Martina Minnerop

The brain in myotonic dystrophy 1 and 2: evidence for a predominant white matter disease

Myotonic dystrophy types 1 and 2 are progressive multisystemic disorders with potential brain involvement. We compared 22 myotonic dystrophy type 1 and 22 myotonic dystrophy type 2 clinically and neuropsychologically well-characterized patients and a corresponding healthy control group using structural brain magnetic resonance imaging at 3 T (T(1)/T(2)/diffusion-weighted). Voxel-based morphometry and diffusion tensor imaging with tract-based spatial statistics were applied for voxel-wise analysis of cerebral grey and white matter affection (P(corrected) < 0.05). We further examined the association of structural brain changes with clinical and neuropsychological data. White matter lesions rated visually were more prevalent and severe in myotonic dystrophy type 1 compared with controls, with frontal white matter most prominently affected in both disorders, and temporal lesions restricted to myotonic dystrophy type 1. Voxel-based morphometry analyses demonstrated extensive white matter involvement in all cerebral lobes, brainstem and corpus callosum in myotonic dystrophy types 1 and 2, while grey matter decrease (cortical areas, thalamus, putamen) was restricted to myotonic dystrophy type 1. Accordingly, we found more prominent white matter affection in myotonic dystrophy type 1 than myotonic dystrophy type 2 by diffusion tensor imaging. Association fibres throughout the whole brain, limbic system fibre tracts, the callosal body and projection fibres (e.g. internal/external capsules) were affected in myotonic dystrophy types 1 and 2. Central motor pathways were exclusively impaired in myotonic dystrophy type 1. We found mild executive and attentional deficits in our patients when neuropsychological tests were corrected for manual motor dysfunctioning. Regression analyses revealed associations of white matter affection with several clinical parameters in both disease entities, but not with neuropsychological performance. We showed that depressed mood and fatigue were more prominent in patients with myotonic dystrophy type 1 with less white matter affection (early disease stages), contrary to patients with myotonic dystrophy type 2. Thus, depression in myotonic dystrophies might be a reactive adjustment disorder rather than a direct consequence of structural brain damage. Associations of white matter affection with age/disease duration as well as patterns of cerebral water diffusion parameters pointed towards an ongoing process of myelin destruction and/or axonal loss in our cross-sectional study design. Our data suggest that both myotonic dystrophy types 1 and 2 are serious white matter diseases with prominent callosal body and limbic system affection. White matter changes dominated the extent of grey matter changes, which might argue against Wallerian degeneration as the major cause of white matter affection in myotonic dystrophies.

Neuropsychological features of patients with spinocerebellar ataxia (SCA) types 1, 2, 3, and 6.

A subtype-specific impairment of cognitive functions in spinocerebellar ataxia (SCA) patients is still debated. Thirty-two SCA patients (SCA1, 6; SC2, 3; SCA3, 15; SCA6, 8) and 14 matched healthy controls underwent neuropsychological evaluation testing attention, executive functions, episodic and semantic memory, and motor coordination. Severity of ataxia was assessed with the Scale for the Assessment and Rating of Ataxia (SARA), nonataxia symptoms with the Inventory of Non-Ataxia Symptoms. Depressive symptoms were evaluated with the Beck Depression Inventory. The SARA scores of our SCA patients (range 1–19.5) indicated an overall moderate ataxia, most pronounced in SCA6 and SCA1. Mean number of nonataxia symptoms (range 0–2.2) were most distinct in SCA1 and nearly absent in SCA6. SCA1 performed poorer than controls in 33% of all cognitive test parameters, followed by SCA2, SCA3, and SCA6 patients (17%). SCA 1–3 patients presented mainly attentional and executive dysfunctions while semantic and episodic memory functions were preserved. Attentional and executive functions were partly correlated with ataxia severity and fine motor coordination. All patients exhibited mildly depressed mood. Motor and dominant hand functions were more predictive for depressed mood than cognitive measures or overall ataxia. Besides motor impairments in all patients, SCA patients with extracerebellar pathology (SCA 1–3) were characterized by poor frontal attentional and executive dysfunction while mild cognitive impairments in predominantly cerebellar SCA6 patients appeared to reflect mainly cerebellar dysfunction. Regarding the everyday relevance of symptoms, (dominant) motor hand functioning emerged as a marker for the patient’s mood.

