Medical hypnotic management associated with drug dependence in patients with insomnia and neurological disorders

@#Objectives: We aimed to investigate the demographics and medical management factors associated with dependence on hypnotics among outpatients with neurological disorders and insomnia. Methods: We reviewed electronic medical records of patients who received an initial hypnotic prescription between January 2014 and January 2016 and had later visited a neurological outpatient clinic before January 2018. We assessed patient demographics, the effectiveness of hypnotics, prescription periods, and hypnotic intake methods during the follow-up period. Results: Of 242 patients diagnosed with insomnia, we enrolled 114 patients (more women than men, at 61.4 versus 38.6%) who visited outpatient clinics regularly during the follow-up period. The mean age at onset was 65.8 ± 14.4 years. The most frequent neurological disorder was cerebrovascular disease, followed by neurodegenerative disease. During the 2-year period, 35.9% of participants remained hypnotics-free. Patients on zolpidem showed significantly greater insomnia improvement with hypnotic discontinuation than those on benzodiazepines and combination therapy (p=0.004). However, the type of hypnotics and demographic factors were not found to be independent risk factors. Multivariable analysis showed that longer periods between regular visits and a lower ratio of receiving number of pills to the time interval (days) between regular visits were independent risk factors for dependence on hypnotics. Conclusions: We found that low-dose and/or intermittent intake of hypnotics as well as frequent doctor visits could prevent dependence on hypnotics. It is important to establish the best practical guidelines for medical hypnotics management in outpatient primary care settings, including neurological clinics.

Atypical parkinsonism with marked asymmetry due to a superimposed developmental venous anomaly

@#Intracranial developmental venous anomalies (DVAs) are the most common cerebral vascular malformation and are usually asymptomatic. Movement disorders are rarely associated with DVAs within basal ganglia regions. We report a case of markedly asymmetric parkinsonism due to unilateral DVA in the basal ganglia, which occurred together with symmetrical nigrostriatal dopaminergic deficits. A 57-year-old woman presented with resting tremor in the right hand lasting for 6 months. She also experienced problems with gait and started falling while walking one month ago. The neurological examination found a resting tremor in the right hand and moderate rigidity and bradykinesia in the right extremities. She reported light headedness on standing up. The patient displayed minimal response to treatment with 300 mg levodopa. The FP-CIT PET scan revealed symmetrical decrease of radiotracer uptake in bilateral basal ganglia. Brain MRI and cerebral angiography identified a large DVA draining the basal ganglia, thalamus, and surrounding deep white matter in the left side. Conclusion: A DVA may contribute to the prominent asymmetrical manifestation in our patient, in combination with symmetrical dopaminergic loss from neurodegenerative Parkinsonian syndrome. A marked asymmetry in patients with signs of atypical Parkinsonism can be a clue for further imaging investigation to exclude superimposed structural lesions such as DVAs.

Erratum to: The KMDS-NATION Study: Korean Movement Disorders Society Multicenter Assessment of Non-Motor Symptoms and Quality of Life in Parkinson's Disease NATION Study Group

The original version of this article contained wrong informations of some authors which should be changed.

The Effect of Pulsatility Index on Infarct Volume in Acute Lacunar Stroke

PURPOSE: Lacunar stroke, in the context of small vessel disease, is a type of cerebral infarction caused by occlusion of a penetrating artery. Pulsatility index (PI) is an easily measurable parameter in Transcranial Doppler ultrasound (TCD) study. PI reflects distal cerebral vascular resistance and has been interpreted as a surrogate marker of small vessel disease. We hypothesized that an increased PI, a marker of small vessel disease, might be associated with a larger infarct volume in acute lacunar stroke. MATERIALS AND METHODS: This study included 64 patients with acute lacunar stroke who underwent TCD and brain MRI. We evaluated the association between the mean PI value of bilateral middle cerebral arteries and infarct volume on diffusion-weighted MRI using univariate and multivariate linear regression. RESULTS: The mean infarct volume and PI were 482.18±406.40 mm3 and 0.86±0.18, respectively. On univariate linear regression, there was a significant positive association between PI and infarct volume (p=0.001). In the multivariate model, a single standard deviation increase of PI (per 0.18) was associated with an increase of 139.05 mm3 in infarct volume (95% confidence interval, 21.25 to 256.85; p=0.022). CONCLUSION: We demonstrated that PI was an independent determinant of infarct volume in acute lacunar stroke. The PI value measured in acute stroke may be a surrogate marker of the extent of ischemic injury.

