Factors affecting mortality of refractory status epilepticus.

OBJECTIVE: The aim of this study was to determine the factors affecting the mortality of refractory status epilepticus (RSE) in comparison with non-refractory status epilepticus (non-RSE). MATERIAL-METHOD: Included in this retrospective study were 109 status epilepticus cases who were hospitalized in the neurological intensive care unit Katip Celebi University. Fifty-two were RSE and 57 were non-RSE. All clinical data were gathered from the hospital archives. Factors which may cause mortality were categorized for statistical analysis. RESULTS: While elderly age, continuous clinical seizure activity, absence of former seizure, infection, prolonged stay of ICU, anesthesia, and cardiac comorbidity were significantly related to mortality in the RSE subgroup, potentially fatal accompanying diseases were significantly related to mortality in the non-RSE subgroup. No significant relationship was found between mortality and refractoriness. Multivariate analysis revealed that a Glasgow Coma Score (GCS) at presentation of 8 or lower was the independent predictor of mortality both in the general SE population (P = .017) and in the RSE subgroup (P = .007). Intubation (P = .011) and hypotension (P = .011) were the other independent predictors of mortality in the general SE population. No independent predictor of mortality was detected in the non-RSE subgroup. DISCUSSION/CONCLUSION: Intubation, hypotension, and a low GCS at presentation could be the main factors which could alert clinicians of an increased risk of mortality in SE patients. Although non-RSE and RSE had similar rates of mortality in the ICU, the mortality-related factors of SE vary in the RSE and the non-RSE subgroups.

Differences in obsessive-compulsive symptom dimensions between patients with epilepsy with obsessive-compulsive symptoms and patients with OCD.

Clinical correlates of obsessive-compulsive symptoms (OCS) were evaluated in 100 adult consecutive outpatients with epilepsy, using the Obsessive-Compulsive Inventory (OCI-R), Beck Depression Inventory (BDI), Dissociative Experiences Scale (DES-II), and the Schizotypal Personality Questionnaire (SPQ). Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS) was applied to determine the types and severity of OCS to the 45 patients with epilepsy who were over 21 points on the OCI-R scale and 30 patients who were with diagnosed obsessive-compulsive disorder (OCD) among the patients in the psychiatry outpatient clinic, as a control group. As a result, it was found that patients with epilepsy with OCS tend to have more symmetry/exactness obsessions and compulsions, whereas patients with OCD had significantly more contamination/cleaning and aggressiveness obsessions and compulsions. In addition, OCS was found to be significantly higher in temporal lobe epilepsy (TLE) and extratemporal epilepsy than generalized epilepsy. However, OCS were correlated with depression, dissociation, and schizotypy in patients with epilepsy, while only depression was predictive when regression analysis was performed for OCS. This study is the first study to compare patients with OCD with patients with epilepsy in terms of the nature of OCS and first identified the differences in OCS dimensions between patients with epilepsy with OCS and patients with OCD.

Gender-Related Differences in Semiology of Psychogenic Non-Epileptic Seizures.

INTRODUCTION: The aim of the study is to detect possible gender-related differences in the semiology of psychogenic non-epileptic seizures (PNES). METHODS: One hundred fifty-five patients (male: female=63:92) aged 13 to 67 years, who were diagnosed with PNES by video-monitoring electroencephalogram (EEG) between 2010 and 2017, were included in this retrospective study. Patients were grouped according to their gender. The primary semiological characteristics of PNES for each case were defined, standardized, and categorized by an epileptologist during video-monitoring EEG. The chi-square test and the Fisher exact test were used statistically. RESULTS: An age histogram showed peaks at ages 20 to 23 and at ages 40 to 43, which were more prominent in the female gender. Whereas major motor activity (p=0.032), lateralizing motor activity (p=0.017), and opisthotonic posture and pelvic thrust motion (p=0.017) were significantly related to the male gender, weeping (p<0.001) was significantly related to the female gender. CONCLUSION: Our study showed that there are some semiological differences between the genders in PNES. In male patients, lateralized motor findings are more prominent and not accompanied by ictal crying in seizures, which may lead to further confusion with epileptic seizures. It is important to know the semiological characteristics for early and accurate diagnosis.

Effects of low-frequency repetitive transcranial magnetic stimulation and neuromuscular electrical stimulation on upper extremity motor recovery in the early period after stroke: a preliminary study.

