Masafuchi Ryo

Neurological safety of fingolimod: An updated review

Fingolimod (FTY) is the first oral medication approved for treatment of relapsing–remitting multiple sclerosis (RRMS). Its effectiveness and safety were confirmed in several phase III clinical trials, but proper evaluation of safety in the real patient population requires long‐term post‐marketing monitoring. Since the approval of FTY for RRMS in Japan in 2011, it has been administered to approximately 5000 MS patients, and there have been side‐effect reports from 1750 patients. Major events included infectious diseases, hepatobiliary disorders, nervous system disorders and cardiac disorders. In the present review, we focus especially on central nervous system adverse events. The topics covered are: (i) clinical utility of FTY; (ii) safety profile; (iii) post‐marketing adverse events in Japan; (iv) white matter (tumefactive) lesions; (v) rebound after FTY withdrawal; (vi) relationship between FTY and progressive multifocal leukoencephalopathy; (vii) FTY and progressive multifocal leukoencephalopathy‐related immune reconstitution inflammatory syndrome; and (viii) neuromyelitis optica and leukoencephalopathy.

Fingolimod-induced leukoencephalopathy in a patient with neuromyelitis optica spectrum disorder

Fingolimod (FTY720) is used for reducing the annualized relapse rate and slowing progression of neurological disability in relapsing-remitting forms of multiple sclerosis (MS). However, its safety is not confirmed in patients with neuromyelitis optica spectrum disorder (NMOSD), who characteristically have positive aquaporin-4 (AQP-4) antibody. A 54-year-old female with a relapsing-remitting course of optic neuritis and myelitis for six years, diagnosed initially as MS, had been treated with interferon beta-1b and oral corticosteroid. Magnetic resonance imaging (MRI) consistently revealed lesions on the optic nerve and spinal cord, but never on the brainstem or cerebral white matter during acute exacerbation. After treatment was switched to fingolimod from interferon beta-1b, multiple new lesions appeared at the brainstem and cerebral white matter. Following discontinuation of fingolimod, these lesions completely cleared, concomitantly with clinical improvement. During fingolimod treatment, she was recognized to be positive for AQP-4 antibody. Fingolimod may be contraindicated in patients with NMOSD.

Combined use of dopamine transporter imaging (DAT-SPECT) and 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy for diagnosing Parkinson's disease

BACKGROUND To examine whether combined use of 123I-FP-CIT dopamine transporter single photon emission computed tomography (DAT-SPECT) and 123I-MIBG myocardial scintigraphy (MIBG) is superior to either modality alone for diagnosing Parkinsons disease (PD). METHODS Patients with probable PD (n=120) who underwent both DAT-SPECT and MIBG myocardial scintigraphy within short intervals were enrolled. Specific binding ratio (SBR) of DAT-SPECT images and heart-to-mediastinum (H/M) ratio of MIBG images were used as quantitative measures. We classified patients into 4 groups based on SBR value and H/M ratio, or into two groups based on the striatal asymmetry index (SAI) of DAT-SPECT, and examined the clinical features of each group. We also investigated the characteristics of SWEDDs (scans without evidence of dopaminergic deficits) patients. Finally, we calculated the sensitivity and specificity of each method and the combined method. RESULTS SBR value was significantly correlated with both early and delayed H/M ratio values. Motor complications and hallucinations were observed at high frequency in the group with both lower SBR and H/M ratio, and hallucinations appeared in the group with larger SAI. SWEDDs were observed 8.3% of patients. The sensitivity and specificity of diagnosing PD were 91.7% and 15.0% by SBR of DAT-SPECT, 78.3% and 90.0% by H/M ratio of MIBG uptake, and 74.2% and 95.0% by the combined modalities, respectively. CONCLUSIONS Combined use of DAT-SPECT and MIBG myocardial scintigraphy increases the specificity of PD diagnosis, and is helpful for understanding the clinical features or predicting complications.

Postural deformities in Parkinson's disease -Mutual relationships among neck flexion, fore-bent, knee-bent and lateral-bent angles and correlations with clinical predictors.

BackgroundVarious postural deformities appear during progression of Parkinson’s disease (PD), but the underlying pathophysiology of these deformities is not well understood. The angle abnormalities seen in individual patients may not be due to distinct causes, but rather they may have occurred in an interrelated manner to maintain a balanced posture.MethodsWe measured the neck flexion (NF), fore-bent (FB), knee-bent (KB) and lateral-bent (LB) angles in 120 PD patients, and examined their mutual relationships, and correlations with clinical predictors such as sex, age, disease duration, Hoehn and Yahr (H&Y) stage, medication dose (levodopa equivalent dose, LED; total dose of dopamine agonists, DDA). The relationship between the side of the initial symptoms and the direction of LB angle was also investigated.ResultsOur main findings were: (1) Significant relationships between NF and KB, NF and LB, FB and KB, KB and LB were observed. (2) NF angle was larger in males than in females, but FB, KB and LB angles showed no significant difference between the sexes. (3) FB and KB angles became larger with advancing age. (4) NF and FB angles were associated with disease duration. (5) NF, FB, KB and LB angles all increased significantly with increase of H&Y stage. (6) FB angle was significantly associated with LED, but DDA did not show a significant relationship with any of the measured angles. (7) Direction of LB angle was not associated with the side of initial symptoms.ConclusionsPostural abnormalities are interrelated, possibly to maintain a balanced posture.

