Cognitive deficits in behavioral-variant frontotemporal dementia (bvFTD) and AD are linked to frontal and temporal lobe gray matter (GM) pathology. The aim of this study was to assess the relative contribution of white (WM) and GM abnormalities to cognitive dysfunction in bvFTD and AD. Fractional anisotropy (FA) for the corpus callosum, cingulum (Cg), and uncinate fasciculus (Unc) was determined in 17 bvFTD and 10 AD patients who underwent neuropsychological testing. Regressions were performed to assess the relative contribution of WM and GM abnormalities to cognitive deficits. Multiple regression analysis revealed that in bvFTD, the left anterior Cg FA was related to executive function, the right anterior Cg FA to visual-spatial attention and working memory, the right posterior Cg to visual-constructional abilities and the left Unc FA to Modified Trails Errors. After adding corresponding GM volumes, the left anterior Cg FA, the right anterior cingulate FA, the right posterior cingulate FA and the left uncinate FA remained significant predictors of the cognitive tasks. In the AD group, the left posterior Cg FA and right descending Cg FA were related to visual recall performance but did not remain significant predictors when GM volumes were added to the regression. These results suggest that reduced integrity of specific WM tracts contribute to cognitive deficits observed in bvFTD after accounting for GM atrophy. In AD, memory impairment was related to WM tract injury but this relationship was no longer observed when GM volumes were included.
Cingulum; Executive function; Frontotemporal dementia; Alzheimer’s disease; White matter tracts
Activated microglia are thought to be an important contributor to tissue damage in multiple sclerosis (MS). The level of microglial activation can be measured non-invasively using [11C]-R-PK11195, a radiopharmaceutical for positron emission tomography (PET). Prior studies have identified abnormalities in the level of [11C]-R-PK11195 uptake in patients with MS, but treatment effects have not been evaluated. Nine previously untreated relapsing-remitting MS patients underwent PET and magnetic resonance imaging (MRI) of the brain at baseline and after one year of treatment with glatiramer acetate. Parametric maps of [11C]-R-PK11195 uptake were obtained for baseline and post-treatment PET scans, and the change in [11C]-R-PK11195 uptake pre- to post-treatment was evaluated across the whole brain. Region of interest analysis was also applied to selected subregions. Whole brain [11C]-R-PK11195 binding potential per unit volume decreased 3.17% (95% CI: −0.74%, −5.53%) between baseline and one year (p = 0.018). A significant decrease was noted in cortical gray matter and cerebral white matter, and a trend towards decreased uptake was seen in the putamen and thalamus. The results are consistent with a reduction in inflammation due to treatment with glatiramer acetate, though a larger controlled study would be required to prove that association. Future research will focus on whether the level of baseline microglial activation predicts future tissue damage in MS and whether [11C]-R-PK11195 uptake in cortical gray matter correlates with cortical lesion load.
multiple sclerosis; positron emission tomography; microglia; copolymer 1; immunology; PK11195
In this review we summarize progress in research on Parkinson's disease-related pain as reported in articles published in the Journal of Neurology in the years 2011 and 2012.
Neuropathic pain; Central pain; Parkinson disease
Population-based stroke registries can provide valid stroke incidence because they ensure exhaustiveness of case ascertainment. However, their results are difficult to extrapolate because they cover a small population. The French Hospital Discharge Database (FHDDB), which routinely collects administrative data, could be a useful tool for providing data on the nationwide burden of stroke. The aim of our pilot study was to assess the validity of stroke diagnosis reported in the FHDDB. All records of patients with a diagnosis of stroke between 2004 and 2008 were retrieved from the FHDDB of Dijon Teaching Hospital. The Dijon Stroke Registry was considered as the gold standard. The sensitivity, positive predictive value (PPV), and weighted kappa were calculated. The Dijon Stroke Registry identified 811 patients with a stroke, among whom 186 were missed by the FHDDB and thus considered false-negatives. The FHDDB identified 903 patients discharged following a stroke including 625 true-positives confirmed by the registry and 278 false-positives. The overall sensitivity and PPV of the FHDDB for the diagnosis of stroke were, respectively, 77.1 % (95 % CI 74.2–80) and 69.2 % (95 % CI 66.1–72.2). For cardioembolic and lacunar strokes, the FHDDB yielded higher PPVs (respectively 86.7 and 84.6 %; p < 0.0001) than those of other stroke subtypes. The PPV but not sensitivity significantly increased over the years (p < 0.0001). Agreement with the stroke registry was moderate (kappa 52.8; 95 % CI 46.8–58.9). The FHDDB-based stroke diagnosis showed moderate validity compared with the Dijon Stroke Registry as the gold standard. However, its accuracy (PPV) increased with time and was higher for some stroke subtypes.
