Seizure-related complication rate in a residential population with epilepsy and intellectual disability (ECOMRAID-trial).

INTRODUCTION: The aim of the ECOMRAID trial (Epileptic seizure related Complication RAte in residential population of persons with epilepsy and Intellectual Disability) was to study seizure-related complications (status epilepticus, respiratory complications, or other severe complications) in people with epilepsy and intellectual disability living in a residential setting. The results of the present study are a prerequisite for performing a prospective study into the effectiveness of nocturnal surveillance patients with high risk for Sudden unexpected death in epilepsy (SUDEP). MATERIAL AND METHODS: A retrospective study was conducted in three general residential care institutions and one residential specialized epilepsy clinic. In this 5-year cohort, we collected the following data: age (at inclusion and in case of death), sex, type of residential care, different types of complications, rescue/emergency medication administration, transfers to another department (internal midcare / monitoring unit or general hospital) and a self-designed SUDEP risk score. Our primary research questions were to assess the number of patients who experienced seizure-related complications and their individual complication rates. The secondary research questions were to document the relationship of these complications with the SUDEP risk score, with the type of residential living, and with the frequency of interventions by caregivers. RESULTS: We included 370 patients (1790 patient-years) and in 135 of them, we found 717 seizure-related complications. The following complication rates were found: all complications: at 36%, status epilepticus: at 13%, respiratory complications: at 5%, and other complications at 26%. In residential care institutions, we found fewer patients with complications compared to the specialized epilepsy clinic (all complications 24% vs 42%, OR 0.44, p < 0.01; status epilepticus 5% vs 17%, OR 0.27, p < 0.01; other: complications 19% vs 30%, OR 0.56, p < 0.05). In residential care institutions, we found more "other complications" than in the specialized epilepsy clinic (89% vs 71%, OR 3.13, p < 0.0001). The annual frequency of all complications together was higher in residential care institutions (range 0 to 21 vs 0 to 10, p < 0.05). Rescue medication was given to 75% of the patients, but more often in the specialized epilepsy clinic (median 2.6 vs 0.5 times/patient/year, p < 0.001). In the specialized epilepsy clinic, more patients were transferred to a midcare / monitoring unit or general hospital (56% vs 9%, OR 13.44, p < 0.0001) with higher yearly frequencies (median 0.2 vs 0.0, p < 0.001). There were no reported cases of SUDEP. The median SUDEP risk score was higher in the specialized epilepsy clinic (5 vs 4, p < 0.05) and was weakly correlated with the status epilepticus (ρ = 0.20, p < 0.001) and (total) complication rate (ρ = 0.18, p < 0.001). CONCLUSION: We found seizure-related complications in more than one-third of the patients with epilepsy and intellectual disability living in a residential setting over a period of 5 years. The data also quantify seizure-related complications in patients with epilepsy and intellectual disability.

Subgroup classification in patients with psychogenic non-epileptic seizures.

INTRODUCTION: In this open non-controlled clinical cohort study, the applicability of a theoretical model for the diagnosis of psychogenic non-epileptic seizures (PNES) was studied in order to define a general psychological profile and to specify possible subgroups. METHODS: Forty PNES patients were assessed with a PNES "test battery" consisting of eleven psychological instruments, e.g., a trauma checklist, the global cognitive level, mental flexibility, speed of information processing, personality factors, dissociation, daily hassles and stress and coping factors. RESULTS: The total PNES group was characterized by multiple trauma, personality vulnerability (in a lesser extent, neuropsychological vulnerabilities), no increased dissociation, many complaints about daily hassles that may trigger seizures and negative coping strategies that may contribute to prolongation of the seizures. Using factor analysis, specific subgroups were revealed: a 'psychotrauma subgroup', a 'high vulnerability somatizing subgroup' (with high and low cognitive levels) and a 'high vulnerability sensitive personality problem subgroup'. CONCLUSION: Using a theoretical model in PNES diagnosis, PNES seem to be a symptom of distinct underlying etiological factors with different accents in the model. Hence, describing a general profile seems to conceal specific subgroups with subsequent treatment implications. This study identified three factors, representing two dimensions of the model, that are essential for subgroup classification: psychological etiology (psychotrauma or not), vulnerability, e.g., the somatization tendency, and sensitive personality problems/characteristics ('novelty seeking'). For treatment, this means that interventions could be tailored to the main underlying etiological problem. Also, further research could focus on differentiating subgroups with subsequent treatment indications and possible different prognoses.

Patients with psychogenic non-epileptic seizures referred to a tertiary epilepsy centre: patient characteristics in relation to diagnostic delay.