Smoking upregulates α4β2* nicotinic acetylcholine receptors in the human brain

Abstract The role of the α4β2* nicotinic acetylcholine receptors (nAChR) in tobacco addiction in humans is largely unresolved. We visualized brain α4β2* nicotinic acetylcholine receptors of smokers and non-smokers with positron emission tomography using 2-[ 18 F]fluoro-3-(2( S )azetidinylmethoxy)pyridine, commonly known as 2-[ 18 F]F-A-85380. The total brain distribution volume of 2-[ 18 F]F-A-85380 was significantly increased in smokers. Statistical parametric mapping revealed that the most prominent regional differences of distribution volumes (DV) were found in cerebellum and brainstem with an increased uptake in smokers. The up-regulation of α4β2* nAChR upon chronic nicotine exposure via tobacco smoking incorporates subcortical brain regions which may play an important role in nicotine addiction.

Voxel-based analysis of multiple-system atrophy of cerebellar type: complementary results by combining voxel-based morphometry and voxel-based relaxometry

Voxel-based relaxometry (VBR) is a novel morphometric method that analyses the relaxation rate R2 derived from multi-echo T2-weighted images on a voxel-by-voxel basis. We used VBR to study the brain morphology of 14 patients suffering from multiple-system atrophy of cerebellar type (MSA-C) and compared the results with those obtained by voxel-based morphometry (VBM) of T1-weighted images. VBR analysis revealed reduction of relaxation rate R2 in the cerebellum and brainstem reflecting infratentorial brain atrophy. The affected regions largely corresponded to those regions in which VBM showed reductions of grey and white matter. In addition, R2 was increased in the putamen, a region in which VBM did not show abnormalities. Our data show that the combination of VBR and VBM provided convergent and complimentary information about the brain morphology of MSA-C.

Structural and functional MRI abnormalities of cerebellar cortex and nuclei in SCA3, SCA6 and Friedreich’s ataxia

Spinocerebellar ataxia type 3, spinocerebellar ataxia type 6 and Friedreichs ataxia are common hereditary ataxias. Different patterns of atrophy of the cerebellar cortex are well known. Data on cerebellar nuclei are sparse. Whereas cerebellar nuclei have long been thought to be preserved in spinocerebellar ataxia type 6, histology shows marked atrophy of the nuclei in Friedreichs ataxia and spinocerebellar ataxia type 3. In the present study susceptibility weighted imaging was used to assess atrophy of the cerebellar nuclei in patients with spinocerebellar ataxia type 6 (n = 12, age range 41-76 years, five female), Friedreichs ataxia (n = 12, age range 21-55 years, seven female), spinocerebellar ataxia type 3 (n = 10, age range 34-67 years, three female), and age- and gender-matched controls (total n = 23, age range 22-75 years, 10 female). T1-weighted magnetic resonance images were used to calculate the volume of the cerebellum. In addition, ultra-high field functional magnetic resonance imaging was performed with optimized normalization methods to assess function of the cerebellar cortex and nuclei during simple hand movements. As expected, the volume of the cerebellum was markedly reduced in spinocerebellar ataxia type 6, preserved in Friedreichs ataxia, and mildy reduced in spinocerebellar ataxia type 3. The volume of the cerebellar nuclei was reduced in the three patient groups compared to matched controls (P-values < 0.05; two-sample t-tests). Atrophy of the cerebellar nuclei was most pronounced in spinocerebellar ataxia type 6. On a functional level, hand-movement-related cerebellar activation was altered in all three disorders. Within the cerebellar cortex, functional magnetic resonance imaging signal was significantly reduced in spinocerebellar ataxia type 6 and Friedreichs ataxia compared to matched controls (P-values < 0.001, bootstrap-corrected cluster-size threshold; two-sample t-tests). The difference missed significance in spinocerebellar ataxia type 3. Within the cerebellar nuclei, reductions were significant when comparing spinocerebellar ataxia type 6 and Friedreichs ataxia to matched controls (P < 0.01, bootstrap-corrected cluster-size threshold; two-sample t-tests). Susceptibility weighted imaging allowed depiction of atrophy of the cerebellar nuclei in patients with Friedreichs ataxia and spinocerebellar ataxia type 3. In spinocerebellar ataxia type 6, pathology was not restricted to the cerebellar cortex but also involved the cerebellar nuclei. Functional magnetic resonance imaging data, on the other hand, revealed that pathology in Friedreichs ataxia and spinocerebellar ataxia type 3 is not restricted to the cerebellar nuclei. There was functional involvement of the cerebellar cortex despite no or little structural changes.