Stroke; Registry; Hospital discharge data; Validation; Administrative data
Although familial Alzheimer’s disease (FAD) is an early onset AD (EAD), most patients with EAD do not have a familial disorder. Recent guidelines recommend testing for genes causing FAD only in those EAD patients with two first-degree relatives. However, some patients with FAD may lack a known family history or other indications for suspecting FAD but might nonetheless be carriers of FAD mutations. The study was aimed to identify clinical features that distinguish FAD from non-familial EAD (NF-EAD). A retrospective review of a university-based cohort of 32 FAD patients with PSEN1-related AD and 81 with NF-EAD was conducted. The PSEN1 patients, compared to the NF-EAD patients, had an earlier age of disease onset (41.8 ± 5.2 vs. 55.9 ± 4.8 years) and, at initial assessment, a longer disease duration (5.1 ± 3.4 vs. 3.3 ± 2.6 years) and lower MMSE scores (10.74 ± 8.0 vs. 20.95 ± 5.8). Patients with NF-EAD were more likely to present with non-memory deficits, particularly visuospatial symptoms, than were FAD patients. When age, disease duration, and MMSE scores were controlled in a logistical regression model, FAD patients were more likely to have significant headaches, myoclonus, gait abnormality, and pseudobulbar affect than those with NF-EAD. In addition to a much younger age of onset, FAD patients with PSEN1 mutations differed from those with NF-EAD by a history of headaches and pseudobulbar affect, as well as myoclonus and gait abnormality on examination. These may represent differences in pathophysiology between FAD and NF-EAD and in some contexts such findings should lead to genetic counseling and appropriate recommendations for genetic testing for FAD.
Dementia; Early onset Alzheimer’s disease; Familial Alzheimer’s disease; PSEN1 gene
The “MS in the 21st Century” initiative was established with the purpose of (1) defining how multiple sclerosis (MS) treatment and standards of care should look in the 21st century; (2) developing a minimum standard of care across the world; and (3) motivating the broad MS community to align standards of care and challenge the current treatment paradigm. The aim was to develop a consensus statement to reach and influence the broader MS community. An expert steering group from Europe and Canada—consisting of neurologists, patient advocates, a pharmacoepidemiologist/pharmacoeconomist, and representatives from national MS centers—participated in a series of workshop-driven meetings between February 2011 and 2012. After three phases of discussions, the steering group identified that the overall vision for future care of MS should be full access to personalized treatment, with reimbursement, to achieve freedom from disease. They constructed seven overall principles that support this vision: personalized care, patient engagement, commitment to research, regulatory body education and reimbursement issues, new endpoints in clinical trials, more therapy options, and MS centers of excellence. This consensus statement outlines the key aspects of the seven principles that need to be addressed. The “MS in the 21st Century Steering Group” hopes that this consensus statement acts as a call to action for healthcare providers and decision-makers to address simultaneously the overarching principles that will guide patient management in order to improve outcomes for people with MS.
Multiple sclerosis; Care; Management; Consensus statement
Motor disability in MS is commonly assessed by the Expanded Disability Status Scale (EDSS). Categorical rating scales are limited by subjective error and inter-rater variability. Therefore, objective and quantitative measures of motor disability may be useful to supplement the EDSS in the setting of clinical trials. It was previously shown that grip-force-variability (GFV) is increased in MS. We hypothesized that GFV may be an objective measure of motor disability in MS. To investigate whether the increase in GFV in MS is correlated to the clinical disability as assessed by the EDSS and to microstructural changes in the brain as assessed by diffusion tensor imaging, GFV was recorded in a grasping and lifting task in 27 MS patients and 23 controls using a grip-device equipped with a force transducer. The EDSS was assessed by neurologists experienced in MS. Patients underwent diffusion tensor imaging at 3T to assess the fractional anisotropy (FA) of the cerebral white matter as a measure of microstructural brain integrity. GFV was increased in MS and correlated to changes in the FA of white matter in the vicinity of the somatosensory and visual cortex. GFV also correlated with the EDSS. GFV may be a useful objective measure of motor dysfunction in MS linked to disability and structural changes in the brain. Our data suggests that GFV should be further explored as an objective measure of motor dysfunction in MS. It could supplement the EDSS, e.g., in proof of concept studies.
