Reversible Pisa syndrome caused by chronic subdural hematoma in a patient with Parkinson's disease: a case report.

BACKGROUND: Pisa syndrome (PS), characterized by lateral trunk flexion, is quite common in patients with Parkinson's disease (PD). Patients with PS are older and have a significantly longer disease duration, more severe motor phenotype, ongoing combined treatment with levodopa and dopamine agonists, and higher levodopa equivalent daily dose. We describe here, to the best of our knowledge, the first case of a woman with PD who developed acute-onset PS caused by chronic subdural hematoma (CSDH). CASE PRESENTATION: A 70-year-old woman developed acute-onset lateral flexion of her trunk to the left side while standing, and she was admitted to our hospital. One month before, she had a mild head trauma with loss of consciousness. At 65 years of age, she noticed difficulty with walking and clumsiness with her hands. She was diagnosed as having PD (Hoehn and Yahr stage 2) and levodopa was initiated. Her symptoms were markedly improved. At 67 years of age, she developed orthostatic hypotension and was treated sequentially with fluids, compression stockings, and midodrine. Urgently performed brain computed tomography (CT) showed a CSDH in the right hemisphere resulting in a marked compression of the hemisphere. After surgical evacuation, her PS disappeared. She has fully recovered to her preoperative level of function. CONCLUSION: The present case provides a valuable insight, that is, the mesial frontal lobe and its connections from the posterior parietal cortex play crucial roles in maintaining the body schema and in the pathophysiology of PS. This case suggests that CSDH should be considered when clinicians examine acute-onset PS, even in patients with neurodegenerative disorders such as PD. Appropriate patient triage and timely neurosurgical intervention should be considered.

Mesial Frontal Lobe Infarction Presenting as Pisa Syndrome.

Pisa syndrome is usually seen in patients with Alzheimer's disease treated with a cholinesterase inhibitor, dementia with Lewy bodies, Parkinson's disease, or atypical parkinsonism including multiple system atrophy. An 86-year-old woman presented with an acute onset of lateral flexion of her trunk to the left side, i.e., Pisa syndrome. She also showed left hemiparesis predominantly in her lower extremity. Her diffusion-weighted magnetic resonance images showed acute infarction in the right premotor area and supplementary motor area. Clopidogrel (75 mg daily) was prescribed. After two weeks from the onset of symptoms, her Pisa syndrome improved. The pathophysiology of Pisa syndrome has not yet been fully understood, but different mechanisms have been assumed. In this patient, it is possible that the infarction in her unilateral frontal lobe impaired the information processing from the temporoparietal cortex to the frontal lobe, including the premotor area and supplementary motor area for anticipatory postural control.

Middle Cerebral Artery Occlusion Presenting as Upper Limb Monochorea.

BACKGROUND: Hemichorea is usually caused by a structural lesion in the contralateral basal ganglia or subthalamic nuclei or it develops as a form of a neurologic complication including hyperglycemia. We report a rare case of a patient who developed choreic movement in the right upper extremity associated with a contralateral middle cerebral artery (MCA) occlusion. METHODS: A 76-year-old man presented with chorea in the right upper limb, known as monochorea, which occurred after recovery from losing consciousness while standing. He was found to have idiopathic orthostatic hypotension. His diffusion-weighted magnetic resonance imaging did not show signal changes indicative of acute ischemic lesions. A left carotid artery angiogram showed occlusion of the left MCA. (123)I-N-isopropyl-4-iodoamphetamine single-photon emission computed tomography of the brain showed marked hypoperfusion in the left MCA territory. His cerebrovascular reserve capacity determined using acetazolamide was relatively decreased in this territory. This decrease in cerebrovascular reserve capacity, however, did not require surgical treatment, such as extracranial-intracranial bypass surgery. RESULTS: The recurrence of chorea was not observed after antiplatelet therapy and instruction on how to cope with orthostatic hypotension. CONCLUSIONS: It is considered that transient hemodynamic ischemia in the right basal ganglia-thalamocortical circuits because of the combination of MCA occlusion and hypotension was the underlying cause of the monochorea in this patient.Vascular imaging studies for early identification of occlusion or severe stenosis of cerebral major arteries should be carried out in patients acutely presenting with chorea, even in the absence of other clinical signs.