OBJECTIVE: To assess the efficacy of inhibitory repetitive transcranial magnetic stimulation (rTMS) and neuromuscular electrical stimulation (NMES) on upper extremity motor function in patients with acute/subacute ischemic stroke. METHODS: Twenty-five ischemic acute/subacute stroke subjects were enrolled in this randomized controlled trial. Experimental group 1 received low frequency (LF) rTMS to the primary motor cortex of the unaffected side + physical therapy (PT) including activities to improve strength, flexibility, transfers, posture, balance, coordination, and activities of daily living, mainly focusing on upper limb movements; experimental group 2 received the same protocol combined with NMES to hand extensor muscles; and the control group received only PT. Functional magnetic resonance imaging (fMRI) scan was used to evaluate the activation or inhibition of the affected and unaffected primary motor cortex. RESULTS: No adverse effect was reported. Most of the clinical outcome scores improved significantly in all groups, however no statistically significant difference was found between groups due to the small sample sizes. The highest percent improvement scores were observed in TMS + NMES group (varying between 48 and 99.3%) and the lowest scores in control group (varying between 13.1 and 28.1%). Hand motor recovery was significant in both experimental groups while it did not change in control group. Some motor cortex excitability changes were also observed in fMRI. CONCLUSION: LF-rTMS with or without NMES seems to facilitate the motor recovery in the paretic hand of patients with acute/subacute ischemic stroke. TMS or the combination of TMS + NMES may be a promising additional therapy in upper limb motor training. Further studies with larger numbers of patients are needed to establish their effectiveness in upper limb motor rehabilitation of stroke.

GNE Myopathy in Turkish Sisters with a Novel Homozygous Mutation.

Background. Hereditary inclusion body myopathy is caused by biallelic defects in the GNE gene located on chromosome 9p13. It generally affects adults older than 20 years of age. Methods and Results. In this study, we present two Turkish sisters with progressive myopathy and describe a novel mutation in the GNE gene. Both sisters had slightly higher levels of creatine kinase (CK) and muscle weakness. The older sister presented at 38 years of age with an inability to climb steps, weakness, and a steppage gait. Her younger sister was 36 years old and had similar symptoms. The first symptoms of the disorder were seen when the sisters were 30 and 34 years old, respectively. The muscle biopsy showed primary myopathic features and presence of rimmed vacuoles. DNA analysis demonstrated the presence of previously unknown homozygous mutations [c.2152 G>A (p.A718T)] in the GNE genes. Conclusion. Based on our literature survey, we believe that ours is the first confirmed case of primary GNE myopathy with a novel missense mutation in Turkey. These patients illustrate that the muscle biopsy is still an important method for the differential diagnosis of vacuolar myopathies in that the detection of inclusions is required for the definitive diagnosis.

Correlation between hippocampal sulcus width and severity of obstructive sleep apnea syndrome.

The aim of the present study was to evaluate the relationship between obstructive sleep apnea syndrome (OSAS) severity and the hippocampal sulcus width in a cohort of subjects with OSAS and controls. A total of 149 OSAS patients and 60 nonapneic controls were included in the study. Overnight polysomnograpy was performed in all patients. Hippocampal sulcus width of the patients was measured by a radiologist blinded to the diagnosis of the patients. Other variables noted for each patient were as follows: gender, age, body mass index, apnea hypopnea index, Epworth sleepiness scale, sleep efficacy, mean saturation, lowest O2 saturation, longest apnea duration, neck circumference, waist circumference, hip circumference. A total of 149 OSAS patients were divided into three groups: mild OSAS (n = 54), moderate OSAS (n = 40), severe OSAS (n = 55) groups. The control group consisted of patients with AHI <5 (n = 60). Hippocampal sulcus width was 1.6 ± 0.83 mm in the control group; while 1.9 ± 0.81 mm in mild OSAS, 2.1 ± 0.60 mm in moderate OSAS, and 2.9 ± 0.58 mm in severe OSAS groups (p < 0.001). Correlation analysis of variables revealed that apnea hypopnea index (rs = 0.483, p < 0.001) was positively correlated with hippocampal sulcus width. Our findings demonstrated that severity of OSAS might be associated with various pathologic mechanisms including increased hippocampal sulcus width.