Multiple sclerosis; DTI; Clinical neurophysiology; Outcome research
Carotid intima-media thickness (IMT) is a surrogate marker for evaluating atherosclerotic vascular diseases. The phosphodiesterase inhibitor cilostazol attenuates the increase in carotid IMT in diabetes patients. We studied whether cilostazol can reduce the progression of carotid IMT in symptomatic ischemic stroke patients. From our prospective registry of acute ischemic stroke patients who were admitted during a 4.5-year period, follow-up carotid ultrasound was performed in a random sample of survivors. Patients were divided into two groups: the cilostazol group, who continued cilostazol treatment during the follow-up period; and the control group, who were prescribed antiplatelets other than cilostazol. Analysis of covariance and propensity score-matched analysis were used to evaluate the difference between groups. Among a total of 1,049 cases in our registry, 208 patients were utilized to construct two comparable sets by propensity score analysis, including 101 who received cilostazol and 107 who took antiplatelet medication without cilostazol. Both maximum and mean carotid IMT values were significantly reduced in the cilostazol group but increased in the control group (maximum left –0.048 ± 0.186 vs. 0.022 ± 0.163 mm, p = 0.001; maximum right –0.037 ± 0.173 vs. 0.050 ± 0.200 mm, p = 0.001; mean left –0.052 ± 0.102 vs. 0.023 ± 0.112 mm, p < 0.001; and mean right –0.038 ± 0.106 vs. 0.042 ± 0.139 mm, p < 0.001). After matching by propensity score, the improvements in both maximum and mean carotid IMT values in the cilostazol group remained significant. This study shows that cilostazol causes a significant regression in carotid IMT in symptomatic stroke patients.
Electronic supplementary material
The online version of this article (doi:10.1007/s00415-012-6599-y) contains supplementary material, which is available to authorized users.
Stroke; Carotid intima-media thickness; Atherosclerosis; Cilostazol
Enlarged Virchow-Robin spaces (EVRS) are considered to be a sign of cerebral small vessel disease. Hypertension is an important risk factor for cerebral small vessel disease, whereas ambulatory blood pressure (BP) is the strongest predictor of hypertension-related brain damage. However, the association between ambulatory BP levels and EVRS has never been investigated. The aim of this study was to determine the association between ambulatory BP levels and EVRS. In 143 first-ever lacunar stroke patients, we performed 24-h ambulatory BP monitoring after the acute stroke phase. On brain MRI we counted EVRS in the basal ganglia and the centrum semiovale. We graded the number of EVRS at each level into a three-category severity scale. We assessed the association between BP levels and EVRS by ordinal regression analysis. After adjusting for age, sex, extensive white matter lesions, and asymptomatic lacunar infarcts, higher day systolic (OR 1.21; 95 % CI 1.00–1.46 per 10 mmHg), day diastolic (1.18; 95 % CI 1.02–1.37 per 5 mmHg) and 24-h diastolic (OR 1.18; 95 % CI 1.01–1.37 per 5 mmHg) ambulatory BP levels were associated with EVRS at the basal ganglia level. No relation was found between ambulatory BP levels and EVRS in the centrum semiovale. Higher day ambulatory BP levels are associated with EVRS in the basal ganglia. This association was independent of the presence of extensive white matter lesions and asymptomatic lacunar infarcts. Our results imply that basal ganglia EVRS should be regarded as a separate manifestation of BP-related brain damage.
Enlarged Virchow-Robin spaces; Blood pressure; Ambulatory blood pressure monitoring; Cerebral small vessel disease; Enlarged perivascular spaces
Pharmacological treatment of pain in multiple sclerosis (MS) is challenging due to the many underlying pathophysiological mechanisms. Few controlled trials show adequate pain control in this population. Emerging evidence suggests that pain might be more effectively classified and treated according to symptoms and underlying mechanisms. The new mechanism-based classification we propose here distinguishes nine types of MS-related pain: trigeminal neuralgia and Lhermitte’s phenomenon (paroxysmal neuropathic pain due to ectopic impulse generation along primary afferents), ongoing extremity pain (deafferentation pain secondary to lesion in the spino-thalamo-cortical pathways), painful tonic spasms and spasticity pain (mixed pains secondary to lesions in the central motor pathways but mediated by muscle nociceptors), pain associated with optic neuritis (nerve trunk pain originating from nervi nervorum), musculoskeletal pains (nociceptive pain arising from postural abnormalities secondary to motor disorders), migraine (nociceptive pain favored by predisposing factors or secondary to midbrain lesions), and treatment-induced pains. Identification of various types of MS-related pain will allow appropriate targeted pharmacological treatment and improve clinical practice.