OBJECTIVE: This clinical study examines patient and seizure characteristics of patients with psychogenic non-epileptic seizures (PNES) in a tertiary epilepsy centre. The main focus was whether a new subgroup of PNES patients emerged with a relatively short referral time and possible specific characteristics. METHODS: All PNES patients referred to a specialist program in our centre between mid 2007 and mid 2009 were consecutively included. This yielded a study cohort of 90 patients. RESULTS: The majority of the patients have a patient history with many medical symptoms and they were or had been in treatment by a medical specialist. Furthermore diffuse psychological/psychiatric symptoms and subsequent treatments are also remarkably common, in general without a clear psychological diagnosis. The average time between seizure onset and referral to an epilepsy centre is remarkably low (4.29 years). About 50% of the patients were referred within 2 years of seizure onset. This 'active high speed referral group' had significantly more previous psychological complaints, significantly more previous psychological/psychiatric treatments and a trend towards more previous medical investigations. CONCLUSION: There seems to be a new subgroup of PNES patients with a short referral time, characterized by a more active attitude towards examination of the symptoms in combination with an active attitude to apply for treatment. However, the PNES cohort as a whole is characterized by having somatoform symptoms based on a process of somatization.

Cognitive slowing in multiple sclerosis is strongly associated with brain volume reduction.

INTRODUCTION: In this study, we investigated the influence of in vivo disease pathology (measured as magnetic resonance imaging (MRI) lesion load and brain volume reduction) on cognitive functioning, especially the speed of processing, in multiple sclerosis (MS) patients. Since MS is characterized by cognitive slowing rather than impaired accuracy, we used the Amsterdam Neuropsychological Tasks (ANT) program, a computerized test proven to be very sensitive to cognitive slowing in MS patients. METHODS: Thirty-two patients performed the ANT and underwent MRI scanning. Using the ANT computerized tests, we investigated focused, divided, sustained attention, executive function and psychomotor function, and examined associations of speed, speed fluctuation and accuracy of performance of these tests with MRI lesion load and brain volume parameters. RESULTS: A decrease in the speed of processing and response speed stability, and a decrease in psychomotor accuracy and stability were clearly associated with less brain volume, and with higher lesion loads, in particular at frontal and occipital areas. Correlations with brain volume reduction were found for all domains, except for visuo-spatial processing. In particular, speed and speed fluctuation scores correlated with brain volume reduction, while accuracy of performance, in general, did not correlate. Only some test speed scores and speed fluctuation scores correlated with lesion load measurements. CONCLUSION: This study shows that, in MS patients, accuracy of processing is not compromised unless high working memory demands are involved. Problems in neurocognitive functioning in MS are mainly modulated by speed and stability of speed processing, in particular when attention-demanding controlled information processing is required. Abnormalities in these domains are most strongly associated with brain volume loss, confirming that pathology beyond focal lesions is important in MS.

Brain atrophy and lesion load as explaining parameters for cognitive impairment in multiple sclerosis.

Multiple sclerosis (MS) is a multifocal demyelinating disease of the central nervous system, with lesions widespread through the brain and spinal cord. An important manifestation is cognitive impairment, which, though difficult to measure, may have a major social impact. To better understand the relationship between structural tissue damage and cognitive impairment, we examined the extent and spatial distribution of brain lesions, as measured by magnetic resonance imaging (MRI), in relation to abnormal cognitive performance as measured by the Brief Repeatable Battery (BRB) in 82 MS patients. Possible confounders, like fatigue, pain and depression were also assessed. Brain MR image analysis included hyperintense T2 and hypointense T1 lesion load in the whole brain and the four lobes separately, as well as whole brain volume measurements. Cognitive impairment (defined as more than two abnormal tests) was found in 67% of the patients. Moderately strong correlations were found between the subtests of the BRB and the lesion loads in the brain regions hypothesized to be associated with that cognitive test, although these correlations were in general not much stronger than those between the subtests and the overall lesion load (due to strong interrelationships). The Spatial Recall Test correlated best with parietal lesion load; the Symbol Digit Modalities Test, the Paced Auditory Serial Addition Task (PASAT) and the Word List Generation best with frontal, parietal and temporal lesion load; while the Verbal List Generation Test Index correlated only with atrophy. Atrophy and lesion load were the main factors determining the test scores, explaining 10-25% of the variance in the test results, and were more important than fatigue, pain and depression; only depression had a minor, but significant, additional effect on the PASAT. In conclusion, cognitive impairment in MS is moderately dependent on amount (and distribution) of structural brain damage, especially in the more physically impaired patients group.

Axonal damage accumulates in the progressive phase of multiple sclerosis: three year follow up study.