Early detection of cognitive impairment in Parkinson’s disease with use of the Wisconsin Card Sorting Test

Impairment of cognitive function is one of the most common and important features of Parkinson’s disease (PD), and often appears in the early stage of PD. There are several ways to assess cognition in the clinical or research setting. The Montreal Cognitive Assessment (MoCA) is a promising tool, and its sensitivity and specificity for detecting mild cognitive impairments in PD are 90% and 87%, respectively. On the other hand, the Wisconsin Card Sorting Test (WCST) is a “set-shifting” neuropsychological test that evaluates the ability to display flexibility in the face of changing schedules of reinforcement, and is an indicator of several frontal lobe functions. In order to ascertain whether WCST is a useful test for detecting early changes of cognitive function in PD, we performed MoCA and WCST simultaneously and compared the results. In addition, as the majority of PD patients have an impaired sense of smell at an early stage, we conducted a smell test at the same time as the psychological tests. In PD patients, CA was 2.1 ± 1.9, PEN was 7.1 ± 6.1, and DMS was 2.4 ± 2.1, and all were significantly worse than those of age-matched normal subjects. MoCA scores tended to correlate with the WCST sub-scores (CA: r=0.27, p=0.075, PEN: r=0.30, p<0.05 and DMS: r=0.30, P=0.055). Smell test scores were significantly correlated with MoCA scores (r=0.47, p<0.001) and also showed a weak correlation with CA (r=0.28, p=0.074) (Figure 2).

123I-Meta-iodobenzylguanidine (MIBG) myocardial scintigraphy in patients showing scans without evidence of dopaminergic deficits (SWEDDs)

OBJECTIVE Scans without evidence of dopaminergic deficits (SWEDDs) in dopamine transporter single-photon emission computed tomography (DAT-SPECT) are found in 3.6-19.6% of patients with clinically suspected Parkinsons disease (PD). We investigated whether combined use of 123I-meta-iodobenzylguanidine (MIBG) myocardial scintigraphy would be helpful to differentiate PD among SWEDDs patients. PATIENTS AND METHODS 145 patients with clinically suspected PD underwent both DAT-SPECT and MIBG myocardial scintigraphy. Striatal binding ratio (SBR) of DAT-SPECT and heart-to-mediastinal (H/M) ratio and washout rate (WR) of MIBG myocardial scintigraphy were calculated. RESULTS Among 18 SWEDDs patients (12.4%), 11 were finally diagnosed with PD based on follow-up for at least two years after the DAT-SPECT and MIGB myocardial scintigraphy scans. Among the latter group, 8 patients showed an H/M ratio of less than 2.2, and 9 showed WR above 30%. CONCLUSION Our results indicate that the combination of low H/M ratio and high WR of MIBG myocardial scintigraphy of SWEDDs patients may be helpful for detection of PD patients.

MRI Signal Abnormalities of the Inferior Olivary Nuclei in Spinocerebellar Ataxia Type 2

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant spinocerebellar degeneration, associated with extended repeats of the trinucleotide CAG in the ATXN2 gene on the long arm of chromosome 12. Magnetic resonance imaging (MRI) of SCA2 showed significant atrophies of the brainstem, middle cerebellar peduncles, and cerebellum. We report two genetically proven SCA2 patients who showed hypertrophy of the inferior olivary nuclei on proton density- and T2-weighted MRI. This pattern has never been reported in patients with SCA1, SCA3, or SCA6, and may make it possible to differentiate SCA2 from other hereditary spinocerebellar ataxias.

Early Motor Fluctuations in a Patient with Striatonigral Degeneration

We report a 44-year-old female with striatonigral degeneration (SND) who showed wearing-off oscillations after 4 months of levodopa treatment. The patient presented with asymmetric left-side dominant rigidity, and levodopa was effective at first. However, she began to show wearing-off oscillations of motor symptoms, which gradually worsened thereafter. Fluid-attenuated inversion recovery sequence magnetic resonance imaging (MRI) showed linear lateral putamen hyperintensities, and positron emission tomography (PET) studies using 18F-fluorodopa (FD) and 11C-N-methylspiperon (NMSP) showed a marked decrease of radioactivity in the right putamen, especially in the posterior putamen. The results of MRI and 2 PET studies with FD and NMSP were well consistent with the diagnosis of SND.