The association of nocturia with sleep disorders and metabolic and chronic pulmonary conditions: data derived from the polysomnographic evaluations of 730 patients.

AIM: To evaluate the prevalence of nocturia among different degrees of obstructive sleep apnea (OSA) and its association with various clinical conditions. MATERIALS AND METHODS: In 730 OSA patients, the prevalence and frequency of nocturia was determined, and the association of nocturia with clinical and laboratory variables such as the apnea-hypopnea index (AHI), apnea duration, and minimum oxygen saturation and clinical conditions such as diabetes mellitus, coronary heart disease, and chronic obstructive pulmonary disease (COPD) was determined. RESULTS: The overall prevalence of nocturia (≥2 wakes/night) was 50.9%. Prevalences ofnocturia in simple snoring and mild, moderate, and severe OSA patients were 40.6%, 44.4%, 58.6%, and 57.1%, respectively (P < 0.005). The frequency of nocturia significantly increases with the severity of OSA (1.4 ± 1.0 wakes/night in mild OSA vs. 2.0 ? 1.4 wakes/night in severe OSA, P = 0.001). Age, AHI, average oxygen saturation, and presence of diabetes mellitus, hypertension, and COPD were found to be significant risk factors associated with nocturia (P <0.001). CONCLUSION: The frequency of nocturia increases as the severity of OSA increase. The increased prevalence of nocturia in patients with OSA, diabetes mellitus, hypertension, and COPD indicates the complex physiological background of this bothersome urologic symptom.

Histopathological and genetic features of patients with limb girdle muscular dystrophy type 2C.

OBJECTIVE: In this study, it was aimed to describe the clinical, histopathological and genetic features of 20 patients with gamma sarcoglycanopathy confirmed by muscle biopsies and genetic analysis. MATERIAL AND METHOD: We retrospectively reviewed 20 patients from whom muscle biopsy specimens were obtained between 2007 and 2012. All patients were clinically diagnosed as muscular dystrophy and biopsy materials were collected from five different centers of neurological disorders. All DNAs were extracted from muscle tissues or blood samples of patients and genetic tests (mutation analyses for gamma sarcoglycan gene and deletion-duplication analyses for all 4 sarcoglycan genes) were performed. RESULTS: The mean age of the patients was 7.6 years (2 -21 years). Only one case (5%) was older than 14 years. The mean CPK level was 10311 U/L (1311 - 35000 U∕L). There were 4 siblings in these series. Expression defects of gamma sarcoglycan staining were determined in (15 males, and 5 females) all patients with muscle biopsy specimens. But only in 9 of them, disease-causing defects could be determined with genetic analyses. CONCLUSION: The present study has demonstrated that both examination of muscle biopsy specimens and DNA analysis remain important methods in the differential diagnosis of muscular dystrophies. Because dystrophinopathies and sarcoglycanopathies have similar clinical manifestation.

Spinal reflexes in brain death.

Spontaneous and reflex movements have been described in brain death and these unusual movements might cause uncertainties in diagnosis. In this study we evaluated the presence of spinal reflexes in patients who fulfilled the criteria for brain death. Thirty-two (22 %) of 144 patients presented unexpected motor movements spontaneously or during examinations. These patients exhibited the following signs: undulating toe, increased deep tendon reflexes, plantar responses, Lazarus sign, flexion-withdrawal reflex, facial myokymia, neck-arm flexion, finger jerks and fasciculations. In comparison, there were no significant differences in age, sex, etiology of brain death and hemodynamic laboratory findings in patients with and without reflex motor movement. Spinal reflexes should be well recognized by physicians and it should be born in mind that brain death can be determined in the presence of spinal reflexes.

Carotid intima-media thickness increase in patients with habitual simple snoring and obstructive sleep apnea syndrome is associated with metabolic syndrome.