BACKGROUND: Neurofilament phosphoforms (Nf) are principal components of the axoskeleton released during axonal injury. Cerebrospinal fluid (CSF) levels of Nf phosphoforms might be useful surrogate markers for disability in multiple sclerosis (MS), aid in distinguishing clinical subtypes, and provide valuable prognostic information. METHOD: Thirty four patients with MS were included in a three year follow up study along with 318 controls with other non-inflammatory neurological diseases. CSF levels of two Nf heavy chain (NfH) phosphoforms (NfH(SMI35), NfH(SMI34)) were quantified at baseline and three year follow up using new ELISA techniques. Levels of NfH phosphoforms, the degree of phosphorylation (NfH(SMI34):NfH(SMI35) ratio), and changes in NfH levels between baseline and follow up (Delta NfH) were related to the clinical phenotype (RR or SP/PP), to three clinical scales (Kurtzke's EDSS, ambulation index (AI), and nine hole peg test (9HPT)), and to progression of disability. RESULTS: A significantly higher proportion (59%) of patients with SP/PPMS experienced an increase in NfH(SMI35) levels between baseline and follow up compared with those with RRMS (14%, p<0.05). CSF NfH(SMI34) levels at baseline were higher in patients with SP/PP (11 pg/ml) compared with RR (7 pg/ml, p<0.05) and NfH(SMI35) levels were higher at follow up in SP/PP (129 pg/ml) compared with levels below assay sensitivity in RR (p<0.05). NfH(SMI35) correlated with the EDSS (r(s) = 0.54, p<0.01), the AI (r(s) = 0.42, p<0.05), and the 9HPT (r(s) = 0.59, p<0.01) at follow up. CONCLUSION: The increase in NfH during the progressive phase of the disease together with the correlation of NfH(SMI35) with all clinical scales at follow up suggests that cumulative axonal loss is responsible for sustained disability and that high NfH(SMI35) levels are a poor prognostic sign.

CSF nitric oxide metabolites are associated with activity and progression of multiple sclerosis.

OBJECTIVE: To investigate the relationship of CSF and the serum nitric oxide metabolites nitrite and nitrate (NOx) to disease activity and progression in patients with multiple sclerosis (MS). METHODS: The study was divided into cross-sectional and follow-up. In the cross-sectional study, 20 patients with relapsing-remitting (RR), 21 with secondary progressive (SP), and 10 with primary progressive (PP) MS and 14 control subjects were included. Patients were assessed on clinical (Expanded Disability Status Scale [EDSS], Ambulation Index [AI], 9-Hole Peg Test [9-HPT]) and MRI measurements. In the follow-up study, 34 MS patients from the cross-sectional study agreed to be assessed again after an average of 3.0 +/- 0.5 years. NOx was measured using a vanadium-based assay. RESULTS: In the cross-sectional study, CSF NOx was raised in patients with RR-MS (p = 0.001) and PP-MS (p = 0.02) vs controls. Higher CSF NOx levels were found in patients with mild disability (AI < or = 6.0; EDSS < or = 4.0; Multiple Sclerosis Severity Score [MSSS] < or = 4.8) vs patients with advanced disease (AI > 6.0 [p = 0.002]; EDSS > 4.0 [p = 0.02]; MSSS > 4.8 [p = 0.01]). In the subgroup of patients having Gd-enhancing MRI lesions (n = 11), correlation between the volume of enhancement and CSF NOx was found (r = 0.74, p = 0.01). In the follow-up study, patients with disability progression had higher baseline CSF NOx levels than those who were stable on EDSS (p = 0.02) or AI (p = 0.03). A positive correlation was found between baseline CSF NOx and the change in MR T2-weighted lesion load (r = 0.4, p = 0.03). CONCLUSIONS: CSF nitrite and nitrate levels were increased in mildly disabled patients with MS and found to correlate with the volume of Gd-enhanced lesions on MRI. Raised baseline CSF NOx was associated with clinical and MRI progression in MS patients over 3-year follow-up.

Multiple sclerosis: Neurofilament light chain antibodies are correlated to cerebral atrophy.

