Incidence and outcome of acquired demyelinating syndromes in Dutch children: update of a nationwide and prospective study.

INTRODUCTION: Acquired demyelinating syndromes (ADS) are immune-mediated demyelinating disorders of the central nervous system in children. A nationwide, multicentre and prospective cohort study was initiated in the Netherlands in 2006, with a reported ADS incidence of 0.66/100,000 per year and MS incidence of 0.15/100,000 per year in the period between 2007 and 2010. In this study, we provide an update on the incidence and the long-term follow-up of ADS in the Netherlands. METHODS: Children < 18 years with a first attack of demyelination were included consecutively from January 2006 to December 2016. Diagnoses were based on the International Paediatric MS study group consensus criteria. Outcome data were collected by neurological and neuropsychological assessments, and telephone call assessments. RESULTS: Between 2011 and 2016, 55/165 of the ADS patients were diagnosed with MS (33%). This resulted in an increased ADS and MS incidence of 0.80/100,000 per year and 0.26/100,000 per year, respectively. Since 2006 a total of 243 ADS patients have been included. During follow-up (median 55 months, IQR 28-84), 137 patients were diagnosed with monophasic disease (56%), 89 with MS (37%) and 17 with multiphasic disease other than MS (7%). At least one form of residual deficit including cognitive impairment was observed in 69% of all ADS patients, even in monophasic ADS. An Expanded Disability Status Scale score of ≥ 5.5 was reached in 3/89 MS patients (3%). CONCLUSION: The reported incidence of ADS in Dutch children has increased since 2010. Residual deficits are common in this group, even in monophasic patients. Therefore, long-term follow-up in ADS patients is warranted.

Incidence of acquired demyelinating syndromes of the CNS in Dutch children: a nationwide study.

Acquired demyelinating syndromes (ADS) can be a first presentation of multiple sclerosis (MS) in children. The incidence of these disorders in Europe is currently unknown. Children (<18 years old) living in the Netherlands who presented with ADS were included from January 1, 2007 to December 31, 2010 by the Dutch pediatric MS study group and the Dutch surveillance of rare pediatric disorders. Demographic and clinical data were collected. Eighty-six patients were identified over 4 years, resulting in an incidence of 0.66/1,00,000 per year. Most patients presented with polyfocal ADS without encephalopathy (30%), followed by polyfocal ADS with encephalopathy (24%), optic neuritis (ON, 22%), monofocal ADS (16%), transverse myelitis (3%), and neuromyelitis optica (3%). Patients with polyfocal ADS with encephalopathy were younger (median 3.9 years) than patients with ON (median 14.6 years, p < 0.001) or monofocal ADS (median 16.0 years, p < 0.001). Patients with polyfocal ADS without encephalopathy (median 9.2 years) were also younger than monofocal ADS patients (median 16.0 years, p < 0.001). There was a slight female preponderance in all groups except the ON group, and a relatively large number of ADS patients (29%) reported a non-European ancestry. Familial autoimmune diseases were reported in 23%, more often in patients with relapsing disease than monophasic disease (46 vs. 15%, p = 0.002) and occurring most often in the maternal family (84%, p < 0.001). During the study period, 23% of patients were subsequently diagnosed with MS. The annual incidence of ADS in the Netherlands is 0.66/1,00,000 children/year. A polyfocal disease onset of ADS was most common.

Intense T cell depletion followed by autologous bone marrow transplantation for severe multiple sclerosis.