The KMDS-NATION Study: Korean Movement Disorders Society Multicenter Assessment of Non-Motor Symptoms and Quality of Life in Parkinson's Disease NATION Study Group

BACKGROUND AND PURPOSE: Nonmotor symptoms (NMS) in Parkinson's disease (PD) have multisystem origins with heterogeneous manifestations that develop throughout the course of PD. NMS are increasingly recognized as having a significant impact on the health-related quality of life (HrQoL). We aimed to determine the NMS presentation according to PD status, and the associations of NMS with other clinical variables and the HrQoL of Korean PD patients. METHODS: We surveyed patients in 37 movement-disorders clinics throughout Korea. In total, 323 PD patients were recruited for assessment of disease severity and duration, NMS, HrQoL, and other clinical variables including demographics, cognition, sleep scale, fatigability, and symptoms. RESULTS: In total, 98.1% of enrolled PD subjects suffered from various kinds of NMS. The prevalence of NMS and scores in each NMS domain were significantly higher in the PD group, and the NMS worsened as the disease progressed. Among clinical variables, disease duration and depressive mood showed significant correlations with all NMS domains (p<0.001). NMS status impacted HrQoL in PD (rS=0.329, p<0.01), and the association patterns differed with the disease stage. CONCLUSIONS: The results of our survey suggest that NMS in PD are not simply isolated symptoms of degenerative disease, but rather exert significant influences throughout the disease course. A novel clinical approach focused on NMS to develop tailored management strategies is warranted to improve the HrQoL in PD patients.

Erratum: Analysis of Dosage Mutation in PARK2 among Korean Patients with Early-Onset or Familial Parkinson's Disease

Authors would like to change annotation of variants in Table 1 and its legend according to HGVS nomenclature recommendation.

Analysis of Dosage Mutation in PARK2 among Korean Patients with Early-Onset or Familial Parkinson's Disease

BACKGROUND AND PURPOSE: There is some controversy regarding heterozygous mutations of the gene encoding parkin (PARK2) as risk factors for Parkinson's disease (PD), and all previous studies have been performed in non-Asian populations. Dosage mutation of PARK2, rather than a point mutation or small insertion/deletion mutation, was reported to be a risk factor for familial PD; dosage mutation of PARK2 is common in Asian populations. METHODS: We performed a gene-dosage analysis of PARK2 using real-time polymerase chain reaction for 189 patients with early-onset PD or familial PD, and 191 control individuals. In the case of PD patients with heterozygous gene-dosage mutation, we performed a sequencing analysis to exclude compound heterozygous mutations. The association between heterozygous mutation of PARK2 and PD was tested. RESULTS: We identified 22 PD patients with PARK2 mutations (11.6%). Five patients (2.6%) had compound heterozygous mutations, and 13 patients (6.9%) had a heterozygous mutation. The phase could not be determined in one patient. Three small sequence variations were found in 30 mutated alleles (10.0%). Gene-dosage mutation accounted for 90% of all of the mutations found. The frequency of a heterozygous PARK2 gene-dosage mutation was higher in PD patients than in the controls. CONCLUSIONS: Heterozygous gene-dosage mutation of PARK2 is a genetic risk factor for patients with early-onset or familial PD in Koreans.