OBJECTIVES: Sleep disorders are emerging risk factors for atherosclerosis. Increased carotid intima-media thickness (CCA-IMT) is a surrogate marker of cardiovascular risk. The aim of the present study was to investigate the relationship between CCA-IMT and habitual simple snoring or obstructive sleep apnea syndrome (OSAS) and the other cardiovascular risk factors. METHODS: Sleep disorders were diagnosed and staged by polysomnography. Patients were then classified into either habitual simple snoring (n = 20, group 1) or OSAS (n = 67, group 2), which was subclassified as mild-moderate (n = 27) or severe (n = 40). CCA-IMT was measured by B-mode ultrasonography. The other major risk factors were investigated. RESULTS: The mean CCA-IMT was 0.65 ± 0.02 mm (mean ± SD) in group 1 versus 0.75 ± 0.02 mm in group 2 (p = 0.03). Using CCA-IMT ≥ 0. 9 mm as the threshold value also yielded significant results between the two groups (p = 0.03). The mean CCA-IMT did not differ between patients with mild-moderate and severe OSAS, whereas metabolic risk factors and metabolic syndrome (MS) were more prominent in the latter. Age, MS, neck and waist circumference, waist/ hip circumference, and fasting glucose level were higher in patients with CCA-IMT ≥ 0.9 mm. CONCLUSIONS: CCA-IMT increase was associated with OSAS, but did not correlate with its severity, which could be due to the higher incidence of MS in this group.

Diagnostic value of lumbar root stimulation at the early stage of Guillain-Barré syndrome.

OBJECTIVE: The aim of this study is to investigate diagnostic value of electrical lumbar root stimulation (RS) at the laminar level in the early stage of Guillain-Barré syndrome (GBS). METHODS: Fifteen patients (30 sides) and nine controls (17 sides) were included in the study. Conventional nerve conduction studies, needle electromyography, F responses and electrical lumbar RS were obtained from both groups. The needle electrical stimulation was performed at the L2-3 intervertebral level. Vastus lateralis, tibialis anterior and soleus muscles were investigated bilaterally and simultaneously in the first and fourth weeks. RESULTS: In all patients, the amplitudes elicited by lumbar RS were significantly attenuated while the conventional electrophysiological findings were normal and/or not diagnostic in 6 of 15 patients (40%) within the first week. Motor latencies by the lumbar RS were prolonged in the patients, compared to the controls, but the results were not statistically significant. CONCLUSIONS: M-responses elicited by lumbar RS appear to be helpful in disclosing proximal conduction abnormalities of GBS early in the course. SIGNIFICANCE: Lumbar RS seems to be a useful method in making the diagnosis of GBS early and there is no considerable side effect of this particular method.

A regional panorama of dysferlinopathies.

OBJECTIVE: We describe the characteristic features of 11 patients (6 men and 5 women) with dysferlinopathies confirmed by muscle biopsies. In addition, we aimed to provide a realistic comprehensive picture of the severe muscle diseases in the Aegean Region of Turkey. MATERIAL AND METHOD: We retrospectively reviewed 90 patients who underwent muscle biopsy examinations between 2008 and 2011 in the pathology laboratory of Izmir Dr.Behcet Uz Children's Hospital. Biopsy specimens of all patients clinically diagnosed as muscular dystrophy referred from 4 different centers of neurological disorders were collected. RESULTS: Dystrophinopathy was the most (n=45) and gammasarcoglycanopathy was the second common (n=13) muscular dystrophy in this series. The mean age of all 90 patients was 8.8 years (3 months- 64 years). Only 14 cases (15.5%) were older than 14, and 23 cases were younger than two years. Dysferlinopathy was the most common dystrophy in the older age group. There were statistical significant differences between the types of dystrophy and inflammation (0.021), creatine kinase levels (p= 0.001), age (p=0.001), and gender (p < 0.001) of the patients. CONCLUSION: The present study revealed that dysferlinopathies is not an uncommon form of muscular dystrophies in western Turkey. We have concluded that if avoidance from unnecessary therapeutic interventions is desired, we must be aware of the relative frequencies of dysferlinopathies.

Ability of emergency physicians to detect early ischemic changes of acute ischemic stroke on cranial computed tomography.

OBJECTIVE: The objective of this study was to evaluate the ability of emergency physicians (EPs) to diagnose early ischemic changes due acute ischemic stroke on cranial computed tomography (CT). SUBJECTS AND METHODS: Three EPs interpreted CT scans obtained within 3 h of symptom onset in 50 patients with acute stroke. The CT scans were interpreted by the EPs and compared to official neuroradiologist reports as a gold standard. ĸ statistics were calculated to determine agreement among the three readers. Sensitivities and specificities were analyzed for each reader. RESULTS: The EPs' sensitivities were 50, 45.5, and 45.5%, and specificities were 64.3, 82.1, and 64.3%, respectively. Focal parenchymal hypodensity was the criterion for which the EPs were the most sensitive (77.3%). The ability of EPs to recognize early ischemic changes on CT scans in acute ischemic stroke was moderate based on sensitivities. CONCLUSION: Based on this study, EPs must be trained especially for recognizing early ischemic changes in acute ischemic stroke to improve their accuracy of interpretation.

