Repeated polysomnography and multiple sleep latency test in narcolepsy type 1 and other hypersomnolence disorders.

BACKGROUND: The diagnosis of narcolepsy is based on clinical information, combined with polysomnography (PSG) and the Multiple Sleep Latency Test (MSLT). PSG and the MSLT are moderately reliable at diagnosing narcolepsy type 1 (NT1) but unreliable for diagnosing narcolepsy type 2 (NT2). This is a problem, especially given the increased risk of a false-positive MSLT in the context of circadian misalignment or sleep deprivation, both of which commonly occur in the general population. AIM: We aimed to clarify the accuracy of PSG/MSLT testing in diagnosing NT1 versus controls without sleep disorders. Repeatability and reliability of PSG/MSLT testing and temporal changes in clinical findings of patients with NT1 versus patients with hypersomnolence with normal hypocretin-1 were compared. METHOD: 84 patients with NT1 and 100 patients with non-NT1-hypersomnolence disorders, all with congruent cerebrospinal fluid hypocretin-1 (CSF-hcrt-1) levels, were included. Twenty-five of the 84 NT1 patients and all the hypersomnolence disorder patients underwent a follow-up evaluation consisting of clinical assessment, PSG, and a modified MSLT. An additional 68 controls with no sleep disorders were assessed at baseline. CONCLUSION: Confirming results from previous studies, we found that PSG and our modified MSLT accurately and reliably diagnosed hypocretin-deficient NT1 (accuracy = 0.88, reliability = 0.80). Patients with NT1 had stable clinical and electrophysiological presentations over time that suggested a stable phenotype. In contrast, the PSG/MSLT results of patients with hypersomnolence, and normal CSF-hcrt-1 had poor reliability (0.32) and low repeatability.

Repeated measures of hypocretin-1 in Danish and Italian patients with narcolepsy and in controls.

STUDY OBJECTIVES: The assay currently used worldwide to measure cerebrospinal fluid hypocretin-1 (CSF-hcrt-1) for diagnosing narcolepsy uses a competitive radioimmunoassay with polyclonal anti-hcrt-1 antibodies. This assay detects multiple hypocretin-1 immunoreactive species in the CSF that are all derived from full-length hcrt-1. We aimed to revalidate CSF-hcrt-1 cut-offs for narcolepsy type 1 (NT1) diagnosis and to evaluate temporal changes in CSF-hcrt-1 levels in patients suspected of having central hypersomnia. METHOD: We carried out a repeat lumbar puncture with a mean follow-up of 4.0 years, to measure CSF-hcrt-1 in patients suspected of having central hypersomnia in a follow-up study. Data from CSF samples of patients with NT1 and of controls without known hypersomnia, from the Italian-Stanford and Danish populations, were examined using a receiver-operating characteristic analysis. RESULTS: The optimal CSF-hcrt-1 cut-offs for identifying NT1 were 129 pg/ml and 179 pg/ml for the Italian-Stanford and Danish populations, respectively. The sensitivity was 0.93-0.99 and the specificity was 1. Follow-up lumbar puncture measurements of CSF-hcrt-1 were obtained from 73 patients. 30 of 32 patients with low CSF-hcrt-1 levels continued to be categorized as low, with an unaltered diagnosis; two patients showed a marked increase in CSF-hcrt-1, attaining normal values at follow-up. One of these patients relapsed to low CSF-hcrt-1 after follow-up. All 41 patients with normal CSF-hcrt-1 at baseline had normal CSF-hcrt-1 at follow-up. CONCLUSION: CSF-hcrt-1 measurement can provide an accurate test for diagnosing NT1, although it is important to validate the CSF-hcrt-1 cut-off for specific testing locations. Stable CSF-hcrt-1 levels support the already established prognosis of narcolepsy as permanent once the disorder has fully developed.

New, diagnostic flicker test for optic neuritis shows specific stages following disease onset.

