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OBJECTIVES: Voriconazole serum concentration, which is affected by several factors, is associated with treatment response and toxicity. There is paucity of data on voriconazole therapeutic drug monitoring (TDM) among Southeast Asians, who exhibit a higher prevalence of CYP2C19-poor metabolisers compared with Caucasians and East Asians. Hence, there are concerns for higher risk of voriconazole accumulation and toxicity. We aim to determine the utility of voriconazole TDM through establishing: (1) proportion of patients achieving therapeutic troughs without dose adjustments; (2) characterisation of patients with sub-therapeutic, therapeutic and supra-therapeutic levels; (3) appropriate dose titrations/dose required for therapeutic troughs; (4) correlation between troughs and adverse events, treatment response/fungal breakthrough. PATIENTS AND METHODS: A single-centre retrospective analysis of data from adults (≥21 years old) with ≥1 voriconazole trough measured at Singapore General Hospital from 2015 to 2017 was performed. RESULTS: Thirty-two patients (45.7%) among 70 patients achieved therapeutic troughs (defined as 2.0-5.5 mg/L) without dose adjustments. Eleven patients (15.7%) experienced hepatotoxicity (troughs 0.5 to >7.5 mg/L). Neurotoxicity occurred in three patients (4.3%) (troughs ≥6.7 mg/L) and all patients had symptom resolution upon dose reduction. Treatment failure of invasive fungal infection appeared less in patients with therapeutic troughs compared with sub-therapeutic troughs (11.4% vs. 14.2%). Two patients experienced treatment failure despite supra-therapeutic voriconazole troughs. CONCLUSIONS: TDM should be implemented due to significant unpredictability in dose exposure. TDM can reduce unnecessary switches to alternatives due to intolerability and rule in the possibility of resistant organisms in the event of treatment failure despite therapeutic troughs, alerting clinicians to switch to alternatives promptly.

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BACKGROUND: The relationship between a number of primary sleep disorders and Parkinson's disease (PD) is still debated. There are limited case control polysomnographic studies in PD and most of these study sample sizes are small. METHODOLOGY/FINDINGS: We conducted one of the largest case-control studies involving overnight polysomnographic evaluation, with prospective recruitment of unselected Parkinson's disease patients and healthy controls from an Asian population. The cases were recruited from the specialized movement disorder outpatient clinics in a tertiary referral center, and controls from the same geographical locations. All subjects underwent an overnight polysomnographic study and a multiple sleep latency test. A total of 124 subjects including 56 patients and 68 controls frequency-matched for age and sex were included. Multivariate analysis revealed that patients had significantly shorter total sleep time than controls (p = 0.01), lower sleep efficiency (p = 0.001) and increased REM latency (p = 0.007). In patients, multivariate analysis showed that reduced total sleep time was significantly associated with increased age (p = 0.001) and increased levodopa dose (p = 0.032). The mean Insomnia Severity Index was higher in PD patients (9.0±7.1) compared to controls (3.3±3.9, p<0.001). The mean Epworth Sleepiness Scale score was higher in PD patients (9.3±5.9 vs. 5.7±4.8, p<0.001). Nocturnal arousals, obstructive sleep apnea, periodic leg movements and objective abnormal sleepiness were not increased in our patients. CONCLUSIONS/SIGNIFICANCE: Our case-control polysomnographic study, the first-ever performed in an Asian population, revealed altered sleep architecture and reduced sleep in PD patients compared to controls. Reduced total sleep time was associated with increased age and levodopa dose. However, nocturnal arousals, primary sleep disorders and abnormal sleepiness were not increased in our PD patients suggesting that ethnic/genetic differences may be a factor in the pathophysiology of these conditions.