Plasma Total Homocysteine Level Is Associated with the Pulsatility Index of Cerebral Arteries in Lacunar Infarction

PURPOSE: The pulsatility index (PI), measured by transcranial Doppler (TCD), is a surrogate marker for distal vascular resistance in cerebral arteries, and elevated plasma total homocysteine (tHcyt) is regarded as a cause of ischemic stroke, including lacunar infarction. We investigated the relationship between the PI of cerebral arteries and plasma tHcyt in patients with lacunar infarction. MATERIALS AND METHODS: Plasma tHcyt level and TCD examination were performed in 94 patients with lacunar infarction. Mean flow velocity (MFV) and PI were assessed at the ipsilateral middle cerebral artery (MCA) and contralateral MCA, relative to the infarction, and the basilar artery (BA). Multivariate regression analysis was conducted between log-transformed tHcyt levels (logHcyt) and the PI of individual arteries. RESULTS: There was a significant correlation between logHcyt and the PI in all tested arteries (ipsilateral MCA: r=0.21, p=0.03; contralateral MCA: r=0.21, p=0.04; BA: r=0.35, p=0.01). In multivariate regression analysis, this significance remained unchanged after adjusting for vascular risk factors, creatinine, hematocrit and platelet count (ipsilateral MCA: beta=0.26, p=0.01; contralateral MCA: beta=0.21, p=0.04; BA: beta=0.39, p=0.001). There was no significant association between logHcyt and MFV of individual arteries. CONCLUSION: A significant association between plasma tHcyt and the PI of cerebral arteries indicates that homocysteine plays a role in the increase of distal arterial resistance in lacunar infarction.

Neurogenic Bladder in Lyme Disease / 대한배뇨장애요실금학회지

Lyme disease is a multi-systemic, tick-borne infectious disease caused by a spirochete, Borrelia burgdorferi. Various urologic symptoms are associated with Lyme disease, which can be primary or late manifestations of the disease. Although voiding dysfunction is a rarely reported symptom in patients with Lyme disease, it is one of the most disabling complications of Lyme disease. Korea is not an endemic area of Lyme disease, thus, fewer cases have been reported. Herein, we report a case of a 32-year-old man with rapidly progressive bilateral ptosis, dysphagia, spastic paraparesis, and voiding difficulty in whom Lyme disease was diagnosed through serologic tests for antibodies and Western blot testing. A urodynamic study demonstrated detrusor areflexia and bulbocavernosus reflex tests showed delayed latency, indicating demyelination at S2-S4 levels. He received a 4-week course of intravenous ceftriaxone (2 g/day). The patient has recovered from the bilateral ptosis and spastic paraparesis but still suffers from neurogenic bladder.

Association between Single Nucleotide Polymorphisms of alpha2A-, alpha2B-, and alpha2C-Adrenergic Receptor Genes and Risk of Cerebral White Matter Lesion / 대한뇌졸중학회지

BACKGROUND: An alpha2-adrenergic receptor (alpha2-AR, ADRA2) mediates induction of hypotension and inhibition of lipolysis and insulin secretion. We evaluated whether single nucleotide polymorphisms (SNPs) of alpha2A (ADRA2A), alpha2B (ADRA2B), and alpha2C (ADRA2C) adrenergic receptors are associated with cerebral white matter lesion (cWML). METHODS: Total 336 study subjects who had no stroke were enrolled in this study. The Indices of cWML include total WML (TWML), periventricular WML (PVWML), and subcortical WML (SCWML) on brain fluid-attenuated inversion recovery (FLAIR) image. Common genetic variants of ADRA2A (1780G>A), ADRA2B (Ins/Del301-303), and ADRA2C (Ins/Del322-325) were examined. RESULTS: Among 336 study subjects, cWML was found in 66 patients (20%). In multivariate analysis, there were no significant effects of all tested ADRA2 polymorphisms on TWML. Significant association of ADRA2A 1780 AA genotype was found in PVWML (OR: 3.368, 95% CIs: 1.280-8.865, adjusted p-value after false discovery rate (FDR) correction=0.014) but not SCWML. CONCLUSION: Although SNPs of three ADRA2 subtypes failed to reach a significance in overall risk for cWML, the ADRA2A 1780G>A polymorphism may be associated with development of PVWML.

Myasthenia Gravis Presenting as Isolated Respiratory Failure: A Case Report

Myasthenia gravis (MG) is often complicated by respiratory failure, known as a myasthenic crisis. However, most of the patients who develop respiratory symptoms do so during the late course of disease and have other neurological signs and symptoms. However, in some patients respiratory failure is the initial presenting symptom. We report the case of a 68-year-old woman with MG who presented with isolated respiratory failure as her first presenting symptom. As illustrated by this case, it is important to consider neuromuscular disorders in cases of unexplained respiratory failure.