BACKGROUND: Previously, results of the digital flicker test (DFT) have shown distinct patterns in acute optic neuritis (ON) and healthy eyes. We aimed to examine the diagnostic potential of the DFT in acute ON and to investigate the temporal development of the DFT response following ON while comparing with visual evoked potentials (VEP). METHODS: The DFT examines the subjective brightness of a flickering field, varied in 11 different frequencies from 0 to 60 Hz, compared to a steady field. Previous studies have indicated a pronounced darkness enhancement at medial frequencies in acute ON eyes. Darkness enhancement at medial frequencies was expressed as a quantitative covariate (DFTDE). Results were compared with healthy controls and follow-up measurements were compared with VEP. RESULTS: 112 patients were examined <31 days of onset (median 14.0 days (IQR:12.25)). 104 of 112 patients showed an abnormal flicker test (sensitivity 93%). DFT was abnormal in 2 of 55 healthy controls. The DFT showed normalization in 34% at 3 months, 36.4% at 6 months and 71.4% at >8 months from ON onset compared to 13.3%, 22.4% and 28.6% for VEP. Changes to the pattern of the DFT results were shown at specific stages during and following ON. CONCLUSIONS: The DFT is an easy-to-use and sensitive diagnostic test for acute ON. The flicker test shows a more pronounced temporal evolution following ON than VEP and may be of use monitoring the course of ON.

Multifocal visual evoked potential evaluation for diagnosis of acute optic neuritis and for prediction of visual outcome and ganglion cell layer thinning following optic neuritis.

BACKGROUND: While damage to the optic nerve following optic neuritis (ON) is readily quantifiable, the evaluation of prognosis for visual function and neuroaxonal loss in the acute ON is challenging. OBJECTIVE: The objective of this study is to investigate the value of multifocal visual evoked potential (mfVEP) in acute ON, diagnostically for acute ON and prognostically for visual outcome and subsequent ganglion cell/inner plexiform layer thickness (GCLIPLt). METHODS: A prospective cohort study of mfVEP and full-field visual evoked potential (ffVEP) in acute, unilateral ON (onset < 31 days) was conducted. Comparisons with healthy controls (n = 30) and association analysis with follow-up optical coherence tomography (OCT) measurements (of the GCLIPLt) and visual function (Sloan low-contrast visual acuity (LCVA)) were conducted. RESULTS: Seventy-nine ON patients were included (mean: 17 days from onset). Excluding measurements with conduction block, ffVEP (n = 54) and mfVEP (n = 44) showed sensitivities of 89% and 84% to a specificity of 97%. 65/79 patients were re-examined (mean: 200 days follow-up). mfVEP amplitude and latency inter-eye asymmetry in acute ON correlated with GCLIPLt (r = 0.587 and Spearman's ρ = 0.597, for both, p < 0.001). mfVEP amplitude correlated with LCVA inter-eye asymmetry at follow-up (r = 0.421, p < 0.001), mfVEP latency did not. CONCLUSION: mfVEP may support the prognostic evaluation of acute ON patients and prove valuable in future neuroprotective and remyelinating trials. In acute ON, the increase in diagnostic value of mfVEP to ffVEP may be limited due to widespread conduction block.

Diagnostic value of actigraphy in hypersomnolence disorders.

OBJECTIVE: Differentiating between the central hypersomnias presents a challenge to the diagnosis of patients with hypersomnolence. Actitigraphy may support efforts to distinguish them. We aimed to evaluate: 1) the ability of actigraphy to quantify sleep continuity measures in comparison with polysomnography in patients with hypersomnolence; 2) whether actigraphy can distinguish patients with hypersomnolence with normal hypocretin-1 in cerebrospinal fluid from patients with narcolepsy type 1 and from sleep-healthy controls; and 3) the distinct activity profiles and circadian rhythms of patients with narcolepsy type 1, patients with hypersomnolence with normal hypocretin-1 in cerebrospinal fluid, and sleep-healthy controls. METHOD: Polysomnography, multiple sleep latency tests and actigraphy were conducted in 14 patients with narcolepsy type 1, 29 patients with hypersomnolence with normal hypocretin-1 in cerebrospinal fluid and 15 sleep-healthy controls. RESULTS: Actigraphy quantified several sleep continuity measures consistently with polysomnography in all the patients. Actigraphy distinguished patients with hypersomnolence with normal hypocretin-1 in cerebrospinal fluid from patients with narcolepsy type 1 and sleep-healthy controls. Patients with narcolepsy type 1 had poor sleep quality and altered circadian rest-activity rhythm compared with controls. CONCLUSION: Actigraphy is an adequate tool for establishing the amount of night sleep and supports the differential diagnosis of patients with hypersomnolence.

Predictive value of optical coherence tomography, multifocal visual evoked potentials, and full-field visual evoked potentials of the fellow, non-symptomatic eye for subsequent multiple sclerosis development in patients with acute optic neuritis.

