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26.  Trigeminal isolated sensory neuropathy (TISN) and FOSMN syndrome: despite a dissimilar disease course do they share common pathophysiological mechanisms? 
BMC Neurology  2014;14(1):248.
Patients presenting with bilateral trigeminal hypoesthesia may go on to have trigeminal isolated sensory neuropathy, a benign, purely trigeminal neuropathy, or facial-onset sensory motor neuronopathy (FOSMN), a malignant life-threatening condition. No diagnostic criteria can yet differentiate the two conditions at their onset. Nor is it clear whether the two diseases are distinct entities or share common pathophysiological mechanisms.
Seeking pathophysiological and diagnostic information to distinguish these two conditions at their onset, in this neurophysiological and morphometric study we neurophysiologically assessed function in myelinated and unmyelinated fibres and histologically examined supraorbital nerve biopsy specimens with optic and electron microscopy in 13 consecutive patients with recent onset trigeminal hypoesthesia and pain.
The disease course distinctly differed in the 13 patients. During a mean 10 year follow-up whereas in eight patients the disease remained relatively stable, in the other five it progressed to possibly life-threatening motor disturbances and extra-trigeminal spread. From two to six years elapsed between the first sensory symptoms and the onset of motor disorders. In patients with trigeminal isolated sensory neuropathy (TISN) and in those with FOSMN neurophysiological and histological examination documented a neuronopathy manifesting with trigeminal nerve damage selectively affecting myelinated fibres, but sparing the Ia-fibre-mediated proprioceptive reflex.
Although no clinical diagnostic criteria can distinguish the two conditions at onset, neurophysiological and nerve-biopsy findings specify that in both disorders trigeminal nerve damage manifests as a dissociated neuronopathy affecting myelinated and sparing unmyelinated fibres, thus suggesting similar pathophysiological mechanisms.
PMCID: PMC4301795  PMID: 25527047
Trigeminal nerve; Neuronopathy; Trigeminal neuropathy; FOSMN; Facial pain
27.  Recurrent posterior circulation infarction caused by anomalous occipital bony process in a young patient 
BMC Neurology  2014;14(1):252.
Structural anomaly of the cervical spine or craniocervical junction has been reported as one of the rare causes of ischemic stroke. We report a case of a young patient with recurrent posterior circulation infarction that may have been associated with an anomalous occipital bony process compressing the vertebral artery.
Case presentation
A 23-year-old man experienced recurrent posterior circulation infarction 5 times over a period of 5 years. He had no conventional vascular risk factors. Young age stroke work-up including thorough cardiac, intra- and extracranial vascular evaluation and laboratory tests for the hypercoagulable state or connective tissue disease yielded unremarkable results. An anomalous bony process from the occipital base compressing the left vertebral artery was observed on brain CT. All the recurrent strokes were explainable by the arterial thromboembolism originating from the compressed left vertebral artery. Therefore, the left vertebral artery compressed by the anomalous occipital bony process may have been the culprit behind the recurrent thromboembolic strokes in our patient. Intractable recurrent strokes even under optimal medical treatment led us to make a decision for the intervention. Instead of surgical removal of the anomalous occipital bony process, the left vertebral artery was occluded permanently by endovascular coiling after confirming that this would cause no neurological deficits or flow disturbance in the posterior circulation. There was no recurrence of stroke for 2 years after permanent occlusion of the left vertebral artery.
Arterial thromboembolism originating from the left vertebral artery compressed by the anomalous occipital bony process is a rare but not to be overlooked cause of posterior circulation infarction. When intractable to medical treatment, endovascular occlusion of the vertebral artery without flow disturbance to the posterior circulation may be a useful treatment option when surgical removal is not feasible.
PMCID: PMC4302142  PMID: 25519166
Recurrent strokes; Occipital bony process; Young age stroke; Endovascular treatment
28.  Donepezil can improve daily activities and promote rehabilitation for severe Alzheimer’s patients in long-term care health facilities 
BMC Neurology  2014;14(1):243.
Cholinesterase inhibitors can delay the progression of Alzheimer’s disease (AD). Several clinical trials of the drug in moderate to severe AD have consistently reported clinically positive effects. A combining effect with psychosocial intervention was reported in mild to moderate AD patients. Since a therapeutic approach or rehabilitation combined with cholinesterase inhibitors for severe AD patients remains controversial, we performed a prospective intervention for patients in Long-Term Care Health Facilities (LTCHF).
Two LTCHFs (N1, N2) were enrolled. N1 is a 126-bed facility that does not treat with donepezil but rather with psychosocial intervention (reality orientation and reminiscence). N2 is a 150-bed facility with a 50-bed special dementia unit, in which the physician can prescribe donepezil. On top of the similar psychosocial intervention, rehabilitation is performed in N2. Thirty-two severe AD patients (MMSE < 6) in N1 and N2 (16 vs. 16) were compared for the effect of donepezil (10 mg/d for 3 months) with or without psychosocial intervention (n = 8 vs. 8 for each facility). The Vitality Index was used to assess daily activities and the introduction of rehabilitation.
The response ratio (MMSE 3+) of donepezil was 37.5% in N2. The combination of donepezil with the psychosocial intervention improved the Vitality Index total score, and Communication, Eating, and Rehabilitation subscores (Wilcoxon, p = 0.016, 0.038, 0.023, and 0.011, respectively). Most of them were smoothly introduced to rehabilitation, and the proportion of accidental falls decreased. Psychosocial intervention in N1 without the drug only improved the total score (Wilcoxon, p = 0.046).
A combined therapeutic approach of donepezil and psychosocial intervention can have a positive effect, even for severe patients through the introduction of rehabilitation and decreasing accidental falls. However, these findings require replication in a larger cohort.
PMCID: PMC4280048  PMID: 25516360
Alzheimer’s disease; Donepezil; Cholinesterase inhibitors; Life expectancy; Nursing home
29.  Interferon-β-related tumefactive brain lesion in a Caucasian patient with neuromyelitis optica and clinical stabilization with tocilizumab 
BMC Neurology  2014;14(1):247.