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OBJECTIVE: Electrodiagnostic evaluation of distal sensorimotor neuropathy can be technically challenging. Conventional nerve conduction studies (NCS) often include unilateral upper and lower limb evaluation for patients with suspected sensorimotor peripheral neuropathy. For patients with predominantly lower extremity complaints, NCS of both lower limbs are performed occasionally. Side-to-side NCS parameters have not been adequately addressed. METHODS: We performed NCS prospectively on 132 patients presenting with complaints of bilateral numbness or weakness in the extremities and 45 normal controls. The laterality index (LI) was defined as ratio of the smaller to the larger amplitude in a sensory or motor NCS, as a novel side-to-side comparison parameter. RESULTS: Ten patients had at least 1 sensory or motor NCS with LIs exceeding that of normal controls. Patients 1-7 (group 1) had diagnoses of autoimmune or neoplasia-related conditions and all had 3 or more NCS with abnormal LIs. In contrast, patients 8-10 (group 2) had diabetes mellitus and all had 2 or less NCS with abnormal LIs (unpaired t test; P = 0.002). In group 1, patients 1-4, 6, and 7 all had both upper and lower limb LI abnormalities. In contrast, only 1 patient (patient 9) had upper limb LI abnormality in group 2. CONCLUSIONS: Patients with abnormal LIs were uncommon in our cohort. Patients with diabetes mellitus had significantly less abnormal LIs than those with autoimmune or neoplasia-related etiologies. There is evidence of vasculitic inflammation documented in diabetic neuropathy. However, this process may be significantly less prominent compared with the former 2 conditions. Our findings of predominantly lower limb LI abnormalities suggest the presence of a length-dependent distal neuropathic process in diabetes mellitus. The LI is a simple and useful adjunct to detect asymmetrical NCS abnormalities. It may also provide helpful information regarding the underlying etiology.

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INTRODUCTION: Comprehensive sleep architecture and respiratory event data in local patients with suspected obstructive sleep apnoea (OSA) from overnight polysomnography (PSG), the gold standard for the evaluation of sleep-related breathing disorders, are not widely available. We present 1 year retrospective PSG data with the objective of describing PSG characteristics of patients evaluated for OSA in Singapore. MATERIALS AND METHODS: PSG data of patients evaluated for OSA in 1 year (January through December 2005) in the Sleep Laboratory of a public tertiary hospital were retrospectively reviewed. RESULTS: Five hundred and eighty-four diagnostic PSG studies were performed in patients with symptoms suggestive of sleep-disordered breathing, including snoring, excessive daytime sleepiness, unrefreshing sleep, or recurrent unexplained awakenings. There were 449 male patients (76.9%) and 135 female patients (23.1%), with a mean age of 47.5 years (SD 12.7). Men were on average younger than women, 46.1 years versus 52.0 years (P <0.0005). The mean body mass index (BMI) was 27.9 (SD 6.7), with no significant difference between genders. An association was shown between apnoea-hypopnoea index (AHI) and BMI (Pearson correlation index r = 0.362). Men had overall significantly higher AHI (16.5 vs 9), shorter mean sleep onset latency (11 vs 16.5 minutes), more light sleep (65.5% vs 58.9%), less deep sleep (17.7% vs 23%), and more respiratory event related arousals per hour of sleep (11.6 vs 5.1) (P <0.0005). Severity was classified: AHI <5 ("Normal Overall AHI") (28.3%), AHI 5-15 ("Mild") (22.3%), AHI >15-30 ("Moderate") (18.3%), AHI >30 ("Severe") (31.2%). There was no significant age difference among the 4 groups. More severe OSA patients were significantly heavier, and had more light sleep, less deep sleep, less REM sleep, more respiratory event related arousals and lower levels of oxygen desaturation. CONCLUSION: OSA is predominant in middle-aged, overweight Singapore males and much less common in females who tend to be older. A majority of patients have moderate to severe OSA, which significantly disturbs normal sleep architecture. The relatively lower BMI compared to Caucasian OSA populations may be related to local craniofacial characteristics and/or higher percentage of body fat for BMI which has been described in Singaporeans.

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Restless legs syndrome (RLS) is a poorly understood sleep-related movement disorder which can be primary or associated with other conditions, most commonly iron deficiency, uremia and peripheral nerve disease. We present a case of RLS with an unusual secondary cause: primary hyperparathyroidism with hypercalcemia. This patient experienced complete and sustained relief of RLS symptoms immediately after parathyroidectomy, with normalization of her serum parathyroid hormone (PTH) and calcium levels. Early recognition and treatment of this uncommonly detected underlying cause is important because it is potentially curative in this frequently disabling condition for which usually only symptomatic treatment is available.

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Levetiracetam is a relatively new antiepileptic drug, which has been reported to have promising antimyoclonic properties, especially in posthypoxic myoclonus, progressive myoclonic epilepsy (PME) and spinal myoclonus. Eight patients with intractable myoclonus of various etiologies were given levetiracetam as add-on therapy in an open-label trial. Physician and patient self-assessments were recorded over 1 year. Symptomatic improvement occurred only with posthypoxic myoclonus, which was rapid, dramatic and sustained. All other forms of myoclonus either did not improve or worsened (1 essential myoclonus, 2 myoclonus-dystonia, 2 PME, 2 mitochondrial disease). Levetiracetam has promising but selective antimyoclonic potential, which should be the subject of further study.

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