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.

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 Parkinson's 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.

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.

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

BACKGROUND: Various 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. METHODS: We 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. RESULTS: Our 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. CONCLUSIONS: Postural abnormalities are interrelated, possibly to maintain a balanced posture.

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.

Significance of the presence of metabolic syndrome in patients with asymptomatic arteriosclerosis affecting the aorta and the cerebral, extra-cranial carotid and coronary arteries.

OBJECTIVE: The presence of metabolic syndrome (MetS) is strongly associated with stroke and cardiovascular diseases. However, the relationship between MetS and the localization of atherosclerosis at various sites remains uncertain. In this study, in order to reveal the relevance of MetS to atherosclerosis at several sites, we investigated the relationships among vascular risk factors, asymptomatic cerebral infarction and atherosclerosis in the aorta and carotid and coronary arteries in adults without overtly symptomatic cerebrovascular or cardiovascular disease. METHODS: The subjects in this study included 2,759 Japanese participants (1,845 men and 914 women, mean age: 52 years) with no history of stroke or cardiovascular events. The diagnosis of MetS was made based on modifications to criteria obtained from the National Cholesterol Education Program Adult Treatment Panel. In all subjects, the presence of cerebral infarction in the extra-cranial carotid, coronary and aortic arteries was investigated using MRI, B-mode ultrasonography and CT. RESULTS: Of the 2,759 subjects, 796 (28.9%) fulfilled the criteria for MetS. The presence of MetS increased the odds ratio (OR) to 1.89 (95% confidence interval (CI): 1.35-2.65, p-value <0.0001) for asymptomatic cerebral infarction, 1.70 (95% CI: 1.37-2.10, p-value <0.0001) for carotid arteriosclerosis, 2.07 (95% CI: 1.62-2.27, p-value <0.0001) for coronary calcification and 1.67 (95% CI: 1.33-2.09, p-value<0.0001) for aortic calcification. CONCLUSION: The presence of MetS was found to be significantly correlated with arteriosclerosis in all regions, including the cerebral small-vessels, extra-cranial carotid arteries, coronary arteries and abdominal aorta. MetS might be a predictor for small and large vessel disease throughout the body.

Is mild renal dysfunction a risk factor for carotid atherosclerosis in apparently healthy adults?

OBJECTIVE: Renal dysfunction may be related to cerebrovascular disease. The aim of this study was to assess the relationship between mild renal dysfunction and carotid artery atherosclerosis detected by ultrasonography in apparently healthy subjects. METHODS: A total of 2,106 persons (1,368 men and 738 women, mean age+/-S.D.: 56 +/- 10 years) with no history of stroke were enrolled. Kidney function was evaluated in terms of estimated glomerular filtration rate (eGFR), calculated by using the relationship 194Cr(-1.094)×Age(-0.287)×0.739 (if female), where Cr is serum creatinine concentration. Atherosclerosis on ultrasonography was defined as regional intimal thickening or nodular lesion. RESULTS: Atherosclerotic lesions were significantly more frequent in subjects with CKD stage 3 than in CKD stage 1 or 2 (p<0.001). Odds ratios for atherosclerotic lesions were significantly increased to 1.11 (95% confidence interval: 1.09-1.12, p<0.001) for increasing age, 1.66 (1.31-2.10, p<0.001) for male sex, 1.76 (1.43-2.16, p<0.001) for systolic blood pressure ≥130 mmHg and/or diastolic blood pressure ≥85 mmHg, 1.61 (1.28-2.01, p<0.001) for LDL-cholesterol ≥140 mg/dL, and 1.59 (1.23-2.05, p=0.003) for smoking habit versus no risk factor. The odds ratio of CKD stage 3 for ≥50% carotid artery stenosis was significantly increased to 3.47 (1.09-11.08, p=0.035), although CKD stage 2 and stage 3 were not significant (0.77, 95% CI: 0.59-1.01, p=0.068; 0.99, 95%CI: 0.67-1.46, p=0.981, respectively). CONCLUSION: Renal dysfunction defined in terms of eGFR might be associated with early-stage carotid atherosclerosis, but traditional vascular risk factors, including increasing age or hypertension, appear to play a major role.