Subacute Progressive Hearing Loss and Lower Body Parkinsonism in Primary Sjögren's Syndrome.

In primary Sjögren's syndrome, it is extremely rare to observe subacute progressive lower-body parkinsonism with severe sensory hearing loss responsive to corticosteroid therapy. Sjögren's syndrome can cause heterogeneous symptoms; therefore, its diagnosis and introduction of treatment are prone to be delayed, particularly in cases without sicca symptoms or seronegative cases, which are more likely to be seen in patients with neurological complications. This report may help clinicians identify atypical early neurological symptoms in primary Sjögren's syndrome.

Cerebral infarction developing in a patient without cancer with a markedly elevated level of mucinous tumor marker.

Previous studies have shown the possible role of mucin in cerebral infarction associated with coagulation abnormalities in patients with cancer, particularly adenocarcinoma. We report a 42-year-old woman who developed motor aphasia and cerebral infarction in the left frontal lobe and right parietal lobe. A mucinous tumor marker, CA125 level, was markedly elevated at 1750 U/mL (normal, <36 U/mL), and the D-dimer level was 6.0 µg/mL (normal, <1 µg/mL). She had adenomyosis and no malignancy was revealed. The CA125 and the D-dimer levels became normal after treatment of adenomyosis. Our findings suggest for the first time that marked elevation of mucinous tumor marker level may cause cerebral infarction even in benign conditions.

Gradient echo T2*-weighted magnetic resonance imaging revealing cerebral microbleeds in a patient with microscopic polyangiitis complicated by cerebrovascular disease.

A 67-year-old woman developed alveolar hemorrhage and was positive for the myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA). She was diagnosed as having probable microscopic polyangiitis (MPA) in accordance with the Japanese criteria. Brain computed tomographic and magnetic resonance imaging (MRI) scans revealed asymptomatic chronic cerebral hemorrhage and white matter lesions. She also later developed thalamic infarction. Gradient echo T2-weighted MRI showed cerebral microbleeds. Cerebral microbleeds in our patient represent bleeding-prone necrotizing vasculitis, which is a characteristic pathologic feature of MPA. Although cerebrovascular disease is not major complication of MPA, cerebral hemorrhage occurs more frequently than ischemic infarction, and it can be critical and fatal. Brain MRIs, including gradient echo T2-weighted imaging, should be performed on patients diagnosed as or suspected of having MPA to assess the risk of cerebral hemorrhage.

Efficacy and Safety of Ultrahigh-Dose Methylcobalamin in Early-Stage Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.

Importance: The effectiveness of currently approved drugs for amyotrophic lateral sclerosis (ALS) is restricted; there is a need to develop further treatments. Initial studies have shown ultrahigh-dose methylcobalamin to be a promising agent. Objective: To validate the efficacy and safety of ultrahigh-dose methylcobalamin for patients with ALS enrolled within 1 year of onset. Design, Setting, and Participants: This was a multicenter, placebo-controlled, double-blind, randomized phase 3 clinical trial with a 12-week observation and 16-week randomized period, conducted from October 17, 2017, to September 30, 2019. Patients were recruited from 25 neurology centers in Japan; those with ALS diagnosed within 1 year of onset by the updated Awaji criteria were initially enrolled. Of those, patients fulfilling the following criteria after 12-week observation were eligible for randomization: 1- or 2-point decrease in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score, a percent forced vital capacity greater than 60%, no history of noninvasive respiratory support and tracheostomy, and being ambulatory. The target participant number was 64 in both the methylcobalamin and placebo groups. Patients were randomly assigned through an electronic web-response system to methylcobalamin or placebo. Interventions: Intramuscular injection of methylcobalamin (50-mg dose) or placebo twice weekly for 16 weeks. Main Outcomes and Measures: The primary end point was change in ALSFRS-R total score from baseline to week 16 in the full analysis set. Results: A total of 130 patients (mean [SD] age, 61.0 [11.7] years; 74 men [56.9%]) were randomly assigned to methylcobalamin or placebo (65 each). A total of 129 patients were eligible for the full analysis set, and 126 completed the double-blind stage. Of these, 124 patients proceeded to the open-label extended period. The least square means difference in ALSFRS-R total score at week 16 of the randomized period was 1.97 points greater with methylcobalamin than placebo (-2.66 vs -4.63; 95% CI, 0.44-3.50; P = .01). The incidence of adverse events was similar between the 2 groups. Conclusions and Relevance: Results of this randomized clinical trial showed that ultrahigh-dose methylcobalamin was efficacious in slowing functional decline in patients with early-stage ALS and with moderate progression rate and was safe to use during the 16-week treatment period. Trial Registration: ClinicalTrials.gov Identifier: NCT03548311.

