Clinical features of drug-induced Parkinsonism

Drug-induced Parkinsonism is often reversible after withdrawal of the causative drug. Its clinical course, however, is not well understood, as the majority of cases are caused by drugs prescribed by departments outside of neurology. We reviewed 21 cases of drug-induced parkinsonism for several factors, including age, sex, causative drug and reason for prescription, department by which it was prescribed, and outcome. The age at onset ranged from 40 to 87 years, with an average Hoehn and Yahr Scale score of 4, indicating severe disability. Sulpiride was the most commonly observed causative drug (71.4%). All causative drugs were prescribed in non-neurological departments and over one half were prescribed in non-psychiatric departments; most were prescribed to treat depression or abdominal discomfort. Ten patients (48%) were previously diagnosed with a neuromuscular disease, including cerebrovascular diseases and Parkinson’s disease. Recovery was observed in 15 cases (71%) after withdrawal of the causative drug, but lingering symptoms were observed in the remaining cases. It is suggested that physicians should be more cautious of Parkinsonian side effects when prescribing such drugs

Amyloid β-protein oligomers upregulate the β-secretase, BACE1, through a post-translational mechanism involving its altered subcellular distribution in neurons

Quantification of fluorescence intensities in axons and dendrites. After double immunofluorescent staining of primary neurons with anti-BACE1 (green) and anti-MAP2 (red) antibodies, specimens were examined under a LSM780 microscope. BACE1 fluorescence intensities along MAP2-positive dendrites (red line) and MAP2-negative axons (blue line) were quantified as described in Methods. Scale bar = 10 μm. (PDF 66 kb

High-sensitivity quantitative analysis reveals the non-linear relationship between the dose and deposition of diphenylarsinic acid in the rat central nervous system following its subchronic exposure

In the year 2003, the residents of Kamisu, Japan, were exposed to pentavalent organic arsenic diphenylarsinic acid (DPAA[V]) via their normal drinking water. Following the exposure, they developed cerebellar and brainstem symptoms. Although the relatively high dose of DPAA(V) is assumed to have caused their symptoms, the relationship between the exposed dose of DPAA(V) and the level of their deposition in the central nervous system (CNS) remains unclear. Using liquid chromatography–tandem mass spectrometry, we examined the deposition of DPAA(V) and its pentavalent metabolites in the CNS tissues of Crl:CD(SD) rats following the administration of DPAA(V) for 28 days. We found that the concentrations of DPAA(V) in the CNS were very high, given a dose of 5.0 mg/kg/day. However, very low concentrations of DPAA(V) were detected at a dose of 0.3 or 1.2 mg/kg/day, suggesting the absence of a linear dose-response relationship between the dose and deposition of DPAA(V). We also found that this non-linear relationship was commonly observed in various non-CNS tissues, including the excretory system. Our study showed for the first time the exact relationship between the dose and tissue deposition of the organic arsenic following its subchronic administration

Clinical features of drug-induced Parkinsonism

Drug-induced Parkinsonism is often reversible after withdrawal of the causative drug. Its clinical course, however, is not well understood, as the majority of cases are caused by drugs prescribed by departments outside of neurology. We reviewed 21 cases of drug-induced parkinsonism for several factors, including age, sex, causative drug and reason for prescription, department by which it was prescribed, and outcome. The age at onset ranged from 40 to 87 years, with an average Hoehn and Yahr Scale score of 4, indicating severe disability. Sulpiride was the most commonly observed causative drug (71.4%). All causative drugs were prescribed in non-neurological departments and over one half were prescribed in non-psychiatric departments; most were prescribed to treat depression or abdominal discomfort. Ten patients (48%) were previously diagnosed with a neuromuscular disease, including cerebrovascular diseases and Parkinson’s disease. Recovery was observed in 15 cases (71%) after withdrawal of the causative drug, but lingering symptoms were observed in the remaining cases. It is suggested that physicians should be more cautious of Parkinsonian side effects when prescribing such drugs