Genetic Polymorphism of Thymidylate Synthase Enhancer Region (TSER) in Patients with Silent Brain Infarction

BACKGROUND: Hyperhomocysteinemia is an independent risk factor for silent brain infarction (SBI). The plasma homocysteine (pHcy) level is influenced by the activities of enzymes such as 5,10-methylenetetrahydrofolate reductase (MTHFR). Thymidylate synthase (TS) also competes with MTHFR for their common cofactor, 5,10-methylenetetrahydrofolate (5,10-meTHF). The polymorphism of thymidylate synthase enhancer region (TSER) might affect homocystein metabolism by modulating the activity of TS, and may be a determinant of SBI by elevating pHcy concentrations. Therefore, we studied the polymorphism of TSER in patients with SBI. METHODS: 98 patients with SBI and 92 healthy controls were included in the study. The genotypes of TSER and MTHFR were identified with the PCR-RFLP methods. RESULTS: The mean pHcy level was significantly higher in SBI patients (13.5+/-8.5 micro mol/L) than in controls (10.3+/-4.1 micro mol/L)(p<0.01). The frequencies of MTHFR C677T genotype and TSER 28 bp tandem repeat genotype were not different between the patients and the controls. The pHcy concentrations were not considerably different between the 3R3R and 2R3R genotypes in the population as a whole (p=0.712), nor in subsets of patients with SBI (p=0.484). However, in cases with the TSER 3R3R genotype, the pHcy level was significantly higher in patients (14.0+/-10.26 micro mol/L) than in controls (9.9+/-3.1 micro mol/L)(p=0.006). Folate and pHcy was inversely correlated in the SBI patients with the TSER 3R3R genotype (r=-0.424, p=0.039). CONCLUSIONS: Our findings suggest that the TSER genotype is not a major determinant of pHcy concentrations and is neither a risk factor for SBI in the Korean population. However, further study will be needed to confirm this findings.

A Case of Valproate-Induced Hyperammonemic Encephalopathy with Triphasic Waves / 대한간질학회지

Valproate is a widely used antiepileptic drug with rarely occurring serious side effects. However, valproate may induce hyperammonemic encephalopathy. A 85-year-old woman was admitted with stuporous mental status. Brain MRI showed old cerebral infarction and EEG showed sharp waves in the right frontal region. Under the impression of postictal confusion, we used phenytoin and then she was improved. However, the intermittent vacant staring was seen, and valproate was administered additionally. On the 5th day after adding valproate, her mentality was deteriorated and intermittent triphasic waves appeared on EEG. Due to confused mentality and hyperactivities, we injected lorazepam and then semicomatous mentality was developed. Follow-up EEG showed nearly continuous triphasic waves and slightly elevated ammonia with normal liver function was shown. After stopping antiepileptic drugs, we used lactulose and flumazenil, and then she was fully recovered with normalized EEG. This is a rare case of valproate-induced hyperammonemic encephalopathy with triphasic waves.

The Relationship of Methylenetetrahydrofolate Reductase(MTHFR) C677T, Thymidylate Synthase(TS) Gene Polymorphism and Epilepsy / 대한간질학회지

PURPOSE: Thymidylate synthase (TS) gene encodes a tightly regulated enzyme that catalyzes the conversion of deoxyuridylate to thymidylate, and contains a tandem repeat polymorphism, of which a triple repeat is associated with increased expression of TS. TS is a key enzyme in the folate metabolism and compete with methylenetetrahydrofolate reductase (MTHFR) for limiting supplies of folate required for the remethylation of homocysteine. We studied to clarify the association between MTHFR C677T and TS polymorphism and prognosis in epilepsy. METHODS: 119 patients with antiepileptic drug more than one year were included. We investigated the MTHFR C677T and TS polymorphism using PCR, and analyzed the association between plasma homocysteine, folate levels, clinical profiles (especially seizure frequencies) and polymorphism. RESULTS: In seizure frequencies during one year, TT type in MTHFR and 3R3R type in TS polymorphism had higher frequencies than any other types without statistical significance. In plasma homocysteine levels, TT type had significantly higher homocsyteine levels than any other types, but 3R3R type had higher homocsyteine levels than any other types without statistical significance. Combined analysis of MTHFR C677T and TS polymorphism revealed that plasma homocysteine levels (18.22+/-8.32 micromol/l; p=0.039) and seizure frequencies (6.38+/-7.35/year; p=0.04) in patients with TT/3R3R were significantly higher than any other groups. A significant correlation between plasma homocysteine levels and seizure frequencies also was shown in multivariate linear regression analysis (B=0.160, Std error=0.069, adjusted R2=0.039, p=0.021). CONCLUSION: Epileptic patients with hyperhomocysteinemia, especially when combined with mutant allele for MTHFR and TS genes, have higher seizure frequencies. Therefore, our results suggest that the genotyping for the MTHFR and TS polymorphism may become a useful indicator in determining prognosis of epilepsy.