BACKGROUND: Diagnosis of multiple sclerosis (MS) may sometimes be ascertained at the time of optic neuritis (ON) but other times require the advent of new disease activity. OBJECTIVES: The aim of this study was to examine the predictive value of optical coherence tomography (OCT) and visual evoked potential (VEP) measurements of the non-symptomatic, fellow eye of ON patients, for conversion to MS. METHODS: This is a prospective cohort study in patients with acute ON. OCT thickness measurements of peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell layer-inner plexiform layer (GCLIPL), and multifocal (mf) VEP and full-field (ff) VEP, were performed. Univariate and multivariate Cox regression examined the value of predictors for the conversion to MS. RESULTS: A total of 79 unilateral, acute ON patients, with no MS diagnosis or prior demyelination, were included. Of which, 28 patients developed MS during follow-up. Inferonasal GCLIPL, mean GCLIPL, and pRNFL thickness significantly predicted MS development in multivariate analysis (hazard ratio (HR) = 0.922-0.939, p = 0.0172-0.021). MfVEP mean latency (HR = 1.052, p = 0.006) only predicted MS conversion in univariate analysis. No significant predictive value was shown for the other parameters (p > 0.2). CONCLUSION: While both mfVEP and OCT are useful tools in the evaluation of acute ON patients, only OCT measurements of fellow eyes may serve as an independent predictor of MS development.

Neurological Symptoms in Danes with a History of Poliomyelitis: Lifelong Follow-Up of Late Symptoms, their Association with Initial Symptoms of Polio, and Presence of Postpolio Syndrome.

BACKGROUND: Previous studies suggest that patients with a history of poliomyelitis (PM) later in life experience a variety of symptoms. These studies were carried out in patients who later in life were admitted to hospital or became members of polio societies and may therefore not be representative of all polio patients. Little data have been published concerning patients actually discharged from hospital with a diagnosis of acute paralytic PM. OBJECTIVES: The aim of this study was to compare the prevalence of late symptoms in individuals with a history of paralytic PM with that of controls, and to study whether late symptoms in individuals with a history of PM were associated with symptoms at the acute stage of polio, and finally to compare the prevalence of symptoms in polio patients with postpolio syndrome (PPS) with the prevalence of symptoms in polio patients without PPS. METHODS: A questionnaire concerning various symptoms was sent to a previously established cohort of patients, who during the polio epidemics were discharged from the Department of Infectious Disease at Blegdamshospitalet, Copenhagen, with a diagnosis of paralytic PM, and to age- and gender-matched controls without PM. Information about symptoms at the acute stage of disease was obtained from hospital records. Logistic regression analysis with adjustment for age and gender was applied to compare the occurrence of late symptoms in cases and controls and within the above-mentioned groups of individuals with a history of PM. RESULTS: (i) Compared with controls, individuals with a history of polio significantly more often reported muscle symptoms, pain, neuropathic sensory symptoms, and bulbar symptoms; (ii) the occurrence of symptoms did not seem to be related to symptoms of the initial PM; and (iii) symptom prevalence was significantly higher in individuals with a history of polio who reported PPS as compared with those who did not. CONCLUSION: Our data indicate that individuals with a history of PM late in life experience a variety of symptoms that cannot be attributed to lesions of the anterior horn. Furthermore, late symptoms do not seem to be related to initial symptoms of the acute stage of PM but to reported PPS. The last finding supports the perception that the cause of PPS is not just normal ageing.

Long-term socio-economic consequences and health care costs of poliomyelitis: a historical cohort study involving 3606 polio patients.

Worldwide 10-20 million individuals are living with disabilities after acute poliomyelitis. However, very little is known about the socio-economic consequences and health care costs of poliomyelitis. We carried out a historical register-based study including 3606 individuals hospitalised for poliomyelitis in Copenhagen, Denmark 1940-1954, and 13,795 age and gender-matched Danes. Participants were followed from 1980 until 2012, and family, socio-economic conditions and health care costs were evaluated in different age groups using chi-squared tests, boot-strapped t tests or hazard ratios (HR) calculated in Cox-regression models. The analyses were performed separately for paralytic and non-paralytic polio survivors and their controls, respectively. Compared with controls a higher percentage of paralytic polio survivors remained childless, whereas no difference was observed for non-paralytic polio survivors. The educational level among paralytic as well as non-paralytic polio survivors was higher than that among their controls, employment rate at the ages of 40, 50 and 60 years was slightly lower, whereas total income in the age intervals of 31-40, 41-50 and 51-60 years were similar to controls. Paralytic and non-paralytic polio survivors had a 2.5 [HR = 2.52 (95 % confidence interval (CI); 2.29-2.77)] and 1.4 [HR = 1.35 (95 % CI; 1.23-1.49)]-fold higher risk, respectively, of receiving disability pension compared with controls. Personal health care costs were considerably higher in all age groups in both groups of polio survivors. Individuals with a history of poliomyelitis are well educated, have a slightly lower employment rate, an income similar to controls, but a considerably higher cost in the health care system.