Neuromyelitis optica (NMO) is a severely disabling inflammatory disorder of the central nervous system and is often misdiagnosed as multiple sclerosis (MS). There is increasing evidence that treatment options shown to be beneficial in MS, including interferon-β (IFN-β), are detrimental in NMO.
Case presentation
We here report the first Caucasian patient with aquaporin 4 (AQP4) antibody (NMO-IgG)-seropositive NMO presenting with a tumefactive brain lesion on treatment with IFN-β. Disease started with relapsing optic neuritis and an episode of longitudinally extensive transverse myelitis (LETM) in the absence of any brain MRI lesions or cerebrospinal fluid-restricted oligoclonal bands. After initial misdiagnosis of multiple sclerosis (MS) the patient received subcutaneous IFN-β1b and, subsequently, subcutaneous IFN-β1a therapy for several years. Under this treatment, the patient showed persisting relapse activity and finally presented with a severe episode of subacute aphasia and right-sided hemiparesis due to a large T2 hyperintensive tumefactive lesion of the left brain hemisphere and a smaller T2 lesion on the right side. Despite rituximab therapy two further LETM episodes occurred, resulting in severe neurological deficits. Therapeutic blockade of the interleukin (IL)-6 signalling pathway by tocilizumab was initiated, followed by clinical and radiological stabilization.
Our case (i) illustrates the relevance of correctly distinguishing NMO and MS since these disorders differ markedly in their responsiveness to immunomodulatory and -suppressive therapies; (ii) confirms and extends a previous report describing the development of tumefactive brain lesions under IFN-β therapy in two Asian NMO patients; and (iii) suggests tocilizumab as a promising therapeutic alternative in highly active NMO disease courses.
PMCID: PMC4301061  PMID: 25516429
Neuromyelitis optica; Aquaporin-4 antibodies (NMO-IgG); Interferon-beta; Tocilizumab; Interleukin-6; Rituximab; Azathioprine; Methylprednisolone; Tumefactive brain lesions; Multiple sclerosis
30.  Sequencing bilateral and unilateral task-oriented training versus task oriented training alone to improve arm function in individuals with chronic stroke 
BMC Neurology  2014;14(1):236.
Recovering useful hand function after stroke is a major scientific challenge for patients with limited motor recovery. We hypothesized that sequential training beginning with proximal bilateral followed by unilateral task oriented training is superior to time-matched unilateral training alone. Proximal bilateral training could optimally prepare the motor system to respond to the more challenging task-oriented training.
Participants: Twenty-six participants with moderate severity hemiparesis Intervention: Participants received either 6-weeks of bilateral proximal training followed sequentially by 6-weeks unilateral task-oriented training (COMBO) or 12-weeks of unilateral task-oriented training alone (SAEBO). A subset of 8 COMB0 and 9 SAEBO participants underwent three functional magnetic resonance imaging (fMRI) scans of hand and elbow movement every 6 weeks. Main Outcome Measures: Fugl-Meyer Upper extremity scale, Modified Wolf Motor Function Test, University of Maryland Arm Questionnaire for Stroke, Motor cortex activation (fMRI).
The COMBO group demonstrated significantly greater gains between baseline and 12-weeks over all outcome measures (p = .018 based on a MANOVA test) and specifically in the Modified Wolf Motor Function test (time). Both groups demonstrated within-group gains on the Fugl-Meyer Upper Extremity test (impairment) and University of Maryland Arm Questionnaire for Stroke (functional use). fMRI subset analyses showed motor cortex (primary and premotor) activation during hand movement was significantly increased by sequential combination training but not by task-oriented training alone.
Sequentially combining a proximal bilateral before a unilateral task-oriented training may be an effective way to facilitate gains in arm and hand function in those with moderate to severe paresis post-stroke compared to unilateral task oriented training alone.
PMCID: PMC4276071  PMID: 25494635
Stroke; Bilateral arm training; Upper extremity; fMRI; Sequential training
31.  Combination of anxiety and depression is associated with an increased headache frequency in migraineurs: a population-based study 
BMC Neurology  2014;14(1):238.
Although anxiety and depression have been classified as distinct traits of affective disorders, previous studies have reported their co-occurrence in subjects with migraine. However, few reports are available on the clinical implications of this comorbidity. This study is to assess the comorbidity of anxiety and depression in subjects with migraine and its clinical implications in a population-based sample from Korea.
We selected Korean subjects aged 19–69 years by the stratified random sampling method, and evaluated them using a semi-structured interview, designed to identify headache type, anxiety, and depression. We used Goldberg Anxiety Scale questions and Patient Health Questionnnaire-9 for the diagnosis of anxiety and depression, respectively.
Of the 2,762 participants who completed the interview, 147 subjects (5.4%) were classified as having a migraine during the previous year. Among these 147 subjects, 17 (11.6%) had anxiety and depression, 28 (19.0%) had anxiety alone, 9 (6.1%) had depression alone, and 93 (63.3%) had neither anxiety nor depression. Headache frequency per month was remarkably higher in subjects having migraine with anxiety and depression (median [25–75 percentile values], 8.0 [2.5–21.0]) than in those having migraine with anxiety alone (2.0 [1.0–5.0], p = 0.003), migraine with depression alone (1.0 [0.3–4.0], p = 0.001), and migraine without anxiety or depression (1.0 [0.3–3.0], p < 0.001). The migraine with anxiety alone (7.0 [6.0–8.0], p = 0.011) group and migraine with anxiety and depression (7.0 [5.0–9.0], p = 0.018) group showed higher Visual Analogue Scale scores for pain intensity compare to migraine without anxiety or depression (6.0 [5.0-7.0]) group.
Approximately 1/3 of migraineurs with anxiety had depression and 2/3 of migraineurs with depression had anxiety. Combination of anxiety and depression was associated with an increased headache frequency. Anxiety was associated with exacerbation of headache intensity.