The role of high-sensitivity C-reactive protein in asymptomatic intra- and extracranial large artery diseases.

BACKGROUND: It remains unclear whether high-sensitivity CRP (hs-CRP) is predictive of atherosclerosis in the intracranial artery. The aim of this study is to assess the role of hs-CRP in asymptomatic intracranial artery occlusive diseases. METHODS: Of the 3,366 apparently healthy subjects who received a brain checkup, 138 with > or =25% intracranial artery stenosis on magnetic resonance angiography, 267 with > or =25% extracranial carotid artery stenosis on B-mode ultrasonography and 435 without intracranial artery or extracranial carotid artery stenosis (age-matched controls) were selected for this study. RESULTS: The mean CRP concentration in the subjects with intracranial artery stenosis was not significantly different from that in the control subjects, and the differences of mean CRP concentrations among the subgroups with 25-49, 50-74 and 75% or greater stenosis in the intracranial artery were not significant. The odds ratios of hs-CRP for extracranial carotid artery stenosis tended to increase with increasing CRP concentrations, but those of hs-CRP for intracranial artery stenosis showed no significant difference. CONCLUSION: The degree of atherogenic inflammation in asymptomatic intracranial artery stenosis may be less than that in extracranial carotid artery stenosis.

The significance of multiple risk factors for early carotid atherosclerosis in Japanese subjects.

OBJECTIVE: The aim of this study was to assess the significance of multiple risk factors for early carotid atherosclerosis in the Japanese population. METHODS: The relation between traditional vascular risk factors and serum high-sensitivity CRP (hs-CRP) or atherosclerotic lesions in the carotid arteries detected by B-mode ultrasonography was evaluated. PATIENTS: The subjects were 1,880 persons (1,240 men and 640 women, mean age 55+/-10 years old) without ischemic stroke, infection or collagen diseases. RESULTS: In the men, the odds ratio (OR) for atherosclerotic lesion was increased at 1.90 (95% CI: 1.05-3.43, P=0.032) in those with one risk factor, 2.42 (1.36-4.32, P=0.002) in those with two, and 2.95 (1.69-5.16, P<0.001) in those with three or more. In the women, the OR was similarly increased 1.93 (95% CI: 1.04-3.56, P=0.035) for one risk factor, 2.31 (1.23-4.33, P=0.009) for two, and 3.52 (1.80-6.87, P<0.001) for three or more. The mean hs-CRP concentration increased significantly with the increasing number of risk factors (men and women, P<0.001) and with the degree of carotid arterial stenosis (men, P=0.011; women, P=0.008). CONCLUSION: Multiple risk factors are more predictive than a single risk factor for early carotid atherosclerosis in the Japanese population.

Stroke risk of asymptomatic intra- and extracranial large-artery disease in apparently healthy adults.

BACKGROUND: The predictive value of asymptomatic intracranial artery stenosis for future stroke remains uncertain. The aim of this study is to assess the stroke risk of asymptomatic intracranial artery stenosis and to compare it with that of extracranial artery disease. METHODS: The study subjects were 2,924 participants (mean age 55 years) without any history of stroke. We examined the relation between intra- or extracranial large-artery disease and subsequent cerebrovascular events (mean follow-up 63 months). RESULTS: The incidence rate of total cerebrovascular events in persons with intracranial artery stenosis was 1.3% per year. In the group without plaque in the extracranial carotid arteries, the annual rate of total cerebrovascular events was only 0.6%, but in the group with plaque, the rate was 3.6%. Kaplan-Meier analysis of total events showed a significant difference between the 2 groups (p = 0.002). CONCLUSIONS: The stroke risk in subjects with asymptomatic extracranial artery disease is markedly increased if intracranial artery stenosis is also present.