A Case of Epilepsia Partialis Continua after Gamma Knife Radiosurgery / 대한간질학회지

The gamma knife radiosurgery (GKS) is a safe and effective neurosurgical approach in the treatment of arteriovenous malformation (AVM). Seizures after GKS are rarely reported, but epilepsia partialis continua (EPC) has not been reported yet. We report a patient with EPC accompanied with cerebral edema after GKS in AVM. A 50-year-old man was admitted for EPC, dysarthria and monoparesis 20 days after GKS due to AVM. Brain MRI showed increased cerebral edema around AVM in the left premotor area. Symptoms were relieved by IV dexamethasone and antiepileptic drugs (AEDs). 15 weeks later, EPC recurred and aphasia and right hemiplegia were rapidly aggravated. The follow up brain MRI showed markedly increased cerebral edema compared with previous MRI. EPC was well controlled by AEDs, but aphasia and hemiplegia were not responsive to IV dexamethasone until trying oral prednisolon. We think that cerebral edema induced by EPC, as a complication of GKR, might aggravate hemiparesis.

Urodynamic Study in Patients with Myelitis

BACKGROUND: Voiding disturbance is one of the frequent symptoms of myelitis. Clinical manifestations of urinary disturbance in the patients with myelitis are results of the specific neurological lesion of the spinal cord, but can be varied. To determine the relationship between the neurological spinal cord level and bladder dysfunction, we nalyzed the urodynamic study in 30 patients with myelitis with urinary symptoms. Neurological examination and spinal MR imaging determined the clinical and radiological spinal cord levels. Urodynamic findings were classified as detrusor hyperreflexia (DH), detrusor-external sphincter dyssynergia (DSD), detrusor areflexia/hyporeflexia (DA) or normal. We analyzed the correlation between the neurological spinal level and urodynamic findings. RESULTS: Among the 30 patients, 14 patients were revealed DA, 8 were DH, 2 were DSD, and 6 were normal. Of 22 cervicothoracic lesions, 9 had DA, 7 had DH and 2 had DSD, but 4 had normal urodynamic findings. Four lumbar and sacral lesions had DA. CONCLUSIONS: The Urodynamic study finding in the lumbosacral lesion revealed DA, but, in those with cervicothoracic lesion are varied including DA, DH, DSD and normal. Urodynamic evaluation may provide more information for management of neurourological dysfunction.

Urodynamic Study in Patients with Myelitis

BACKGROUND: Voiding disturbance is one of the frequent symptoms of myelitis. Clinical manifestations of urinary disturbance in the patients with myelitis are results of the specific neurological lesion of the spinal cord, but can be varied. To determine the relationship between the neurological spinal cord level and bladder dysfunction, we nalyzed the urodynamic study in 30 patients with myelitis with urinary symptoms. Neurological examination and spinal MR imaging determined the clinical and radiological spinal cord levels. Urodynamic findings were classified as detrusor hyperreflexia (DH), detrusor-external sphincter dyssynergia (DSD), detrusor areflexia/hyporeflexia (DA) or normal. We analyzed the correlation between the neurological spinal level and urodynamic findings. RESULTS: Among the 30 patients, 14 patients were revealed DA, 8 were DH, 2 were DSD, and 6 were normal. Of 22 cervicothoracic lesions, 9 had DA, 7 had DH and 2 had DSD, but 4 had normal urodynamic findings. Four lumbar and sacral lesions had DA. CONCLUSIONS: The Urodynamic study finding in the lumbosacral lesion revealed DA, but, in those with cervicothoracic lesion are varied including DA, DH, DSD and normal. Urodynamic evaluation may provide more information for management of neurourological dysfunction.