PLA2G6 variants associated with the number of affected alleles in Parkinson's disease in Japan.

This study aimed to evaluate genotype-phenotype correlations of Parkinson's disease (PD) patients with phospholipase A2 group V (PLA2G6) variants. We analyzed the DNA of 798 patients with PD, including 78 PD patients reported previously, and 336 in-house controls. We screened the exons and exon-intron boundaries of PLA2G6 using the Ion Torrent system and Sanger method. We identified 21 patients with 18 rare variants, such that 1, 9, and 11 patients were homozygous, heterozygous, and compound heterozygous, respectively, with respect to PLA2G6 variants. The allele frequency was approximately equal between patients with familial PD and those with sporadic PD. The PLA2G6 variants detected frequently were identified in the early-onset sporadic PD group. Patients who were homozygous for a variant showed more severe symptoms than those who were heterozygous for the variant. The most common variant was p.R635Q in our cohort, which was considered a risk variant for PD. Thus, the variants of PLA2G6 may play a role in familial PD and early-onset sporadic PD.

Somnolence Preceded the Development of a Subthalamic Lesion in Neuromyelitis Optica Spectrum Disorder.

A 67-year-old woman with neuromyelitis optica spectrum disorder (NMOSD) developed severe somnolence. Ten days after admission, fluid-attenuated inversion-recovery magnetic resonance imaging (MRI) revealed hyperintense areas around the bilateral hypothalamus, which were not present on MRI at admission. The orexin level, which is decreased in idiopathic narcolepsy, was slightly decreased in her cerebrospinal fluid. Immunosuppressive treatment and methylphenidate markedly improved her somnolence. This case shows that NMOSD in the acute phase can cause somnolence in a patient without apparent lesions in the hypothalamus.

Clinical Characterization of Definite Autoimmune Limbic Encephalitis: A 30-case Series.

Objective Limbic encephalitis (LE) is an inflammatory condition of the limbic system that has an acute or subacute onset. Several types of antibodies are related to the onset of LE, including anti-N-methyl D-aspartate receptor (NMDAR) antibodies and voltage-gated potassium channel (VGKC)-complex antibodies. However, the characteristics and prevalence of LE remain unclear, especially in Asian cohorts, due to the rarity. We aimed to survey their characteristics. Materials and Methods Data of 30 cases clinically defined as "definite autoimmune LE" (based on the standard criteria) were retrospectively collected. These patients were categorized into four subtypes: NMDAR (+) (n=8), VGKC (+) (n=2), antibodies related to paraneoplastic syndrome (n=2), and an antibody-negative group (uncategorized) (n=18). Results LE is rare in Japan, and affected only 30 of 16,759 hospital patients (0.2%) over a ten-year period. The NMDAR (+) group showed distinctive symptoms, while the other three groups had similar indications. Brain MRI indicated significant medial temporal lobe atrophy at one year follow up after discharge. The prevalence of cognitive dysfunction as a complication was 64% (9/14). First-line immunotherapy resulted in a good outcome. A drastic improvement was seen from 4.0±1.1 to 1.1+ on the modified Rankin Scale. A good treatment outcome was observed in all groups (NMDAR, VGKC, and uncategorized), suggesting the importance of an early clinical diagnosis and the early initiation of treatment. Furthermore, we reviewed 26 cases that were clinically diagnosed as definitive autoimmune LE in previous case reports. Conclusion Our findings show that the establishment of a clinical diagnosis based on the clinical criteria of definitive autoimmune LE is important for the initiation of immunotherapy.

