐photon emission computed tomography showed hypoperfusion in the pons, which was improved by steroid therapy. This case highlights the utility of N‐isopropyl‐p‐[123I]iodoamphetamine single‐photon emission computed tomography for assessing pontine dysfunction in CLIPPERS patients both before and after steroid therapy.

Development of a high-throughput screening assay for drug discovery in SOD1-mediated ALS

ALS is a progressive disease with selective motor neuron <MN> death. The cell death of MN in ALS is supposed to be not fully consistent with apoptosis, necrosis, or autophagy. Recently, it was reported that the shift of balance between YAP Cs as prosurvival factors and activated p73 promotes apoptosis in transcriptional repression-induced atypical death <TRIAD>. In this study, G93ASOD1 Tg mice were examined to investigate for possible relationships between the mechanism of MN death in ALS and TRIAD. The levels of YAP Cs in the spinal cords of Tg mice decreased with disease progression, whereas FL-YAP, a p73 cofactor that promotes apoptosis, was preserved. Also, the ratio of phosphorylation of p73 increased in Tg mice. Our results suggest that the progressive decrease in the levels of YAP Cs and the relative increase in phosphorylated p73 are correlated with disease progression in ALS model mice.