BACKGROUND: Certain stem cell transplantation procedures might slow down inflammatory pathology in multiple sclerosis (MS). AIMS: To halt disease progression in aggressive MS by a bone marrow transplantation (BMT) protocol aimed at maximum T cell suppression. METHODS: Autologous BMT was performed in 14 patients with rapid secondary progressive MS (median EDSS score at baseline, 6; median disease duration, five years). To accomplish rigorous T cell ablation, a strong conditioning protocol was chosen--cyclophosphamide, total body irradiation, and antithymocyte globulin. To minimise the possibility of reinfusing mature T cells in the graft, bone marrow, not peripheral blood, was used as the CD34+ stem cell source. RESULTS: Median follow up was 36 months (range, 7-36). Post-transplant haemopoietic recovery was successful in all patients. Early toxicity included Epstein-Barr virus related post-transplantation lymphoproliferative disorder. Longterm effects were development of antithyroid antibodies (three) and myelodysplastic syndrome (one). One patient died of progressive disease five years after transplantation. Treatment failure, defined by EDSS increase sustained for six months or more, was seen in nine patients and stabilisation or improvement in five. Other clinical parameters generally showed the same outcome. No gadolinium enhanced lesions were seen on post-treatment magnetic resonance imaging, in either cerebral or spinal cord scans. However, cerebrospinal fluid oligoclonal bands remained positive in most cases. CONCLUSIONS: This strong immunosuppressive regimen did not prevent clinical progression in patients with aggressive secondary MS. The lack of efficacy, together with some serious side effects, does not favour the use of similar rigorous T cell depleting protocols in the future.

Connecting impairment, disability, and handicap in immune mediated polyneuropathies.

BACKGROUND: In the World Health Organisation (WHO) International Classification of Impairments, Disabilities, and Handicaps (ICIDH), it is suggested that various levels of outcome are associated with one another. However, the ICIDH has been criticised on the grounds that it only represents a general, non-specific relation between its entities. OBJECTIVE: To examine the significance of the ICIDH in immune mediated polyneuropathies. METHODS: Four impairment measures (fatigue severity scale, MRC sum score, "INCAT" sensory sum score, grip strength with the Vigorimeter), five disability scales (nine hole peg test, 10 metres walking test, an overall disability sum score (ODSS), Hughes functional grading scale, Rankin scale), and a handicap scale (Rotterdam nine items handicap scale (RIHS9)) were assessed in 113 clinically stable patients (83 with Guillain-Barré syndrome, 22 with chronic inflammatory demyelinating polyneuropathy, eight with a gammopathy related polyneuropathy). Regression analyses with backward and forward stepwise strategies were undertaken to determine the correlation between the various levels of outcome (impairment on disability, impairment on handicap, disability leading to handicap, and impairment plus disability on handicap). RESULTS: Impairment measures explained a substantial part of disability (R(2) = 0.64) and about half of the variance in handicap (R(2) = 0.52). Disability measures showed a stronger association with handicap (R(2) = 0.76). Combining impairment and disability scales accounted for 77% of the variance in handicap (RIHS9) scores. CONCLUSIONS: In contrast to some suggestions, support for the ICIDH model is found in the current study because significant associations were shown between its various levels in patients with immune mediated polyneuropathies. Further studies are required to examine other possible contributors to deficits in daily life and social functioning in these conditions.

Hematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study.