Electronic supplementary material
The online version of this article (doi:10.1186/s12883-014-0238-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4279894  PMID: 25494868
Migraine; Anxiety; Depression; Epidemiology; Comorbidity
32.  The Mini-BESTest - a clinically reproducible tool for balance evaluations in mild to moderate Parkinson’s disease? 
BMC Neurology  2014;14(1):235.
The Mini-BESTest is a clinical balance test that has shown a high sensitivity in detecting balance impairments in elderly with Parkinson's disease (PD). However, its reproducibility between different raters and between test occasions has yet to be investigated in a clinical context. Moreover, no one has investigated the reproducibility of the Mini-BESTest's subcomponents (i.e. anticipatory postural adjustments; postural responses; sensory orientation and dynamic gait).
We aimed to investigate the inter-rater and test-retest reproducibility (reliability as well as agreement) of the Mini-BESTest, as well as its subcomponents, in elderly with mild to moderate PD, performed under conditions assimilating clinical practice.
This was an observational measurement study with a test-retest design.
Twenty-seven individuals with idiopathic PD (66 - 80 years, mean age: 73; Hoehn & Yahr: 2-3; 1-15 years since diagnosis) were included. Two test administrators, having different experiences with the Mini-BESTest, administered the test individually, in separate rooms in a hospital setting. For the test-retest assessment, all participants returned 7 days after the first test session to perform the Mini-BESTest under similar conditions. Intra-class correlation coefficients (ICC2.1), standard error of measurement (SEMagreement), and smallest real difference (SRD) were analyzed.
The Mini-BESTest showed good reliability for both inter-rater and test-retest reproducibility (ICC = 0.72 and 0.80). Regarding agreement, the measurement error (SRD) was found to be 4.1 points (accounting for 15% of the maximal total score) for inter-rater reproducibility and 3.4 points (12% of the maximal total score) for test-retest reproducibility. The investigation of the Mini-BESTest's subcomponents showed a similar pattern for both inter-rater and test-retest reproducibility, where postural responses had the largest proportional measurement error, and sensory orientation showed the highest agreement.
Our findings indicate that the Mini-BESTest is able to distinguish between individuals with mild to moderate PD; however, when used in clinical balance assessments, the large measurement error needs to be accounted for.
PMCID: PMC4272769  PMID: 25496796
Reliability; Measurement error; Psychometric; Balance; Balance evaluation systems test; Test-retest; Inter-rater; Smallest real difference
33.  Subcortical white matter infarcts predict 1-year outcome of fatigue in stroke 
BMC Neurology  2014;14(1):234.
Fatigue is common in stroke survivors. Lesion location may influence the risk of poststroke fatigue (PSF) but it is uncertain whether location has an impact on the prognosis of PSF. This study examined the association between PSF outcome and infarct location.
The study sample comprised 435 Chinese patients with acute ischemic stroke admitted to the acute stroke unit of a university affiliated regional hospital in Hong Kong. Three and fifteen months after the onset of the index stroke a research assistant administered the Fatigue Severity Scale (FSS). PSF was defined as a FSS score of 4.0 or above. Of the 139 patients with PSF three months poststroke, 97 (69.8%) attended the 15-month follow-up, when 50 (51.5%) patients still had PSF (‘non-remitters’) and 47 (48.5%) did not report fatigue (‘remitters’). The presence and location of infarcts were evaluated with magnetic resonance imaging.
In comparison with the remitters, the non-remitters were more likely to have subcortical white matter infarcts (40.0% vs 21.3%, p = 0.046). These infarcts remained an independent predictor of non-remission of PSF in the multivariate analysis, with an odds ratio of 4.208 (p = 0.011).
The results suggest that subcortical white matter infarcts may influence the outcome of PSF. Further investigations are needed to explore whether infarcts have any impact on the response of PSF to pharmacological or psychological interventions.
PMCID: PMC4272810  PMID: 25496671
Fatigue; Stroke; Infarcts; MRI; Outcome
34.  Mononeuritis multiplex as the first presentation of refractory sarcoidosis responsive to etanercept 
BMC Neurology  2014;14(1):237.
Several disorders may present with mononeuritis multiplex and the etiological diagnosis can be challenging.
Case presentation
We report a 42 year-old female who presented with severe lower limb neuropathic pain, asymmetric weakness and sensory impairment and was diagnosed with mononeuritis multiplex. Biopsy showed a granulomatous vasculitic process with eosinophils, scarce granulomata and axonal neuropathy and granulomatosis with poliangiitis was assumed. Steroids, cyclophosphamide, alemtuzumab, azathioprine, mycophenolate mofetil and rituximab were used, all with transient and insufficient response. Skin biopsy performed in a further exacerbation allowed sarcoidosis diagnosis. Infliximab and, later, adalimumab induced good clinical and laboratorial response, but neutralizing antibodies developed to both drugs, so etanercept was tried with good clinical response.
To the best of our knowledge, this is the first report of sarcoidosis successfully treated with etanercept. This drug may be considered in refractory sarcoidosis after other TNF-α inhibitors failure, having the advantage of not being associated with neutralizing antibodies development.
PMCID: PMC4275932  PMID: 25494723
35.  Enhancing cognitive-behavioural therapy for recurrent headache: design of a randomised controlled trial 
BMC Neurology  2014;14(1):233.
We have argued against the traditional approach of counselling avoidance of all triggers of headaches and migraine. Problems with this approach include the impossibility of avoiding all triggers and the high costs associated with trying to do so, and that avoidance could lead to reduced tolerance for the triggers. We have developed an alternative approach called Learning to Cope with Triggers (LCT) that encourages avoidance of triggers that are detrimental to health and wellbeing, but uses exposure to other triggers to desensitise headache sufferers to the triggers. This approach has been shown to be more effective than advising avoidance of all triggers. Trigger management is only one component of a comprehensive treatment program and the current study is designed to evaluate a new approach to treating headaches in which LCT has been integrated into an established cognitive-behavioural therapy (CBT) package (LCT/CBT).