OBJECTIVE: To evaluate markers of axonal damage in CSF and serum of patients with different subtypes of MS in relation to measures of disease progression on MRI. METHODS: In 51 patients with MS (21 relapsing-remitting, 20 secondary progressive, 10 primary progressive), levels of heavy and light neurofilaments (NfH and NfL) and antibodies to neurofilaments (anti-NfL and -NfH) as well as the total immunoglobulin G (IgG) were analyzed. MRI analysis included T2 hyperintense, T1 hypointense, and gadolinium enhancing lesions and markers of cerebral atrophy (ventricular and parenchymal fractions). RESULTS: For the total group, correlations were found between the anti-NfL index and the parenchymal fraction (PF) (r = -0.51, p < 0.001), T2 lesion load (r = 0.41, p < 0.05), ventricular fraction (r = 0.37, p < 0.05), and T1 lesion load (r = 0.37, p < 0.05). For the anti-NfH index, a correlation was found with the PF (r = -0.39, p < 0.05). No correlations were found between the IgG index and MRI measures. CONCLUSIONS: Intrathecal production of anti-NfL antibodies may serve as a marker of tissue damage, particularly axonal loss, in MS.

Information processing characteristics in subtypes of multiple sclerosis.

The purpose of this study was to evaluate information processing characteristics in patients with multiple sclerosis (MS). We selected 53 patients with MS and 58 matched healthy controls. Using computerized tests, we investigated focused, divided, sustained attention, and executive function, and attempted to pinpoint deficits in attentional control to peripheral or central processing stages. The results substantiate the hypothesis that the slowing of attention-demanding (controlled) information processing underlying more complex cognitive skills is general, i.e. irrespective of type of controlled processing, with MS patients being 40% slower than controls. MS patients may suffer from focused, and divided and sustained attention deficits, as well as from compromised central processing stages, with secondary progressive (SP) patients showing the most extensive range of deficits, closely followed by primary progressive (PP) patients, while relapsing-remitting (RR) patients appear to be much less affected. General slowing appears to be highest in PP and SP type MS patients (50% slower) versus relapsing-remitting MS (24% slower). In contrast to most previous results, (complex) processing speed appeared to be robustly correlated with severity of MS as measured by the expanded disability status scale and with disease duration. Patients did much less differ in accuracy of processing from controls, suggesting the importance of using time strategies in planning everyday life and job activities to compensate for or alleviate MS-related speed handicaps.

Markers for different glial cell responses in multiple sclerosis: clinical and pathological correlations.

Disease progression in multiple sclerosis occurs within the interface of glial activation and gliosis. This study aimed to investigate the relationship between biomarkers of different glial cell responses: (i) to disease dynamics and the clinical subtypes of multiple sclerosis; (ii) to disability; and (iii) to cross-validate these findings in a post-mortem study. To address the first goal, 51 patients with multiple sclerosis [20 relapsing remitting (RR), 21 secondary progressive (SP) and 10 primary progressive (PP)] and 51 neurological control patients were included. Disability was assessed using the ambulation index (AI), the Expanded Disability Status Scale score (EDSS) and the 9-hole PEG test (9HPT). Patients underwent lumbar puncture within 7 days of clinical assessment. Post-mortem brain tissue (12 multiple sclerosis and eight control patients) was classified histologically and adjacent sites were homogenized for protein analysis. S100B, ferritin and glial-fibrillary acidic protein (GFAP) were quantified in CSF and brain-tissue homogenate by ELISA (enzyme-linked immunosorbent assay) techniques developed in-house. There was a significant trend for increasing S100B levels from PP to SP to RR multiple sclerosis (P < 0.05). S100B was significantly higher in RR multiple sclerosis than in control patients (P < 0.01), whilst ferritin levels were significantly higher in SP multiple sclerosis than in control patients (P < 0.01). The S100B : ferritin ratio discriminated patients with RR multiple sclerosis from SP, PP or control patients (P < 0.05, P < 0.01 and P < 0.01, respectively). Multiple sclerosis patients with poor ambulation (AI > or =7) or severe disability (EDSS >6.5) had significantly higher CSF GFAP levels than less disabled multiple sclerosis or control patients (P < 0.01 and P < 0.001, respectively). There was a correlation between GFAP levels and ambulation in SP multiple sclerosis (r = 0.57, P < 0.01), and between S100B level and the 9HPT in PP multiple sclerosis patients (r = -0.85, P < 0.01). The post-mortem study showed significantly higher S100B levels in the acute than in the subacute plaques (P < 0.01), whilst ferritin levels were elevated in all multiple sclerosis lesion stages. Both GFAP and S100B levels were significantly higher in the cortex of multiple sclerosis than in control brain homogenate (P < 0.001 and P < 0.05, respectively). We found that S100B is a good marker for the relapsing phase of the disease (confirmed by post-mortem observation) as opposed to ferritin, which is elevated throughout the entire course. GFAP correlated with disability scales and may therefore be a marker for irreversible damage. The results of this study have broad implications for finding new and sensitive outcome measures for treatment trials that aim to delay the development of disability. They may also be considered in future classifications of multiple sclerosis patients.