Multiple sclerosis; Pain prevalence; Treatment trial; Neuropathic pain; Spasticity; Migraine
Paroxysmal dyskinesia (PxD) is a group of movement disorders characterized by recurrent episodes of involuntary movements. Familial paroxysmal kinesigenic dyskinesia (PKD) is caused by PRRT2 mutations, but a distinct etiology has been suggested for sporadic PKD. Here we describe a cohort of patients collected from our movement disorders outpatient clinic in the period 1996–2011. Fifteen patients with sporadic PxD and 23 subjects from three pedigrees with familial PKD were screened for mutations in candidate genes. PRRT2 mutations co-segregated with PKD in two families and occurred in two sporadic cases of PKD. No mutations were detected in patients with non-kinesigenic or exertion-induced dyskinesia, and none in other candidate genes including PNKD1 (MR-1) and SLC2A1 (GLUT1). Thus, PRRT2 mutations also cause sporadic PKD as might be expected given the variable expressivity and reduced penetrance observed in familial PKD. Further genetic heterogeneity is suggested by the absence of candidate gene mutations in both sporadic and familial PKD suggesting a contribution of other genes or non-coding regions.
Electronic supplementary material
The online version of this article (doi:10.1007/s00415-012-6592-5) contains supplementary material, which is available to authorized users.
Paroxysmal kinesigenic dyskinesia; Infantile convulsions and paroxysmal choreoathetosis; Benign familial neonatal convulsions; Migraine
Effective behavioral therapies exist for patients with brain injury. The main issue is one of access. Can the internet be used as a resource so that suitable patients can build up enough practice to improve? We tested this hypothesis using a web-based application for patients with a right-sided hemianopia causing slow text reading. We studied 33 patients aged 26–81 years who fitted the entry criteria and accessed the therapy website between May 2010 and December 2011, in a longitudinal cohort study. The therapy consisted of reading animated, laterally scrolling text whose content and form was selected by the patients. Reading speeds on static text (main outcome) were assessed after every 5-h period of practice had been accrued. Statistical analysis was carried out using a repeated measures ANOVA. Read-Right therapy produced significant improvements in text reading speeds at all time points with a clear dose effect: 10 % at 5 h, 20 % at 10 h, 39 % at 15 h and 46 % at 20 h. Sub-analyses demonstrated that this was unlikely to be due to either multiple exposure to the testing materials (familiarity) or to the simple passage of time. This is the first example of a clinically proven therapy being delivered effectively to stroke patients over the internet. As therapists’ time is more limited than patients’ capacity to improve, carefully designed, web-based resources like Read-Right represent a realistic way of delivering a sufficient therapy dose to patients so they can obtain clinically meaningful improvements.
Hemianopia; Alexia; Stroke; Internet; Rehabilitation
Statins have anti-inflammatory and immunomodulatory properties in addition to lipid-lowering effects. The present study evaluated the effect of atorvastatin added to interferon beta-1b in multiple sclerosis (MS) in a multicenter, randomized, parallel-group, rater-blinded study performed in eight Swiss hospitals. Seventy-seven patients with relapsing-remitting MS started interferon beta-1b every other day. After 3 months, they were randomized 1:1 to receive atorvastatin 40 mg/day or not in addition to interferon beta-1b until month 15. The primary endpoint was the proportion of patients with new lesions on T2-weighted images at month 15 compared to baseline at month three. At study end, the proportion of patients with new lesions on T2-weighted images was equal in both groups (odds ratio 1.14; 95 % CI 0.36–3.56; p = 0.81). All predefined secondary endpoints including number of new lesions and total lesion volume on T2-weighted images, total number of new Gd-enhancing lesions on T1-weighted images, total brain volume, volume of grey matter, volume of white matter, EDSS, MSFC, relapse rate, time to first relapse, number of relapse-free patients and neutralizing antibodies did not show any significant differences (all p values >0.1). Transient elevations of liver enzymes were more frequent with atorvastatin (p = 0.02). In conclusion, atorvastatin 40 mg/day in addition to interferon beta-1b did not have a beneficial effect on relapsing-remitting MS compared to interferon beta-1b monotherapy over a 12-month period.