The Japanese Early-Stage Trial of High-Dose Methylcobalamin for Amyotrophic Lateral Sclerosis (JETALS): Protocol for a Randomized Controlled Trial.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the upper and lower motor neurons. Currently, only riluzole and edaravone are approved as drugs to treat ALS and new agents with larger effect sizes are warranted. Exploratory analyses in our previous study (study ID #E0302-J081-761) have suggested that high-dose methylcobalamin (E0302) prolonged the overall survival of ALS patients and suppressed ALS progression in patients with a disease duration of less than 12 months. OBJECTIVE: This clinical trial aims to evaluate the efficacy and safety of E0302 for treatment of ALS patients within one year of onset. METHODS: The Japanese early-stage trial of high-dose methylcobalamin for ALS (JETALS) is a prospective, multicenter, placebo-controlled, double-blind, randomized phase III study conducted at 24 tertiary neurology centers and is funded by the Japan Agency for Medical Research and Development. A total of 128 ALS patients within one year of onset were randomized at a 1:1 ratio to receive intramuscular injection with E0302 50 mg or placebo twice a week for 16 weeks. The primary endpoint is changes in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score at 16 weeks. If patients wish to receive E0302 50 mg after the double-blind administration period, E0302 will be provided to them until March 2020 during the continuous administration period. RESULTS: This study began in October 2017 and is being conducted at 24 participating institutions in Japan. The study is in progress and the patient enrollment period is scheduled to end in August 2019, with follow-up scheduled to end in March 2020. CONCLUSIONS: This study is being performed to revalidate the efficacy and safety of E0302 in patients with early-stage ALS in the first year of symptom onset. If positive results are obtained, the aim is to apply for E0302 approval as a new drug for the treatment of ALS. TRIAL REGISTRATION: ClinicalTrials.gov NCT03548311; https://clinicaltrials.gov/ct2/show/NCT03548311 (Archived by WebCite at http://www.webcitation.org/74Fw3rDzb). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/12046.

Segmental zoster paresis of limbs: report of three cases and review of literature.

OBJECTIVES: Segmental zoster paresis is a relatively rare complication characterized by focal motor weakness, which may occur in limbs affected by herpes zoster. We demonstrate the clinical characteristics of segmental zoster paresis by reviewing the cases of 138 patients, including 3 of our patients. CASE REPORT AND REVIEW SUMMARY: We report 3 patients with zoster paresis of the limbs. Patients 1 and 3 showed motor weakness in the left shoulder and arm after developing a herpetic rash in the left C5-C6 dermatomes. Patient 2 showed weakness in the right thigh and groin after a right L2-L3 herpetic eruption. The electromyograms of all 3 patients showed abnormal spontaneous activity in the affected muscles. Intravenous acyclovir and corticosteroid pulse therapy were added to oral antiviral drugs for patients 1 and 2. All 3 patients recovered favorably. Our review of the literature revealed that antiviral treatment may prevent the occurrence of zoster paresis; however, there is insufficient evidence to show what treatment hastens recovery from zoster paresis. CONCLUSIONS: Segmental zoster paresis is still underrecognized by neurologists. Awareness of this disorder is important because it may eliminate unnecessary invasive investigations and lead to appropriate treatment. Further studies on the treatment are necessary.

Successful treatment of relapsing neuro-Sweet's disease with corticosteroid and dapsone combination therapy.

Sweet's disease with central nervous system involvement, tentatively named neuro-Sweet's disease, has rarely been reported. Although systemic corticosteroid therapy is highly effective for neurologic symptoms in neuro-Sweet's disease, relapse is common. Here, we describe the case of a 38-year-old Japanese man who presented with relapsing neuro-Sweet's disease that was successfully treated with a combination of corticosteroid and dapsone. Dapsone should be considered as a therapeutic option for neuro-Sweet's disease patients showing relapse.

Chronic subdural haematoma presenting as freezing of gait.