Sleep analysis of patients with nocturia and benign prostatic obstruction.

OBJECTIVE: To analyze the timing of nocturia during sleep and its effect on sleep quality using the polysomnography (PSG) findings from patients with benign prostatic obstruction. METHODS: From August 2009 to August 2010, 20 patients diagnosed with benign prostatic obstruction were enrolled in the present study. The sleep evaluation was performed by PSG. The Epworth index was used to evaluate the sleepiness of the patients. The effect of nocturia on sleep quality is evaluated by sleep efficacy, total sleep time, and rapid eye movement sleep duration, calculated from the hypnograms derived from the polysomnograms. RESULTS: The mean age, total International Prostate Symptom Score, nocturia frequency on International Prostate Symptom Score, and frequency of nocturia recorded during PSG was 60.4 ± 8.5 years (range 44-74), 19.3 ± 4.9 (range 10-28), 3.5 ± 1.05 (range 2-5), and 1.35 ± 1.2 (range 0-4), respectively. In 6 patients (30%), the Epworth sleepiness score was pathologic (score >8). Nocturia correlated positively with increased daytime sleepiness, however it did not correlate with sleep efficacy or total sleep time. These parameters were affected by the apnea-hypopnea index, the major determinant of obstructive sleep apnea. Of the 20 patients, 14 (70%) experienced nocturia during PSG, and in these patients, we recorded 23 nocturia episodes that mostly occurred in the superficial sleep stage (16 [70%] of 23). Only 7 nocturia episodes (30%) occurred in the deep sleep stage. The sleep quality of patients with deep sleep nocturia did not differ from that of patients with superficial sleep nocturia. CONCLUSION: The results of our study have shown that nocturia predominantly occurs during the superficial sleep or rapid eye movement stage and is related to increased daytime sleepiness in patients with benign prostatic obstruction. The timing and frequency of nocturia had no significant affect on sleep quality; however, the presence of obstructive sleep apnea negatively interfered with these parameters.

Cerebral oxygenation during sleep in patients with obstructive sleep apnea: a near-infrared spectroscopy study.

OBJECTIVE: The aim of the present study was to investigate cerebral hemodynamics in patients with sleep-disordered breathing of variable severity using cerebral near-infrared spectroscopy. DESIGN: Prospective study. SETTING: Tertiary training and research hospital. METHODS: The study was performed in patients referred for daytime sleepiness, habitual nocturnal snoring, and witnessed apnea spells from October 2009 to March 2010. Full-night polysomnography was coupled with cerebral near-infrared spectroscopy recording. MAIN OUTCOME MEASURES: Cerebral O2 and peripheral capillary O2 saturation indexes were measured before sleep and during different stages of sleep. RESULTS: Thirty-one patients who fulfilled the inclusion criteria were recruited for the study. During wakefulness, mean peripheral capillary O2 saturation was 96.39 ± 1.54% (range 93-99%), whereas mean cerebral O2 saturation was 69.19 ± 6.96% (range 55-86%). Mean peripheral capillary O2 saturation decreased to 80.42 ± 9.73% (range 51-94%), whereas cerebral O2 saturation decreased to 61.91 ± 7.23% (range 45-79%) during sleep. Peripheral and cerebral hemodynamic status during sleep differed significantly in patients with different disease severity. Indeed, peripheral and cerebral O2 saturation levels were lower in patients with severe obstructive sleep apnea compared to those with mild and moderate apneas (p  =  .001 and p  =  .002, respectively). CONCLUSION: Our data suggest that acute cerebral hemodynamic consequences of sleep-disordered breathing are determined by the duration and type of the respiratory event and that the combination of the two determinants can lead to a failure of cerebral circulatory mechanisms and, eventually, brain tissue hypoxia.

An alternative surgical procedure for a patient with critically restenosed and kinked carotid artery: graft interposition.