Electronic supplementary material
The online version of this article (doi:10.1007/s00415-012-6513-7) contains supplementary material, which is available to authorized users.
Multiple sclerosis; Atorvastatin; Interferon beta; Randomized clinical trial
Focal dystonia is a common, invalidating neurologic condition characterized by involuntary, sustained muscle contractions causing twisting movements and abnormal postures in one body part. Currently, botulinum toxin is the treatment of first choice. We performed a systematic review towards the pharmaco-therapeutic and pharmaco-economic value of botulinum toxin as treatment for focal dystonia, which yielded the following results. Botulinum toxin is the most effective treatment for reducing dystonic symptoms measured with dystonia-specific and general questionnaires, and pain in patients with focal dystonia. Seventy-one percent of patients with cervical dystonia had a reduction in neck pain compared to 12 % in placebo groups. Adverse events occur in 58 % of patients during treatment with botulinum toxin compared to 46 % treated with placebo. Especially dry mouth, neck weakness, dysphagia, and voice changes are common. Adverse events are usually mild and self-limiting. Health-related quality of life, measured with the SF-36 is 20–50 points lower in patients with focal dystonia compared to controls and the effect of botulinum toxin on health-related quality of life is unclear. Botulinum toxin treatment is expensive because the drug itself is expensive. Yearly costs for treating a patient with focal dystonia with botulinum toxin range from EUR 347 to EUR 3,633 and the gain in QALYs with BTX treatment is small. Focal dystonia impairs the productivity and the ability to work. At start of botulinum toxin treatment only 47–50 % was working. Botulinum toxin partly improves this. Overall, we conclude that botulinum toxin is an expensive drug with good effects. From a societal perspective, the costs may well weigh up to the regained quality of life. However, the available literature concerning costs, health-related quality of life and labor participation is very limited. An extensive cost-effectiveness study should be performed incorporating all these aspects.
Electronic supplementary material
The online version of this article (doi:10.1007/s00415-012-6510-x) contains supplementary material, which is available to authorized users.
Botulinum toxin; Focal dystonia; Effectiveness
Sleep disturbances are among the most frequent and incapacitating non-motor symptoms of Parkinson’s disease (PD), and are increasingly recognized as an important determinant of impaired quality of life. Here we review several recent developments regarding the recognition and diagnosis of sleep disorders in PD. In addition, we provide a practical and easily applicable approach to the diagnostic process as a basis for tailored therapeutic interventions. This includes a stepwise scheme that guides the clinical interview and subsequent ancillary investigations. In this scheme, the various possible sleep disorders are arranged not in order of prevalence, but in a ‘differential diagnostic’ order. We also provide recommendations for the use of sleep registrations such as polysomnography. Furthermore, we point out when a sleep specialist could be consulted to provide additional diagnostic and therapeutic input. This structured approach facilitates early detection of sleep disturbances in PD, so treatment can be initiated promptly.
Parkinson’s disease; Sleep disorders; Excessive daytime sleepiness; Polysomnography
Decreased tongue strength (TS) might herald bulbar involvement in patients with amyotrophic lateral sclerosis (ALS) well before dysarthria or dysphagia occur, and as such might be prognostic of short survival. The purpose of this study was to investigate the prognostic value of a decreased TS, in addition to other prognostic factors, such as site of onset, bulbar symptoms, bulbar signs, age, sex, maximum phonation time, time from symptoms to diagnosis, and gastrostomy, for survival time in patients with ALS. TS was measured in four directions in 111 patients who attended the diagnostic outpatient motor neuron clinic of our university hospital. Of these patients, 54 were diagnosed with ALS. TS was considered abnormal if the strength in minimally one direction was at least two standard deviations below the reference values obtained from comparable age category and sex-groups of healthy controls (n = 119). Twenty of the patients with ALS had a decreased TS. Multivariable analysis showed that, in addition to age, TS was an independent prognostic factor for survival time in patients with ALS.