In this report, we describe a case of freezing of gait (FOG) in a patient with chronic subdural haematoma (CSDH). An 81-year-old patient presented with progressive FOG about 6 weeks after a minor head trauma. MRI revealed CSDH in the left hemisphere, resulting in a marked compression of the hemisphere. His FOG disappeared after neurosurgical evacuation of the haematoma. It is suggested that the subdural haematoma in his left frontal cortices caused FOG. CSDH should be considered as a differential diagnosis when FOG develops after a head trauma in elderly patients, and prompt evaluations including neuroimaging and timely neurosurgical intervention are required.

A Case of Painless Legs and Moving Toes Syndrome in Parkinson's Disease Responsive to Dopaminergic Therapy.

Painless Legs and Moving Toes Syndrome (PoLMT) is a rare movement disorder characterized by flexion, extension, abduction, adduction, and torsion of toes without pain. It is considered a variant of Painful Legs and Moving Toes Syndrome (PLMT), which is characterized by similar movements but with pain. Although neuropathy and several central nervous system (CNS) involvements have been reported to be associated with PoLMT, the actual cause and mechanism remain unclear. Here we describe the first case of PoLMT in Parkinson's Disease (PD), parallel to parkinsonism in severity, who demonstrated a good response to dopaminergic therapy.

Occipital lobe seizures and subcortical T2 and T2* hypointensity associated with nonketotic hyperglycemia: a case report.

BACKGROUND: Nonketotic hyperglycemia often causes seizures. Recently, seizures associated with nonketotic hyperglycemia have been found to be associated with subcortical T2 hypointensity on magnetic resonance imaging, especially in the occipital lobes. However, the mechanism remains unclear, although iron accumulation is suggested. We present a case of occipital lobe seizures associated with nonketotic hyperglycemia supporting the hypothesis that the mechanism of subcortical T2 hypointensity is iron accumulation using gradient-echo T2*-weighted magnetic resonance imaging. CASE PRESENTATION: A 65-year-old Japanese man complained of intermittent pastel-colored flashing lights. On neurological examination, he also had lower right-side quadrant hemianopia. No other abnormal neurological findings were found. On laboratory analysis, his blood glucose level was 370 mg/dL, HbA1c was 11.4 %, and serum osmolarity was 326 mOsm/L. No ketones were detected in urine. A magnetic resonance imaging scan of his head showed subcortical T2 and T2* hypointensity in his left occipital lobe. Single-photon emission computed tomography with I123-N-isopropyl-iodoamphetamine revealed hyperperfusion in the left dominant occipital lobe. These magnetic resonance imaging abnormalities resolved during clinical recovery and treatment to control his blood sugar level. Therefore, a diagnosis of occipital lobe seizures associated with nonketotic hyperglycemia was made. CONCLUSIONS: To the best of our knowledge, this is the first case of occipital lobe seizures associated with nonketotic hyperglycemia supporting the role of iron accumulation as a mechanism for subcortical T2 hypointensity using T2*-magnetic resonance imaging.

[Pathogenesis of Parkinson's disease: a common pathway between alpha-synuclein and parkin and the mechanism of Lewy bodies formation].

Parkin, a product of Park2 gene, is an important player in the pathogenic process of Parkinson's disease (PD). Despite numerous studies including search for the substrate of parkin, the mechanism by which loss-of-function of parkin induces selective dopaminergic neuronal death remains unclear. Here we show that antisense knockdown of parkin causes apoptotic cell death of human dopaminergic SH-SY5Y cells associated with caspase activation and accompanied by accumulation of oxidative dopamine (DA) metabolites due to auto-oxidation of DOPA and DA. Forced expression of alpha-synuclein (alpha-SN), another familial PD gene product, prevented accumulation of oxidative DOPA/DA metabolites and cell death caused by parkin loss. Our findings indicate that both parkin and alpha-SN share a common pathway in DA metabolism whose abnormality leads to accumulation of oxidative DA metabolites and subsequent cell death. In addition, we identified a phosphorylated form of IkappaBalpha (pIkappaBalpha), an inhibitor of the NF-kappaB signaling pathway, and the components of the SCF(beta-TrCP), ubiquitin ligase of pIkappaBalpha, are novel protein components in LBs. Subsequently, we showed those proteins are included in the ubiquitin-LB-like inclusions generated by treatment of a proteasome inhibitor. Furthermore, the generation of the inclusions are independent on cell death due to impairment of the proteasome.