Relationship between cerebrospinal fluid biomarkers for inflammation, demyelination and neurodegeneration in acute optic neuritis.

BACKGROUND: Various inflammatory biomarkers show prognostic potential for multiple sclerosis (MS)-risk after clinically isolated syndromes. However, biomarkers are often examined singly and their interrelation and precise aspects of their associated pathological processes remain unclear. Clarification of these relationships could aid the appropriate implementation of prognostic biomarkers in clinical practice. OBJECTIVE: To investigate the interrelation between biomarkers of inflammation, demyelination and neurodegeneration in acute optic neuritis and to assess their association to measures of MS risk. MATERIAL AND METHODS: A prospective study at a tertiary referral centre from June 2011 to December 2012 of 56 patients with optic neuritis as a first demyelinating symptom and 27 healthy volunteers. Lumbar puncture was performed within 28 (median 16) days of onset. CSF levels of CXCL13, matrix metalloproteinase (MMP)-9, CXCL10, CCL-2, osteopontin and chitinase-3-like-1, myelin basic protein (MBP) and neurofilament light-chain (NF-L) were determined. MS-risk outcome measures were dissemination in space (DIS) of white matter lesions on cerebral MRI, CSF oligoclonal bands and elevated IgG-index. RESULTS: IN THE INTERRELATION ANALYSIS THE BIOMARKERS SHOWED CLOSE CORRELATIONS WITHIN TWO DISTINCT GROUPS: Biomarkers of leukocyte infiltration (CXCL13, MMP-9 and CXCL10) were strongly associated (p<0.0001 for all). Osteopontin and chitinase-3-like-1 were also tightly associated (p<0.0001) and correlated strongly to tissue damage markers (NF-L and MBP). The biomarkers of leukocyte infiltration all associated strongly with MS-risk parameters, whereas CHI3L1 and MBP correlated with MRI DIS, but not with CSF MS-risk parameters and osteopontin and NF-L did not correlate with any MS-risk parameters. CONCLUSIONS: OUR FINDINGS SUGGEST TWO DISTINCT INFLAMMATORY PROCESSES: one of leukocyte infiltration, represented by CXCL13, CXCL10 and MMP-9, strongly associated with and potentially predicting MS-risk; the other represented by osteopontin and CHI3L1, suggesting tissue damage-related inflammation, potentially predicting residual disabilities after attack and perhaps cumulative damage over time. These hypotheses should be further addressed in follow-up studies.

CSF abnormalities can be predicted by VEP and MRI pathology in the examination of optic neuritis.

Optic neuritis (ON) is linked to multiple sclerosis (MS). The presence of white matter lesions on cerebral magnetic resonance imaging (MRI) predicts the risk of MS after ON with considerable accuracy. Oligoclonal bands (OCB) are present in 95 % of MS patients, and a lumbar puncture can also be valuable in the evaluation of patients with ON. We analyzed CSF findings in patients referred with ON in the context of MRI and visual evoked potential (VEP) pathology. We assessed the possible contributory role of a lumbar puncture and weigh this against disadvantages of the procedure. Between February 2003 and November 2011, 505 patients were referred by ophthalmologists to the Clinic of Optic Neuritis, Glostrup Hospital, University of Copenhagen. None had MS prior to referral. A total of 437 were included in the study, and all underwent MRI, a lumbar puncture and VEP. Patients with other organic causes of their symptoms and patients with >3 months between onset and tests were excluded. All files were reviewed retrospectively. CSF leukocytes and the IgG index were elevated in 33 and 41 %, respectively, and OCBs were detected in 61 % of patients. CSF abnormalities correlated strongly with VEP and MRI (p < 0.0001). Patients with normal VEP and MRI had a 96 % probability of a normal lumbar puncture. The contributory role of a lumbar puncture in the evaluation of ON seems negligible when patients have a normal VEP and MRI. We suggest that all patients should be evaluated with VEP and MRI before deciding on a lumbar puncture.