A target sample of 120 adult participants who suffer from migraine or tension-type headache, at least six days per month, and have done so for at least 12 months will be recruited. Participants will be randomly assigned to one of three groups: LCT/CBT; Avoid/CBT (CBT combined with instructions to avoid all triggers); and waiting-list control. Measures will include: daily diaries for recording headaches, triggers and medication consumption; headache disability and quality of life; trigger avoidance; locus of control and self-efficacy; and coping strategies. Treatment will involve 12 60-minute sessions scheduled weekly. Assessment will be completed before and after treatment, and at 4 and 12 month follow-up. The data will be analysed to determine which approach is most effective, and predictors of response to treatment.
Migraine and tension-type headache are common and can be disabling. CBT has been demonstrated to be an efficacious treatment for both disorders. However, there is room for improvement. This study aims to increase the efficacy of behavioural approaches and identify factors predictive of a positive response.
Trial registration
Australian and New Zealand Clinical Trials Registry ACTRN12614000435684.
PMCID: PMC4285632  PMID: 25496514
Headache; Migraine; Cognitive behaviour therapy; Coping; Desensitisation
36.  An open-label pilot trial of minocycline in children as a treatment for Angelman syndrome 
BMC Neurology  2014;14(1):232.
Minocycline, a member of the tetracycline family, has a low risk of adverse effects and an ability to improve behavioral performance in humans with cognitive disruption. We performed a single-arm open-label trial in which 25 children diagnosed with Angelman syndrome (AS) were administered minocycline to assess the safety and tolerability of minocycline in this patient population and determine the drug’s effect on the cognitive and behavioral manifestations of the disorder.
Participants, age 4-12 years old, were randomly selected from a pool of previously screened children for participation in this study. Each child received 3 milligrams of minocycline per kilogram of body weight per day for 8 weeks. Participants were assessed during 3 study visits: baseline, after 8-weeks of minocycline treatment and after an 8-week wash out period. The primary outcome measure was the Bayley Scales of Infant and Toddler Development 3rd Edition (BSID-III). Secondary outcome measures included the Clinical Global Impressions Scale (CGI), Vineland Adaptive Behavior Scales 2nd Edition (VABS-II), Preschool Language Scale 4th Edition (PLS-IV) and EEG scores. Observations were considered statistically significant if p < 0.05 using ANOVA and partial eta squared (η2) was calculated to show effect size. Multiple comparisons testing between time points were carried out using Dunnett’s post hoc testing.
Significant improvement in the mean raw scores of the BSID-III subdomains communication and fine motor ability as well as the subdomains auditory comprehension and total language ability of the PLS-IV when baseline scores were compared to scores after the washout period. Further, improvements were observed in the receptive communication subdomain of the VABS-II after treatment with minocycline. Finally, mean scores of the BSID-III self-direction subdomain and CGI scale score were significantly improved both after minocycline treatment and after the wash out period.
The clinical and neuropsychological measures suggest minocycline was well tolerated and causes improvements in the adaptive behaviors of this sample of children with Angelman syndrome. While the optimal dosage and the effects of long-term use still need to be determined, these findings suggest further investigation into the effect minocycline has on patients with Angelman syndrome is warranted.
Trial registration
NCT01531582 –
PMCID: PMC4276108  PMID: 25491305
Angelman syndrome; Cognitive impairment; Ataxia; Epilepsy; Seizure; Autism
37.  An international road map to improve pain assessment in people with impaired cognition: the development of the Pain Assessment in Impaired Cognition (PAIC) meta-tool 
BMC Neurology  2014;14(1):229.
Pain is common in people with dementia, yet identification is challenging. A number of pain assessment tools exist, utilizing observation of pain-related behaviours, vocalizations and facial expressions. Whilst they have been developed robustly, these often lack sufficient evidence of psychometric properties, like reliability, face and construct validity, responsiveness and usability, and are not internationally implemented. The EU-COST initiative “Pain in impaired cognition, especially dementia” aims to combine the expertise of clinicians and researchers to address this important issue by building on previous research in the area, identifying existing pain assessment tools for dementia, and developing consensus for items for a new universal meta-tool for use in research and clinical settings. This paper reports on the initial phase of this collaboration task.
All existing observational pain behaviour tools were identified and elements categorised using a three-step reduction process. Selection and refinement of items for the draft Pain Assessment in Impaired Cognition (PAIC) meta-tool was achieved through scrutiny of the evidence, consensus of expert opinion, frequency of use and alignment with the American Geriatric Society guidelines. The main aim of this process was to identify key items with potential empirical, rather than theoretical value to take forward for testing.
12 eligible assessment tools were identified, and pain items categorised according to behaviour, facial expression and vocalisation according to the AGS guidelines (Domains 1 – 3). This has been refined to create the PAIC meta-tool for validation and further refinement. A decision was made to create a supporting comprehensive toolkit to support the core assessment tool to provide additional resources for the assessment of overlapping symptoms in dementia, including AGS domains four to six, identification of specific types of pain and assessment of duration and location of pain.
This multidisciplinary, cross-cultural initiative has created a draft meta-tool for capturing pain behaviour to be used across languages and culture, based on the most promising items used in existing tools. The draft PAIC meta-tool will now be taken forward for evaluation according to COSMIN guidelines and the EU-COST protocol in order to exclude invalid items, refine included items and optimise the meta-tool.
Electronic supplementary material
The online version of this article (doi:10.1186/s12883-014-0229-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4279897
Pain; Dementia; Assessment; Tool; EU-COST; Cognition
38.  Usefulness of screening tools in the evaluation of long-term effectiveness of DREZ lesioning in the treatment of neuropathic pain after brachial plexus injury 
BMC Neurology  2014;14(1):225.