The Effect of Subthalamic Nucleus Stimulation in Patients with Advanced Idiopathic Parkinson's Disease

BACKGROUND: To determine the efficacy and safety of subthalamic nucleus (STN) stimulation in patients with advanced Parkinson's disease (PD). METHODS: In 5 patients with PD, we evaluated the effect of bilateral STN stimula-tion. Using the Unified PD Rating Scale (UPDRS), Clinical Dyskinesia Rating Scale, Activities of Daily Living(ADL) Score and patient's diary, we evaluated the patients before and at one, three and 12 months after surgery. We examined the patients while they were drug "off" and "on". RESULTS: While patients were "off", stimulation induced a signifi-cant reduction in the UPDRS part III score by 46% at 12 months after the operation, compared to the baseline state. During drug "on" state, levodopa-induced dyskinesias were reduced by 88% at 12 months after the operation. Off-peri-od dystonia was reduced by 45% at 12 months after the operation. ADL scores also improved after the stimulation. Patients' diaries showed significant reduction in the "off" period while awake (73% reduction at 12 months). The daily dose of levodopa was reduced by 56% at 12 months after the operation. There was no significant complication related to the surgical procedure or electrical stimulation. CONCLUSIONS: We conclude that STN stimulation is an effective and safe treatment strategy for the patients with advanced PD.

Single oral levodopa challenge test in de novo patients with idiopathic Parkinson's disease and multiple system atrophy

BACKGROUND: In the previous literature, single oral levodopa challenge test has been reported as one of the methods differentiating multiple system atrophy (MSA) from idiopathic Parkinson's disease (IPD). However many of the patients included in these studies had been on levodopa treatment for a variable period when they were examined. We performed this study to determine the value of single oral levodopa challenge test in differential diagnosis between IPD and MSA. METHODS: After a single oral dose of SinemetR(25/250), we assessed the improvement of motor function in 54 de novo patients with parkinsonian symptoms (33 with IPD and 21 with probable MSA). We measured the time taken to finish 20 taps with unilateral hand on two marks separated 20 cm apart and to walk 10 meter from a sitting position and return. Such performances were assessed 5 times before the medication, every 15 min for first 2 hrs after the medication, and then every 30 min for the next 4 hrs. RESULTS: The mean of the age, mean of the duration of disease and mean of the Hoehn and Yahr scale score were not significantly different between the patients with IPD and those with MSA. The mean of the unified Parkinson's disease rating scale score between the patients with IPD and MSA was not significantly different. Baseline scores of the hand and the walking performance were not significantly different. The median of the time interval between the levodopa intake and maximum beneficial effects, mean of the objective improvement at the peak, and mean of the amount of maximum subjective improvement comparing to the baseline was not significantly different between the patients with IPD and MSA. Also there were no significant differences in all measurements between the patients with striatonigral and olivopontocerebellar type of MSA. CONCLUSIONS: These findings suggest that single oral levodopa challenge test is not so helpful for the differential diagnosis between de novo patients with IPD and MSA.

Two Cases of Acute Cerebellitis

Acute cerebellitis occurrs in the absence of cerebral hemispheric involvement and is exceptionally rare. It is charac-terized by an acute onset of cerebellar dysfunction following a respiratory, gastrointesitnal infection or skin rash. However, almost all patients show good prognosis. We experienced two cases of acute cerebellitis in young adults. One patient was admitted due to gait ataxia and dysarthria. The immunological laboratory findings revealed an acute Ebstein Barr virus infection and an electronystagmogram showed a periodic alternating nystagmus. The other patient was admitted due to severe gait ataxia, with no identification of any organism. CSF examinations revealed elevated protein and brain magnetic resonance images showed cerebellar foliae enhancement bilaterally. Both patients recovered without any disabilities.