Chronic myelitis associated with zoster sine herpete

Rationale: Neurological complications of varicella-zoster virus (VZV) infection include cerebral infarction, meningoencephalitis, segmental sensory disturbance, facial nerve palsy, and myelitis. Chronic myelitis is rarely reported. Diagnosis of VZV infection can be confirmed by elevated anti-VZV immunoglobulin G (IgG) antibody or detection of VZV DNA in the cerebrospinal fluid (CSF), the former reported to be superior. The detection rate of VZV DNA is generally thought to decrease with time after the onset of the condition. The utility of VZV DNA polymerase chain reaction (PCR) is thus thought to be limited to the acute phase of the disease. The presence of skin lesions also helps to render a diagnosis; however, cases of zoster sine herpete (ZSH), the occurrence of segmental symptoms without skin lesions, renders the diagnosis of VZV infection more difficult. Antiviral drugs, such as acyclovir, are the treatment of choice to resolve VZV infections.Patient concerns: A 65-year-old Japanese man felt heaviness and a throbbing pain on the ulnar side of the right forearm. He was previously diagnosed with cervical spondylosis, and received nonsteroidal anti-inflammatory drugs with little improvement. Contrast cervical magnetic resonance imaging showed a swelling and an increased signal intensity of the spinal cord, and an enhancing lesion, all of which were suggestive of myelitis.Diagnosis: We found no evidence for diagnoses of sarcoidosis, Behçet disease, multiple sclerosis, or neuromyelitis optica spectrum disorder. The CSF analysis revealed an elevation of the total protein concentration and that the patient was positive for VZV DNA, while anti-VZV IgG was not elevated. The patient was therefore diagnosed with ZSH myelitis.Interventions: We administered acyclovir and valaciclovir as the first therapy. At the time of recurrence, we used high-dose acyclovir, vidarabine, and high-dose methylprednisolone pulse therapy.Outcomes: The patient\u27s dysesthetic pain in the right upper limb improved following the first antiviral therapy. Two months later, he suffered a recurrence, but the second therapy significantly relieved his symptoms.Lessons: VZV infection should be regarded as an important differential diagnosis of chronic myelitis. VZV DNA PCR should be performed even in the chronic phase of the condition to introduce the possibility of antiviral therapy as a treatment option

Medial medullary infarction caused by antineutrophil cytoplasmic antibody-related vasculitis: Case report and review of the literature

Rationale: Medial medullary infarction accounts for less than 1% of brain infarctions, and medial medullary infarctions is very rarely caused by antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.Patient concerns: We report the case of a 76-year-old man at low risk of arteriosclerosis who presented with disorders on the left side including gaze-evoked nystagmus, paralysis of the extremities, pyramidal signs, sensory disturbance, and dysesthesia. Brain magnetic resonance imaging also showed right medial medullary infarction.Diagnoses: Medial medullary infarction caused by ANCA-related vasculitis was diagnosed based on mild renal dysfunction and high levels of blood leukocytes, C-reactive protein (CRP), and myeloperoxidase (MPO)-ANCA.Interventions and outcomes: He underwent two 3-day courses of steroid pulse therapy involving daily 1000 mg doses of methylpredonine. He then received 30 mg/day (0.5 mg/kg/day) of prednisolone (PSL) without other immunosuppressants. Levels of MPO-ANCA and the inflammatory marker CRP decreased rapidly a month after admission. Once MPO-ANCA became undetectable, the PSL dose was carefully reduced to 10 mg/day. To treat his paralysis, we provided rehabilitation with a Hybrid Assistive Limb five times starting at a month post-onset. His Barthel index score rose from 45 to 70 points.Lessons: Medullary infarction is mostly caused by arteriosclerosis and vertebral arterial dissection. When systemic inflammatory findings are obtained, ANCA-associated vasculitis should be considered a potential cause, and steroid pulse therapy should be promptly administered