Despite high success rate of DREZ lesioning in the treatment of intractable central pain, there is still a significant incidence of patients without satisfactory post-operative effect. The aim of the study was to evaluate the long-term effect of DREZ lesioning using both a subjective assessment using a visual analog scale (VAS) to quantify residual pain and an assessment using the screening tool (painDETECT Questionnaire, PD-Q).
DREZ lesioning was performed in 52 patients from a total 441 cases with brachial plexus injury (11.8%) during a 17-year period (1995–2011). The effect of surgery was retrospectively assessed in 48 patients.
A decrease in pre-operative pain by more than 75% (Group I) was achieved in 70.8% of patients and another 20.8% reported significant improvement (Group II). The surgery was unsucessful in 8.4% (Group III). We found a significant correlation between ‘improvement’ groups from both methods of assessments. Patients from Group I usually complained of residual nociceptive pain according to PD-Q, patients from Group II typically had pain of unclear origin, and all cases those in Group III suffered from neuropathic pain, Cramer’s V = .66, P < .001. Overall, 66.7% of patients had resolved neuropathic pain, 20.8% patients had more serious complaints and may also suffer from residual neuropathic pain, while 12.5% had unresolved neuropathic pain.
DREZ lesioning is a safe and effective method with success rates of about 90%. PD-Q scores correspond to subjective satisfaction with the surgery and it seems to be a suitable screening tool for finding patients with residual neuropathic pain after surgery.
PMCID: PMC4264322  PMID: 25487537
DREZ lesioning; Deafferentation pain; Screening tool; Neuropathic pain; Brachial plexus injury
39.  Neurotrophic keratopathy due to dorsolateral medullary infarction (Wallenberg Syndrome): case report and literature review 
BMC Neurology  2014;14(1):231.
Dorsolateral medullary infarction (Wallenberg Syndrome) is rare in clinical practice; however, the subsequent corneal lesions are more uncommon. To our knowledge, only one such case was previously reported. We report a similar case with successful treatment and recovery, and analyse both cases to address the clinical features and outcomes of such syndrome.
Case presentation
A 43-year-old male presented with neurotrophic keratopathy one month after sustaining dorsolateral medullary infarction. The patient underwent amniotic membrane transplantation twice. Two-year follow-up observation revealed changes in nerve fibers and epithelial cells of corneal by laser confocal microscopy.
By studying both cases, we confirm that neurotrophic keratopathy could be as a delayed-onset complication of Wallenberg syndrome. The recognition that neurotrophic keratopathy can follow dorsolateral medullary infarction could prevent the clinical misdiagnosis.
PMCID: PMC4258269  PMID: 25472780
Dorsolateral medullary infarction; Neurotrophic keratopathy; Wallenberg syndrome
40.  Multiple sclerosis in the far north - incidence and prevalence in Nordland County, Norway, 1970–2010 
BMC Neurology  2014;14(1):226.
The risk of multiple sclerosis (MS) increases with increasing latitude. Taking into consideration that Norway has a large latitude range, a south-to-north gradient would be expected. However, previous studies have reported an uneven distribution of the disease in Norway, with a relatively low prevalence in the most northern parts of the country.
We describe the incidence and prevalence of MS in a county in the north of Norway over a period of 40 years.
All patients with MS living in Nordland County in the period 1970–2010 were identified by reviewing hospital charts. The patients were included if they met the criteria of definitive or probable MS according to Poser [Ann Neurol 13:227-231, 1983] or MS according to McDonalds [Ann Neurol 50:121-127, 2001]. Point prevalence at the beginning of the decades was calculated. The average annual incidence was calculated for 5-year periods.
The total crude prevalence on January 1, 2010 was 182.4 per 100 000. The annual incidence continuously increased from 0.7 per 100 000 in 1970 – 1974 to 10.1 per 100,000 in 2005 – 2009. The time delay from the first symptom to diagnosis was stable from 1975 to 2010. The proportion of primary progressive MS in the prevalence numbers was 38.2% in 1980, and decreases continuously, to 18.6% in 2010. The female to male prevalence ratio has been stable since 1990 at 2.2 to 1.
The prevalence and the incidence of MS have steadily increased over a 40 year period. Nordland County is a high-risk area for MS.
PMCID: PMC4263112  PMID: 25472707
Multiple sclerosis; Norway; Epidemiology; Prevalence; Incidence
41.  Symptom changes in multiple sclerosis following psychological interventions: a systematic review 
BMC Neurology  2014;14(1):222.
Multiple Sclerosis is a disease of the central nervous system involving a variety of debilitating physical, sensory, cognitive and emotional symptoms. This literature review evaluated the impact of psychological interventions on the physiological symptoms associated with the illness.
A systematic literature search was conducted using Medline, PsycINFO, Scopus, and the Cochrane Library databases, as well as reference lists. Relevant studies were selected and assessed according to a preset protocol.
The search produced 220 articles, with 22 meeting inclusion criteria for the review. A total of 5,705 subjects with Multiple Sclerosis were analyzed. Results from the included studies indicate a general improvement in both psychological and physiological outcomes following psychological treatment. The most highly influenced physical symptoms include fatigue, sleep disturbances, pain, and physical vitality.
Findings from the review suggest a positive relationship between psychological interventions and physiological Multiple Sclerosis symptoms. Implications for future research are discussed.
PMCID: PMC4253984  PMID: 25433519
Multiple sclerosis; Psychological interventions; Physical health outcomes; Mind/body connection
42.  Creutzfeldt-Jakob disease mimicking autoimmune encephalitis with CASPR2 antibodies 
BMC Neurology  2014;14(1):227.
Differential diagnosis of severe progressive dementia includes a wide spectrum of inflammatory and neurodegenerative diseases. Particularly challenging is the differentiation of potentially treatable autoimmune encephalitis and Creutzfeldt-Jakob disease. Such a coincidence may indeed complicate the correct diagnosis and influence subsequent treatment.