RATIONALE: Phase I/II studies of autologous hematopoietic stem cell transplantation (HSCT) for multiple sclerosis ( MS) were initiated, based on results of experimental transplantation in animal models of multiple sclerosis and clinical observations in patients treated concomitantly for malignant disease. PATIENTS: Eighty-five patients with progressive MS were treated with autologous HSCT in 20 centers and reported to the autoimmune disease working party of the European Group for Blood and Marrow Transplantation (EBMT). 52 (61 %) were female, median age was 39 [20-58] years. The median interval from diagnosis to transplant was 7 [1-26] years. Patients suffered from severe disease with a median EDSS score of 6.5 [4.5-8.5]. Active disease prior to transplant was documented in 79 of 82 evaluable cases. RESULTS: The stem cell source was bone marrow in 6 and peripheral blood in 79, and stem cells were mobilized into peripheral blood using either cyclophosphamide combined with growth factors or growth factors alone. Three patients experienced transient neurological complications during the mobilization phase. The high dose regimen included combination chemotherapy, with or without anti-lymphocyte antibodies or, with or without, total body irradiation. The stem cell transplants were purged of lymphocytes in 52 patients. Median follow-up was 16 [3-59] months. There were 7 deaths, 5 due to toxicity and infectious complications, 2 with neurological deterioration. The risk of death of any cause at 3 years was 10 (+/-7)% (95 % confidence interval). Neurological deterioration during transplant was observed in 22 patients; this was transient in most but was associated with MS progression in 6 patients. Neurological improvement by > or = 1 point in the EDSS score was seen in 18 (21 %) patients. Confirmed progression-free survival was 74 (+/-12)% at 3 years being 66 (+/-23)% in patients with primary progressive MS but higher in patients with secondary progressive or relapsing-remitting MS, 78 (+/-13)%; p = 0.59. The probability of confirmed disease progression was 20 (+/-11)%. MRI data were available in 78 patients before transplant showing disease activity (gadolinium enhancing, new or enlarging lesions) in 33 %. Posttransplant MRI showed activity at any time in 5/61 (8 %) evaluable cases. CONCLUSION: Autologous HSCT suggest positive early results in the management of progressive MS and is feasible. These multicentre data suggest an association with significant mortality risks especially in some patient groups and are being utilised in the planning of future trials to reduce transplant related mortality.

Quality of life complements traditional outcome measures in immune-mediated polyneuropathies.

OBJECTIVES: To determine whether quality of life complements traditional outcome measures in immune-mediated polyneuropathies using the Medical Outcome Study 36-item short-form health status scale (SF-36). The validity, reliability, and responsiveness of the SF-36 were also analyzed. METHODS: SF-36 and three other measures (Medical Research Council sumscore, sensory sumscore, and Hughes functional scale) were assessed in 114 stable patients (83 with Guillain-Barré syndrome (GBS), 23 with chronic inflammatory demyelinating polyneuropathy (CIDP), eight with a gammopathy-related polyneuropathy) and serially in 20 patients with recently diagnosed GBS (n = 7) or CIDP (n = 13) with changing conditions. The SF-36 values were compared with reported healthy Dutch community scores (controls). The SF-36 validity and reliability were examined by correlation and regression studies with the other measures and by calculating its internal consistency. The standardized response mean and effect size techniques were applied to determine its responsiveness. RESULTS: In the stable group, all SF-36 scores were substantially lower (indicating worse clinical condition) compared with control subjects (p < 0.0001). Improvement in the longitudinal group resulted in a gradual shift of all SF-36 scores toward normal values. Acceptable validity and internal consistency values and moderate to good standardized response mean and effect size scores were demonstrated for the SF-36. The Medical Research Council sumscore and sensory sumscore explained SF-36 values only partially. CONCLUSION: The SF-36 as a generic health status complemented traditional strength and sensory measures in patients with immune-mediated polyneuropathies and appears to be a potentially valuable instrument for measuring quality of life in these conditions.

Clinimetric evaluation of a new overall disability scale in immune mediated polyneuropathies.

OBJECTIVES: To determine the validity, reliability, and responsiveness of a new overall disability sum score in immune mediated polyneuropathies. METHODS: Three impairment measures (MRC sum score, sensory sum score, grip strength (Vigorimeter)) and three disability scales (an overall disability sum score (ODSS), Hughes' functional scale (f score), Rankin scale) were assessed in a cross sectional group of 113 clinically stable patients (83 with Guillain-Barré syndrome, 22 with chronic inflammatory demyelinating polyneuropathy (CIDP), eight with a gammopathy related polyneuropathy). The ODSS was also used serially in 20 patients with recently diagnosed Guillain-Barré syndrome (n = 7) or CIDP (n = 13) and changing clinical conditions. Multiple regression studies were performed to compare the impact of impairment disturbances (independent variables) on the various disability scales (dependent variable). RESULTS: Moderate to good construct validity (stable group: Spearman's rank test (absolute values), r = 0.41-0.79; longitudinal group: multiple correlation coefficient, R = 0.69-0.89; p < 0.006 for all associations) and reliability (intraclass correlation coefficient, R = 0.90-0.95; p < 0.0001) were demonstrated for the ODSS. Its SRM values were high (> 0.8), indicating good responsiveness. Impairment measures accounted for a higher variance proportion of the ODSS compared with the f score and Rankin (R = 0.64 v 0.56 and 0.45, respectively). CONCLUSIONS: All clinimetric requirements were met by the overall (arm and leg) disability sum score in immune mediated polyneuropathies. Its use is therefore suggested in evaluating immune mediated polyneuropathies.