Abnormal Saccadic Intrusions with Alzheimer\u27s Disease in Darkness

Background: Classified as saccadic intrusions, Square-Wave Jerks (SWJs) have been observed during Visual Fixation (VF) in Alzheimer’s Disease (AD). However, the pathological significance of this phenomenon remains unclear.Objective: The present study analyzed the characteristics of SWJs in patients with AD with their eyes open in the dark without VF.Methods: Fifteen patients with AD and 15 healthy age- and sex-matched controls were investigated and compared. Saccadic intrusions with and without VF were detected as SWJs and measured using an electronystagmogram.Results: No significant difference in the frequency of SWJs was observed between control and AD groups with VF, but significantly more SWJs were observed in the AD group than in the control group in the absence of VF (p0.55) in the AD group.Conclusion: SWJs without VF may have pathological significance in AD. In healthy individuals, SWJs are generated by VF and suppressed without VF. Conversely, in AD, SWJs are generated rather than suppressed in the absence of VF. These pathognomonic SWJs without VF also appear to be correlated with higher-order dysfunction, reflecting AD-related cortical damage. These findings suggest that pathological SWJs without VF observed in AD derive from cortical damage and may constitute an important marker of a higher-order function

The effect of truncation on prion-like properties of α-synuclein

Increasing evidence suggests that α-synuclein (αS) aggregates in brains of individuals with Parkinson\u27s disease and dementia with Lewy bodies can spread in a prion-like manner. Although the initial αS nuclei are pivotal in determining αS fibril polymorphs and resulting phenotypes, it is not clear how the initial fibril seeds are generated. Previous studies have shown that αS truncation might have an important role in αS aggregation. However, little is known about how this truncation influences αS\u27s propagation properties. In the present study, we generated αS fibrils from a series of truncated human αS constructs, characterized their structures and conformational stabilities, and investigated their ability to convert the conformation of full-length αS in vitro, in cultured cells, and in WT mice. We show that both C- and N-terminal truncations of human αS induce fibril polymorphs and exhibit different cross-seeding activities. N-terminally 10- or 30-residue–truncated human αS fibrils induced more abundant αS pathologies than WT fibrils in mice, whereas other truncated fibrils induced less abundant pathologies. Biochemical analyses of these truncated fibrils revealed that N-terminal 10- or 30-residue truncations of human αS change the fibril conformation in a manner that increases their structural compatibility with WT mouse αS fibrils and reduces their stability. C-terminally 20-residue–truncated fibrils displayed enhanced seeding activity in vitro. Our findings imply that truncation of αS can influence its prion-like pathogenicity, resulting in phenotypic diversity of α-synucleinopathies

Two distinct prions in fatal familial insomnia and its sporadic form

Abstract Fatal familial insomnia is a genetic prion disease, which is associated with the aspartic acid to asparagine substitution at codon 178 of the prion protein gene. Although the hallmark pathological feature is thalamic and olivary degeneration, there is a patient with an atypical fatal familial insomnia without the hallmark feature. The cause of the pathological variability is unclear. We analysed a Japanese fatal familial insomnia kindred and compared one atypical clinicopathological fatal familial insomnia phenotype case and typical fatal familial insomnia phenotype cases with transmission studies using multiple lines of knock-in mice and with protein misfolding cyclic amplification. We also analysed the transmissibility and the amplification properties of sporadic fatal insomnia. Transmission studies revealed that the typical fatal familial insomnia with thalamic and olivary degeneration showed successful transmission only using knock-in mice expressing human–mouse chimeric prion protein gene. The atypical fatal familial insomnia with spongiform changes showed successful transmission only using knock-in mice expressing bank vole prion protein gene. Two sporadic fatal insomnia cases with thalamic and olivary degeneration showed the same transmissibility as the typical fatal familial insomnia phenotype. Interestingly, one sporadic fatal insomnia case with thalamic/olivary degeneration and spongiform changes showed transmissibility of both the typical and atypical fatal familial insomnia phenotypes. Protein misfolding cyclic amplification could amplify both typical fatal familial insomnia cases and sporadic fatal insomnia cases but not the atypical fatal familial insomnia phenotype or other sporadic Creutzfeldt–Jakob disease subtypes. In addition to clinical findings and neuropathological features, the transmission properties and the amplification properties were different between the typical and atypical fatal familial insomnia phenotypes. It is suggested that two distinct prions were associated with the diversity in the fatal familial insomnia phenotype, and these two prions could also be detected in sporadic fatal insomnia