Case presentation
A 75-year-old woman was admitted due to rapid progressive cognitive impairment. Her husband observed a temporal disorientation and confusion. The initial neurological examination and an extensive neuropsychological evaluation showed significant impairments in almost all tested cognitive domains. All other neurological functions including motor, sensory and coordinative function were intact. Initial diagnostics included EEG, MRI and lumbar puncture with unspecific results. Complementary blood testing revealed a positive result for antineural antibodies to Contactin-associated protein 2 (CASPR2) and the patient received treatment for CASPR2 autoimmune encephalitis. Further symptoms and results, including 14-3-3 proteins, led to suspected Creutzfeldt-Jakob disease. The postmortem examination supported the diagnosis of a definitive Creutzfeldt-Jakob disease.
One could argue that global screening for antineural antibodies may lead to a false diagnosis triggering intense and potentially dangerous procedures. We believe, however, that potentially treatable causes of dementia should aggressively sought out and subsequently treated in an attempt to curtail the course of disease and ultimately reduce the rate of mortality.
PMCID: PMC4255969  PMID: 25434587
CASPR2; VGKC; Creutzfeldt-Jakob disease; Encephalitis; Autoimmune; Autoantibody; Thyroperoxidase antibodies
43.  Prediction of recurrent stroke with ABCD2 and ABCD3 scores in patients with symptomatic 50-99% carotid stenosis 
BMC Neurology  2014;14(1):223.
Although it is preferable that all patients with a recent Transient Ischemic Attack (TIA) undergo acute carotid imaging, there are centers with limited access to such acute examinations. It is controversial whether ABCD2 or ABCD3 scores can be used to triage patients to acute or delayed carotid imaging. It would be acceptable that some patients with a symptomatic carotid stenosis are detected with a slight delay as long as those who will suffer an early recurrent stroke are detected within 24 hours. The aim of this study is to analyze the ability of ABCD2 and ABCD3 scores to predict ipsilateral ischemic stroke among patients with symptomatic 50-99% carotid stenosis.
In this secondary analysis of the ANSYSCAP-study, we included 230 consecutive patients with symptomatic 50-99% carotid stenosis. We analyzed the risk of recurrent ipsilateral ischemic stroke before carotid endarterectomy based on each parameter of the ABCD2 and ABCD3 scores separately, and for total ABCD2 and ABCD3 scores. We used Kaplan-Meier analysis.
None of the parameters in the ABCD2 or ABCD3 scores could alone predict all 12 of the ipsilateral ischemic strokes that occurred within 2 days of the presenting event, but clinical presentation tended to be a statistically significant risk factor for recurrent ipsilateral ischemic stroke (p = 0.06, log rank test). An ABCD2 score ≥2 and an ABCD3 score ≥4 could predict all 12 of these strokes as well as all 25 ipsilateral ischemic strokes that occurred within 14 days. To use ABCD3 score seems preferable over the ABCD2 score because a higher proportion of low risk patients were identified (17% of the patients had an ABCD3 score <4 while only 6% had an ABCD2 < 2).
Although it is preferable that carotid imaging be performed within 24 hours, our data support that an ABCD3 score ≥4 might be used for triaging patients to acute carotid imaging in clinical settings with limited access to carotid imaging. However, our findings should be validated in a larger cohort study.
PMCID: PMC4256835  PMID: 25433667
Stroke; Carotid stenosis; Risk; ABCD2; ABCD3
44.  Neutralizing antibodies and fatigue as predictors of low response to interferon-beta treatment in patients with multiple sclerosis 
BMC Neurology  2014;14(1):215.
The clinical impact of neutralizing antibodies against interferon-beta (NAb) is controversial. Their presence can lead to a decrease in interferon-beta (IFNβ) efficacy. Fatigue reported in patients with multiple sclerosis (MS) may be associated with an unfavorable clinical course. We conducted a prospective multicentre study to assess the association between response to IFNβ, NAb and fatigue.
Patients with relapsing-remitting MS on IFNβ treatment were included. During the second year of treatment, the patients were analyzed for NAb status and non-response criteria to IFNβ (number of relapses ≥1 during the follow-up period, increase in the Expanded Disability Status Scale ≥0.5). The score on the Modified Fatigue Impact Scale (MFIS pathological if score ≥35) was noted for each patient.
Of the 176 patients included: 22.3% were NAb positive, 54.5% presented non-response criteria to IFNβ, and 57.4% had a pathological MFIS score. Fatigue was increased in NAb + patients (p = 0.0014) and they were more likely to present non-response criteria to IFNβ (p = 0.041) than NAb- patients. Multivariate logistic regression analysis showed that the presence of NAb was related to fatigue (p = 0.0032) and denoted disease activity in these patients (p = 0.026).
This study demonstrates the impact of NAb on the non-clinical response to IFNβ. Fatigue assessment is an indicator of IFNβ responsiveness and a predictive biomarker of deterioration on patient’s neurological status.
PMCID: PMC4256902  PMID: 25433670
Multiple sclerosis; Neutralizing antibodies; Fatigue; Interferon-beta; Response to treatment
45.  Influenza-associated MOG antibody-positive longitudinally extensive transverse myelitis: a case report 
BMC Neurology  2014;14(1):224.
Myelin-oligodendrocyte glycoprotein antibody (MOG antibodies) was found in various demyelinated diseases. This is the first report of a patient with longitudinally extensive transverse myelitis with an extremely high titer of MOG antibodies after an influenza infection. This case supports the view that MOG antibodies are linked to longitudinally extensive transverse myelitis and that influenza infection might trigger the MOG antibodies.
Case presentation
A 32-year-old healthy male developed high fever, dysesthesia and paraesthesia below the C2 area, muscle weakness of the bilateral lower extremities, and urinary retention ten days after an influenza type A infection. Magnetic resonance imaging revealed a longitudinal lesion in the spinal cord extending from C2 to the spinal conus. There were no lesions in the brain or optic nerves. Established cell-based immunoassays revealed that he was positive for MOG antibodies (titer = 65,536) and negative for anti-aquaporin 4 antibodies (AQP4 antibodies). He fully recovered after steroid pulse therapy followed by 60 mg prednisolone.