Simvastatin improves final visual outcome in acute optic neuritis: a randomized study.

BACKGROUND: In recent years, small-scale clinical trials have indicated that statins or 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors exert pleiotropic immunomodulatory effects, with potential therapeutic implications in multiple sclerosis (MS). OBJECTIVE: To investigate whether simvastatin treatment (80 mg daily for 6 months) in patients with optic neuritis (ON) had a beneficial effect on visual outcome and on brain MRI. METHODS: Sixty-four patients with acute ON were randomized to simvastatin treatment (n = 32) or placebo (n = 32) for 6 months. None of the patients had been on immunosuppressive therapy for 6 months prior to inclusion or treated with steroids from symptom onset. Contrast sensitivity (Arden plates), visual acuity, colour perception, visual evoked potentials (VEP)--latency and amplitude, Visual Analogue Scale (VAS) score, and gadolinium enhancing and T2 lesions on brain MRI were evaluated at screening visit, day 14 (except brain MRI), day 90 and day 180. RESULTS: Simvastatin had a beneficial effect on VEP in both latency (p = 0.01) and amplitude (p = 0.01), a borderline effect on the Arden score (p = 0.06) and VAS (p = 0.04), and no effect on brain MRI or on relapse rate between the groups. CONCLUSION: This study provides Class I evidence that simvastatin 80 mg daily is well tolerated and possibly effective in patients with acute ON.

The socioeconomic consequences of multiple sclerosis: a controlled national study.

Multiple sclerosis (MS) has serious negative effects on health-, social-, and work-related issues for the patients and their families, thus causing significant socioeconomic burden. The objective of the study was to determine healthcare costs and indirect illness costs in MS patient in a national sample. We used all national records from the Danish National Patient Registry (1998-2006), and identified 10,849 MS patients which were compared with 43,396 randomly age-, sex- and social matched citizens. Healthcare sector costs included frequencies and costs of hospitalizations and weighted outpatient use, frequencies of visits and hospitalizations and costs from primary sectors, and the use and costs of drugs. Productivity costs (the value of lost productivity from time off from work due to illness) and all social transfer payments were also calculated. Patients with MS had significantly higher rates of health-related contact and medication use and very low employment rate which incurred a higher socioeconomic cost. The income level of employed MS patients was significantly lower than that of control subjects. The annual total health sector costs and productivity costs were €14,575 for MS patients vs. €1163 for control subjects (p<0.001), corresponding to an annual mean excess health-related cost of €13,413 for each patient with MS. In addition, the MS patients received an annual mean excess social transfer income of €6843. MS present social and economical consequences more than eight years before diagnosis. We conclude that MS causes major socioeconomic consequences for the individual patient and for society. Productivity costs are a far more important economic factor, especially due to reduced employment, which are enhanced by the early age of diagnose onset.

Neither retinal nor brain atrophy can be shown in patients with isolated unilateral optic neuritis at the time of presentation.

BACKGROUND: Acute monosymptomatic optic neuritis (ON) may be the earliest manifestation of multiple sclerosis (MS). Atrophy has been shown to be a prominent feature of MS with great impact on disability. OBJECTIVES: The objectives of this study were to evaluate retinal and brain atrophy and possible associations at the earliest possible stages of MS. METHODS: In a prospective observational cohort study we included 60 untreated patients with monosymptomatic ON and 19 healthy volunteers. Unaffected fellow eyes were examined with optical coherence tomography (OCT) and normalized brain volumes were calculated based on MRI. Additionally, visual evoked potentials (VEPs) were recorded. RESULTS: Neither OCT measurements nor brain volume measures revealed signs of localized or generalized atrophy in patients compared with healthy volunteers. Stratification of patients into high risk based on the presence of white matter lesions did not reveal differences. The association between OCT measures and brain volumes previously found could not be confirmed at the time of the first clinical event. VEP latency was significantly prolonged in patients with white matter lesions compared to those without lesions. A trend towards a relationship between VEP amplitude of fellow eyes and brain volumes was noted. CONCLUSIONS: In this cohort we were not able to show atrophic features in the retina or the brain, and the association between structural measures of the retina and the brain as indicated in the later stages of MS could not be reproduced. These findings suggest that atrophy does require time to evolve and indicate the complexity of the relationship between local and general structural measures.