ALS; Tongue strength; Survival; Prognosis
Although evidence is accumulating that age modifies the risk of carotid angioplasty and stenting (CAS) versus endarterectomy (CEA) for patients with significant carotid stenosis, the impact of age on cognition after either CEA or CAS remains unclear. In this study, we analyzed the effects of age on cognitive performance after either CEA or CAS using a comprehensive neuropsychological test battery with parallel test forms and a control group to exclude a learning effect. The neuropsychological outcomes after revascularization were determined in 19 CAS and 27 CEA patients with severe carotid stenosis. The patients were subdivided according to their median age (<68 years and ≥68 years); 27 healthy subjects served as a control group. In all patients clinical examinations, MRI scans and a neuropsychological test battery that assessed four major cognitive domains were performed immediately before, within 72 h, and 3 months after CEA or CAS. While patients <68 years of age showed no significant cognitive alteration after either CEA or CAS, a significant cognitive decline was observed in patients ≥68 years in both treatment groups (p = 0.001). Notably, this cognitive deterioration persisted in patients after CEA, whereas it was only transient in patients treated with CAS. These results demonstrate an age-dependent effect of CEA and CAS on cognitive functions. In contrast to the recently observed increased clinical complication rates in older subjects after CAS compared with CEA, CEA appears to be associated with a greater, persistent decline in cognitive performance than CAS in this subgroup of patients.
Carotid artery stent; Carotid artery endarterectomy; Cognition; Age
Patients with an acute basilar artery occlusion (BAO) have a high risk of long-lasting disability and death. Only limited data are available on functional outcome in elderly patients with BAO. Using data from the Basilar Artery International Cooperation Study, we aimed to determine outcomes in patients ≥75 years. Primary outcome measure was poor functional outcome (modified Rankin scale score 4–6). Secondary outcomes were death, insufficient vessel recanalization (defined as thrombolysis in myocardial infarction score 0–1) and symptomatic intracranial hemorrhage (SICH). Patients were divided into four age-groups, based on quartiles: 18–54, 55–64, 65–74, and ≥75 years. Outcomes were compared between patients ≥75 years and patients aged 18–54 years. Risk ratios with corresponding 95 % confidence intervals (CI) were calculated and Poisson regression analyses were performed to calculate adjusted risk ratios (aRR). We included 619 patients [18–54 years n = 153 (25 %), 55–64 years n = 133 (21 %), 65–74 years n = 171 (28 %), and ≥75 years n = 162 (26 %)]. Compared with patients aged 18–54 years, patients ≥75 years were at increased risk of poor functional outcome [aRR 1.33 (1.14–1.55)] and death [aRR 2.47 (1.75–3.51)]. Nevertheless, 35/162 (22 %, 95 % CI 15–28 %) of patients ≥75 years had good functional outcome. No significant differences between age groups were observed for recanalization rate and incidence of SICH. Although patients ≥75 years with BAO have an increased risk of poor outcome compared with younger patients, a substantial group of patients ≥75 years survives with a good functional outcome.
Electronic supplementary material
The online version of this article (doi:10.1007/s00415-012-6498-2) contains supplementary material, which is available to authorized users.
Basilar artery occlusion; Age; Recanalization; Outcome; Mortality
Considerable non-allelic heterogeneity for autosomal recessively inherited Charcot-Marie-Tooth (ARCMT) disease has challenged molecular testing and often requires a large amount of work in terms of DNA sequencing and data interpretation or remains unpractical. This study tested the value of SNP array-based whole-genome homozygosity mapping as a first step in the molecular genetic diagnosis of sporadic or ARCMT in patients from inbred families or outbred populations with the ancestors originating from the same geographic area. Using 10 K 2.0 and 250 K Nsp Affymetrix SNP arrays, 15 (63%) of 24 CMT patients received an accurate genetic diagnosis. We used our Java-based script eHoPASA CMT—easy Homozygosity Profiling of SNP arrays for CMT patients to display the location of homozygous regions and their extent of marker count and base-pairs throughout the whole genome. CMT4C was the most common genetic subtype with mutations detected in SH3TC2, one (p.E632Kfs13X) appearing to be a novel founder mutation. A sporadic patient with severe CMT was homozygous for the c.250G > C (p.G84R) HSPB1 mutation which has previously been reported to cause autosomal dominant dHMN. Two distantly related CMT1 patients with early disease onset were found to carry a novel homozygous mutation in MFN2 (p.N131S). We conclude that SNP array-based homozygosity mapping is a fast, powerful, and economic tool to guide molecular genetic testing in ARCMT and in selected sporadic CMT patients.