This is the first report of influenza A-associated longitudinally extensive transverse myelitis with a high titer anti-MOG antibodies. Our case report supports a relationship between anti-MOG antibodies and longitudinally extensive transverse myelitis, which was triggered by influenza infection. Further studies are needed to establish the clinical significance of anti-MOG antibodies for diagnosis, treatment, and prognosis.
PMCID: PMC4256916  PMID: 25434485
Myelin-oligodendrocyte glycoprotein antibody; Longitudinal extensive transverse myelitis; Neuromyelitis optica; Aquaporin-4 antibody
46.  Neglect-like characteristics of developmental disregard in children with cerebral palsy revealed by event related potentials 
BMC Neurology  2014;14(1):221.
Children with unilateral Cerebral Palsy (CP) often show diminished awareness of the remaining capacity of their affected upper limb. This phenomenon is known as Developmental Disregard (DD). DD has been explained by operant conditioning. Alternatively, DD can be described as a developmental delay resulting from a lack of use of the affected hand during crucial developmental periods. We hypothesize that this delay is associated with a general delay in executive functions (EF) related to motor behavior, also known as motor EFs.
Twenty-four children with unilateral CP participated in this cross-sectional study, twelve of them diagnosed with DD. To test motor EFs, a modified go/nogo task was presented in which cues followed by go- or nogo-stimuli appeared at either the left or right side of a screen. Children had to press a button with the hand corresponding to the side of stimulus presentation. Apart from response accuracy, Event-Related Potentials (ERPs) extracted from the ongoing EEG were used to register covert cognitive processes. ERP N1, P2, N2, and P3 components elicited by cue-, go-, and nogo-stimuli were further analyzed to differentiate between different covert cognitive processes.
Children with DD made more errors. With respect to the ERPs, the P3 component to go-stimuli was enhanced in children with DD. This enhancement was related to age, such that younger children with DD showed stronger enhancements. In addition, in DD the N1 component to cue- and go-stimuli was decreased.
The behavioral results show that children with DD experience difficulties when performing the task. The finding of an enhanced P3 component to go-stimuli suggests that these difficulties are due to increased mental effort preceding movement. As age in DD mediated this enhancement, it seems that this increased mental effort is related to a developmental delay. The additional finding of a decreased N1 component in DD furthermore suggests a general diminished visuo-spatial attention. This effect reveals that DD might be a neuropsychological phenomenon similar to post-stroke neglect syndrome that does not resolve during development. These findings suggest that therapies aimed at reducing neglect could be a promising addition to existing therapies for DD.
PMCID: PMC4258290  PMID: 25433482
Unilateral cerebral palsy; Developmental disregard; Cognitive control; EEG; Event-related potentials; Executive functions; Neglect; Visuo-spatial attention
47.  Early onset frontotemporal dementia with psychiatric presentation due to the C9ORF72 hexanucleotide repeat expansion: a case report 
BMC Neurology  2014;14(1):228.
Frontotemporal dementia (FTD) may present with psychiatric symptoms, usually together with neurological ones and in cases with a family history of dementia. We describe the case of an FTD behavioural variant with a psychiatric presentation and a normal neurological examination, due to a C9Orf72 gene mutation.
Case presentation
The patient was a 57 years-old Caucasian woman with a recent onset of bizarre behaviours and mystic delusions. She had a negative clinical history for previous psychiatric disorders and treatments and this was her first admission to a Psychiatry Ward. A careful assessment was performed including, beyond psychiatric evaluation, the following: blood sampling, neurological examination (including electroencephalogram, electroencephalogram with zygomatic electrodes, Positron Emission Tomography, Cerebrospinal Fluid Analysis), carotid artery Doppler ultrasound, brain Magnetic Resonance Imaging – angio Magnetic Resonance Imaging. Blood sampling for the genetic assessment of mutations associated to primary dementias was performed as well: the genes investigated were FUS, C9Orf72, PSEN-1, PSEN-2.
Serological tests were negative, neurological examination was normal, instrumental examinations showed theta waves in the posterior temporal areas bilaterally and frontotemporal cortical atrophy bilaterally. The genetic assessment of mutations associated revealed she carried a GGGGCC hexanucleotide repeat expansion (at least 80 repeats) in C9Orf72 intron 1. Patients carrying the C9Orf72 mutation are likely to receive a psychiatric diagnosis (mainly mood disorder or schizophrenia) prior to correct diagnosis; this may be particularly problematic for those patients with no neurological signs to orientate diagnosis. Understanding the manner in which such FTD variant may present as a psychiatric syndrome, with a negative neurological examination, is essential to provide the best treatment for patients, as soon as possible, especially when the behavioural anomalies interfere with their care.
PMCID: PMC4264324  PMID: 25433797
Frontotemporal dementia; C9Orf72; Psychiatric Presentation; Behavioural variant
48.  Comparison between the cranial magnetic resonance imaging features of neuromyelitis optica spectrum disorder versus multiple sclerosis in Taiwanese patients 
BMC Neurology  2014;14(1):218.
Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) are inflammatory diseases of the central nervous system with different pathogenesis, brain lesion patterns, and treatment strategies. However, it is still difficult to distinguish these two disease entities by neuroimaging studies. Herein, we attempt to differentiate NMOSD from MS by comparing brain lesion patterns on magnetic resonance imaging (MRI).
The medical records and cranial MRI studies of patients with NMOSD diagnosed according to the 2006 Wingerchuk criteria and the presence of anti-aquaporin 4 (anti-AQP4) antibodies, and patients with MS diagnosed according to the Poser criteria, were retrospectively reviewed.