Assessing grip strength in healthy individuals and patients with immune-mediated polyneuropathies.

Grip strength reference values for a portable dynamometer, the hand-held Vigorimeter, were calculated, and its validity, reliability, and responsiveness were examined in patients with immune-mediated polyneuropathies. We studied 530 healthy controls (age 5-93 years), 113 patients with stable polyneuropathy (83 with Guillain-Barré syndrome [GBS], 22 with chronic inflammatory demyelinating polyneuropathy [CIDP], and 8 with a gammopathy-associated polyneuropathy), and 20 patients with GBS or CIDP and changing clinical conditions (longitudinal group). An arm-disability scale was also assessed. Grip-strength reference values were calculated depending primarily on age and gender. Significant association was obtained between the Vigorimeter and the arm scale (in stable group, Spearman rank: r = -0.52 to -0.62; P or = 0.8) were demonstrated for the Vigorimeter. These results emphasize the clinical usefulness of the Vigorimeter, particularly in patients with immune-mediated polyneuropathies.

Fatigue in immune-mediated polyneuropathies. European Inflammatory Neuropathy Cause and Treatment (INCAT) Group.

OBJECTIVES: To determine the prevalence and severity of ongoing fatigue and to investigate the internal consistency, reliability, and validity of the Fatigue Severity Scale (FSS) in patients with immune-mediated polyneuropathies. METHODS: The FSS was assessed in 113 patients who either experienced Guillain-Barré syndrome in the past or currently have a stable, chronic, inflammatory demyelinating polyradiculoneuropathy or a polyneuropathy associated with a monoclonal gammopathy of undetermined significance, and in 113 age- and sex-matched healthy controls. Data on four additional scales (Medical Research Council sumscore, functional grading scale [f-score], INCAT sensory sumscore, medical outcome study 36-items health survey [SF-36]) were obtained in all patients. SF-36 also was assessed in 59 controls. RESULTS: "Severe" fatigue (FSS scores > or =95th percentile values in controls) was present in 80% of the patients. Fatigue was not significantly related to general strength, sensory deficits, f-score, and duration of symptoms. Severe fatigue was reported in 81% to 86% of patients with normal strength or sensation. Eighty percent of the patients (controls, 12%) reported their fatigue being among the three most disabling symptoms. SF-36 health status scores in the patient group were significantly lower than the obtained values of the controls and partially related to the FSS scores. Good internal consistency, significant reliability, and validity were obtained for the FSS. CONCLUSION: Fatigue is a major symptom in patients with immune-mediated polyneuropathies and may persist for years after apparent recovery. The Fatigue Severity Scale seems appropriate for assessing fatigue in these patients because good internal consistency, reliability, and validity were demonstrated.

[Double vision as a symptom of a serious disorder]. / Dubbelzien als symptoom van een ernstige aandoening.

Three women, aged 54, 69 and 73 years, respectively, developed diplopia together with ptosis of an upper eyelid during light exercise or fatigue or continuous; in one patient the diplopia was followed by headache and vomiting. The diagnoses made were 'intracranial aneurysm', 'myasthenia gravis' and 'temporal arteritis'. Diplopia may be a symptom of a disorder timely diagnosis and treatment of which may prevent serious consequences.