Autosomal recessive CMT; Homozygosity mapping; SNP array; Hereditary neuropathies; Gene
Diagnosis and decisions on life-sustaining treatment (LST) in disorders of consciousness, such as the vegetative state (VS) and the minimally conscious state (MCS), are challenging for neurologists. The locked-in syndrome (LiS) is sometimes confounded with these disorders by less experienced physicians. We aimed to investigate (1) the application of diagnostic knowledge, (2) attitudes concerning limitations of LST, and (3) further challenging aspects in the care of patients. A vignette-based online survey with a randomized presentation of a VS, MCS, or LiS case scenario was conducted among members of the German Society for Neurology. A sample of 503 neurologists participated (response rate 16.4%). An accurate diagnosis was given by 86% of the participants. The LiS case was diagnosed more accurately (94%) than the VS case (79%) and the MCS case (87%, p < 0.001). Limiting LST for the patient was considered by 92, 91, and 84% of the participants who accurately diagnosed the VS, LiS, and MCS case (p = 0.09). Overall, most participants agreed with limiting cardiopulmonary resuscitation; a minority considered limiting artificial nutrition and hydration. Neurologists regarded the estimation of the prognosis and determination of the patients’ wishes as most challenging. The majority of German neurologists accurately applied the diagnostic categories VS, MCS, and LiS to case vignettes. Their attitudes were mostly in favor of limiting life-sustaining treatment and slightly differed for MCS as compared to VS and LiS. Attitudes toward LST strongly differed according to circumstances (e.g., patient’s will opposed treatment) and treatment measures.
End-of-life decisions; Limitation of life-sustaining treatment; Diagnosis; Vegetative state; Minimally conscious state
B cell dyscrasias are often refractory to medical treatments, and hematological stem cell therapy (SCT) may be warranted. It is not clear whether an associated polyneuropathy may also profit from SCT. In exceptional cases SCT has been tried in patients with monoclonal gammopathy and progressive polyneuropathy refractory to medical treatments. In a cohort of 225 patients with monoclonal gammopathy and polyneuropathy, we selected the six patients who underwent SCT and retrospectively examined the effects of SCT on the disease course of the associated polyneuropathy. In all patients except one, the indication for SCT was hemato-oncological (multiple myeloma in 4 patients and primary AL amyloidosis in 1). The remaining patient had an IgG monoclonal gammopathy of undetermined significance and a progressive and painful polyneuropathy for which she was treated with SCT. SCT led to improvement of motor scores and autonomic symptoms in one patient; three patients experienced improvement of neuropathic pain or sensory deficits but showed further progression of weakness. One patient showed no improvement at all. One patient died within 100 days after SCT. In conclusion, SCT as a treatment of refractory hematological malignancy may occasionally have a positive effect on the associated progressive polyneuropathy, although the benefits are very limited and the treatment-related mortality is high.
SCT; Polyneuropathy; B-cell malignancy
Huntington’s disease (HD) is a fatal, neurodegenerative disease for which there is no known cure. Proxy evaluation is relevant for HD as its manifestation might limit the ability of persons to report their health-related quality of life (HrQoL). This study explored patient–proxy ratings of HrQoL of persons at different stages of HD, and examined factors that may affect proxy ratings. A total of 105 patient–proxy pairs completed the Huntington’s disease health-related quality of life questionnaire (HDQoL) and other established HrQoL measures (EQ-5D and SF-12v2). Proxy–patient agreement was assessed in terms of absolute level (mean ratings) and intraclass correlation. Proxies’ ratings were at a similar level to patients’ self-ratings on an overall Summary Score and on most of the six Specific Scales of the HDQoL. On the Specific Hopes and Worries Scale, proxies on average rated HrQoL as better than patients’ self-ratings, while on both the Specific Cognitive Scale and Specific Physical and Functional Scale proxies tended to rate HrQoL more poorly than patients themselves. The patient’s disease stage and mental wellbeing (SF-12 Mental Component scale) were the two factors that primarily affected proxy assessment. Proxy scores were strongly correlated with patients’ self-ratings of HrQoL, on the Summary Scale and all Specific Scales. The patient–proxy correlation was lower for patients at moderate stages of HD compared to patients at early and advanced stages. The proxy report version of the HDQoL is a useful complementary tool to self-assessment, and a promising alternative when individual patients with advanced HD are unable to self-report.
Huntington’s disease; Health-related quality of life; Proxy; Patient-reported outcome; Patient–proxy agreement; Huntington’s disease health-related quality of life questionnaire (HDQoL)