Twenty-five NMOSD and 29 MS patients were recruited. The NMOSD patients became wheelchair dependent earlier than MS patients (log rank test; P = 0.036). Linear ependymal (28% vs. 0%, P = 0.003) and punctate lesions (64% vs. 28%, P = 0.013) were more frequently seen in NMOSD patients. Ten NMOSD patients (40%) had brain lesions that did not meet the Matthews criteria (MS were separated from NMOSD by the presence of at least 1 lesion adjacent to the body of the lateral ventricle and in the inferior temporal lobe; or the presence of a subcortical U-fiber lesion or a Dawson finger-type lesion). The different image patterns of NMOSD didn’t correlate with the clinical prognosis. However, NMOSD patients with more (≧10) brain lesions at onset became wheelchair dependence earlier than those with fewer (<10) brain lesions (log rank test; P < 0.001).
The diagnostic sensitivity of NMOSD criteria can be increased to 56% by combining the presence of linear ependymal lesions with unmet the Matthews criteria. The prognoses of NMOSD and MS are different. A specific imaging marker, the linear ependymal lesion, was present in some NMOSD patients. The diagnosis of NMOSD can be improved by following the evolution of this imaging feature when anti-AQP4 antibody test results are not available.
PMCID: PMC4264553  PMID: 25433369
Neuromyelitis optica; Multiple sclerosis; Anti-aquaporin 4 antibody; Magnetic resonance imaging
49.  Effects of differences in serum total homocysteine, folate, and vitamin B12 on cognitive impairment in stroke patients 
BMC Neurology  2014;14:217.
Vascular cognitive impairment-no dementia (VCIND) refers to the early or mild cognitive impairment induced by cerebral vascular injury. Research shows that serum total homocysteine (tHcy) level is an independent risk factor for cerebral vascular disease and may be closely related to cognitive function.Current studies on the tHcy level in VCIND patients are limited, and the relationship of tHcy with cognitive function remains unclear. This study aims to investigate the tHcy levels in patients with VCIND and to determine their correlation with cognitive function, as well as to provide useful clues for preventing and treating VCIND.
The tHcy, folate, and vitamin B12 levels in 82 patients with VCIND were reviewed retrospectively and compared with those of 80 stroke patients without cognitive impairment and 69 healthy controls by using the Montreal Cognitive Assessment (MoCA) scale and the event-related potential P300 to evaluate cognitive function.
The tHcy levels in the VCIND group were higher than those in the other two groups, whereas the folate and Vitamin B12 levels in the VCIND group were lower than those of the other two groups. The tHcy levels in the stroke group were higher than those in the control group, and the folate and vitamin B12 levels in the stroke group were lower than those in the control group. The patients in the VCIND group with high tHcy exhibited lower MoCA scores and prolonged P300 latency than those in with normal tHcy. Correlation analysis showed that tHcy level is positively correlated with P300 latency period and negatively correlated with MoCA score.
The tHcy levels were significantly higher and the vitamin B12 and folate levels were significantly lower in the patients with VCIND than those in the other groups. The high tHcy levels in the VCIND patients may be correlated with impaired cognitive function.
PMCID: PMC4333896  PMID: 25433800
Cognitive impairment; Cerebrovascular disorder; Neuropsychology; Event related potentials P300; Homocysteine
50.  Impact of a switch to fingolimod versus staying on glatiramer acetate or beta interferons on patient- and physician-reported outcomes in relapsing multiple sclerosis: post hoc analyses of the EPOC trial 
BMC Neurology  2014;14(1):220.
The Evaluate Patient OutComes (EPOC) study assessed physician- and patient-reported outcomes in individuals with relapsing multiple sclerosis who switched directly from injectable disease-modifying therapy (iDMT; glatiramer acetate, intramuscular or subcutaneous interferon beta-1a, or interferon beta-1b) to once-daily, oral fingolimod. Post hoc analyses evaluated the impact of a switch to fingolimod versus staying on each of the four individual iDMTs.
Overall, 1053 patients were randomized 3:1 to switch to fingolimod or remain on iDMT. The primary endpoint was the change in Treatment Satisfaction Questionnaire for Medication (TSQM) Global Satisfaction score. Secondary endpoints included changes in scores for TSQM Effectiveness, Side Effects and Convenience subscales, Beck Depression Inventory-II (BDI-II), Fatigue Severity Scale (FSS), Patient-Reported Outcome Indices for Multiple Sclerosis (PRIMUS) Activities, 36-item Short-Form Health Survey (SF-36) Mental Component Summary (MCS) and Physical Component Summary (PCS) and mean investigator-reported Clinical Global Impressions of Improvement (CGI-I). All outcomes were evaluated after 6 months of treatment.
Changes in TSQM Global Satisfaction scores were superior after a switch to fingolimod when compared with scores in patients remaining on any of the iDMTs (all p <0.001). Likewise, all TSQM subscale scores improved following a switch to fingolimod (all p <0.001), except when compared with glatiramer acetate for the TSQM Side Effects subscale (p = 0.111). FSS scores were found to be superior for fingolimod versus remaining on subcutaneous interferon beta-1a and interferon beta-1b, BDI-II scores were significantly improved for fingolimod except for the comparison with intramuscular interferon beta-1a, and SF-36 scores were superior with fingolimod compared with remaining on interferon beta-1b (MCS and PCS; p = 0.030 and p = 0.022, respectively) and subcutaneous interferon beta-1a (PCS only; p = 0.024). Mean CGI-I scores were superior with fingolimod when compared with continuing treatment with any of the iDMTs (all p <0.001).
After 6 months, a switch to fingolimod showed superiority compared with remaining on each iDMT for a range of patient- and physician-reported outcomes, including global satisfaction with treatment.
Trial registration NCT01216072.
PMCID: PMC4253981  PMID: 25424122
36-item Short-Form Health Survey (SF-36); Beck Depression Inventory-II (BDI-II); Clinical Global Impressions of Improvement (CGI-I); Fatigue Severity Scale (FSS); Fingolimod; FTY720; Multiple sclerosis; Treatment Satisfaction Questionnaire for Medication (TSQM)

Results 26-50 (1206)