According to the literature data, the prevalence of restenosis after carotid endarterectomy ranges between 6 and 36%. The etiological factor is intimal hyperplasia for early period, whereas it is atherosclerosis for late period. A 67-year-old male patient admitted to our clinic with a history of headache and minor stroke. His medical history was significant for right carotid endarterectomy 8 years ago. Recent Doppler ultrasound and digital substraction angiography revealed 75% stenosis and kinking corresponding to the segment distal to the endarterectomy region. Surgical endarterectomy is the treatment of choice in critical carotid stenosis. Endovascular therapy is primarily considered for patients if there is restenosis after carotid endarterectomy. However, the treatment modality is controversial in cases with concomitant carotid stenosis and kinking of internal carotid artery. We present our surgical approach to a case with significant stenosis and kinking of internal carotid artery. We performed a 6-mm-PTFE graft interposition between common and internal carotid artery and resection of the kinking segment.

Surgical treatment of symptomatic coiling or kinking internal carotid artery.

Coiling of the artery is a rare morphologic entity most frequently described in the internal carotid artery. Herein we present two cases with symptomatic kinked internal carotid artery: one suffering from paresthesia of the right arm and speech disturbances and the other suffering from weakness of the left half of the body and speech disturbances. Both patients were treated surgically. None of the patients experienced any peri- or postoperative complications.

The effect of sodium valproate on chronic daily headache and its subgroups.

The objective of the study was to assess the efficacy and tolerability of sodium valproate (VPA) on chronic daily headache (CDH) in a prospective, double-blind, randomized, placebo-controlled trial. Seventy patients were included in the study. Twenty-nine had chronic migraine (CM) and 41 had chronic tension-type headache (CTTH). VPA and placebo were applied for 3 months to 40 and 30 patients, respectively. Visual analog scale (VAS) and pain frequency (PF) were used for evaluation. VPA decreased the maximum pain VAS levels (MaxVAS) and PF at the end of the study (P = 0.028 and P = 0.000, respectively), but did not change general pain VAS (GnVAS) levels (P = 0.198). In CM patients, the decreases in MaxVAS, GnVAS and PF parameters were more in VPA treated patients (P = 0.006, P = 0.03, and P = 0.000, respectively). VPA treatment caused more reduction in PF than placebo in the CTTH subgroup (P = 0.000). VPA is effective in the prophylactic treatment of CDH by reducing MaxVAS levels and PF. It was more effective in CM than in CTTH.

Pheochromocytoma presenting with bithalamic infarction, dementia, and increased intraocular pressure.

The authors describe a case of pheochromocytoma presenting with bithalamic infarction, dementia, and elevated intraocular pressure. The patient received glaucoma treatment to suppress high intraocular pressure in addition to antihypertensive and antidiabetic medication for his complaints. Bilateral fundus examination and visual field defects revealed glaucoma-like changes. Adrenelectomy improved all complaints and all medications were stopped. Intraocular pressure and visual field changes improved. Pheochromocytoma presenting with bithalamic infarction, dementia, and increased IOP in the same patient is unusual. Adrenelectomy can improve dementia, increased IOP, and glaucoma-like changes in such cases.

Comparison of open carpal tunnel release and local steroid treatment outcomes in idiopathic carpal tunnel syndrome.

To compare the efficacy of local steroid injection and open carpal tunnel release, a symptom and functional status questionnaire (Boston Questionnaire) and sensory and motor nerve conduction studies were performed in 90 patients with electrophysiologically proven idiopathic carpal tunnel syndrome, of whom 44 were treated surgically and 46 by two-dose steroid injection. Electrophysiologic studies and the Boston Questionnaire were applied before and at the 3rd and 6th months after treatment. Both groups showed significant improvement at first follow-up. The surgically treated group showed a significant and further improvement of symptoms and conduction values between the 3rd- and 6th-month evaluations, whereas no significant change was observed in the patient group treated by steroid injection. By the end of follow-up, 5% of the hands in the open carpal tunnel release (OCTR) group and 13% of the hands in the local steroid injection (LSIG) group showed electrophysiological worsening, and 5% of the hands in the OCTR group and 22% of the hands in the LSIG group showed symptomatic worsening. Our results show that steroid injection provides an improvement comparable with that from surgical release of the median nerve at a 3-month interval. However, this improvement is not long-lasting.