Bell's palsy: combined treatment of famciclovir and prednisone is superior to prednisone alone.

There is insufficient evidence concerning the efficacy of antiviral treatment of Bell’s palsy (BP). We therefore compared the efficacy of prednisone and famciclovir to prednisone treatment alone in BP. A total of 167 consecutive patients with untreated acute BP were included. Severity of BP was evaluated using the House-Brackmann scale (HBS) and virus antibody tests (herpes simplex virus, varicella zoster virus) were performed. Patients admitted on even dates were treated with prednisone (“P group”) and patients admitted on odd dates were treated with prednisone and famciclovir (“P+F group”). 117 patients completed the follow-up after 3 months or later (67 P/51 P+F). While most patients showed at least partial recovery with both treatment types, improvement of at least 4 grades in the HBS was more common in the “P+F group” (29.4 % vs. 11.9 %), whereas smaller changes of less than 3 grades were more common in the “P group” (29.9 % vs. 17.6 %; Chi-square test, p = 0.02). Patients with complete BP (HBS grade of 5 or 6) had significantly better chances of reaching normal function if treated with famciclovir additionally instead with prednisone alone (73.7 % vs. 47.1 %; Cochran-Armitage trend test, p = 0.03). These results suggest that the combined treatment of famciclovir and prednisolone should be considered (at least) in patients with severe BP.

Sporadic adult onset ataxia of unknown etiology : a clinical, electrophysiological and imaging study.

BackgroundThe sporadic adult onset ataxias of unknown etiology (SAOA) denote the non-hereditary degenerative adult onset ataxias that are distinct from multiple system atrophy (MSA).ObjectiveTo define and characterize the clinical phenotype of sporadic adult onset ataxia of unknown etiology (SAOA).DesignA survey of clinical features, nerve conduction and evoked potentials, autonomic tests, and magnetic resonance imaging (MRI)-based brain morphometry was conducted in patients with SAOA.PatientsStudy subjects were a consecutive sample of 27 patients (11 male, 16 female) who met the diagnostic criteria for SAOA (age 55 ± 13 years; age at disease onset 47 ± 14 years; disease duration 8 ± 7 years).ResultsAll patients presented with a cerebellar syndrome. The most frequent extracerebellar symptoms were decreased vibration sense in 70% and decreased or absent ankle reflexes in 33% of the patients. Nerve conduction studies revealed a polyneuropathy in 26% of the patients. Somatosensory evoked potentials were abnormal in 44%, and central motor conduction time in 17% of patients. Autonomic testing revealed an affected autonomic nervous system in 58% of patients. Voxel-based brain morphometry showed a predominant reduction of gray matter in the cerebellum which was significantly correlated with disease stages. A loss of white matter was found in both middle cerebellar peduncles and the outer edge of the pons.ConclusionsThe data show that SAOA is a predominantly, but not exclusively cerebellar disorder. Clinical, electrophysiological, and imaging findings showed some similarities with multiple system atrophy which raises the question of an overlap of these two disorders.

REM sleep behavioral disorder in pure autonomic failure (PAF)

Pure autonomic failure (PAF) is an idiopathic sporadic disorder characterized by orthostatic hypotension with evidence of more widespread autonomic failure. It has been suggested that PAF belongs to the group of synucleinopathies, as autopsy studies showed α-synuclein-positive Lewy bodies in sympathetic neurons of patients with PAF.1 REM sleep behavioral disorder (RBD) appears to be an almost universal feature of synucleinopathies. Whereas initial studies suggested that RBD specifically occurs in multiple system atrophy (MSA), subsequent studies showed that it is also a frequent feature of Parkinson disease (PD) and dementia with Lewy bodies (DLB).2 Furthermore, patients with isolated RBD often later develop PD.3 We here present a consecutive unselected series of three patients with PAF (M/F: 2/1, …

Grey and white matter loss along cerebral midline structures in myotonic dystrophy type 2

Myotonic dystrophy type 2 (DM2) is an autosomal dominantly inherited multisystemic disorder and a common cause of muscular dystrophy in adults. Although neuromuscular symptoms predominate, there is clinical and imaging evidence of cerebral involvement. We used voxel-based morphometry (VBM) based on T1-weighted magnetic resonance images to investigate brain morphology in 13 DM2 patients in comparison to 13 sex- and age-matched controls. Further, we employed novel computational surface-based methods that specifically assess callosal thickness. We found grey and white matter loss along cerebral midline structures in our patient group. Grey matter reductions were present in brainstem and adjacent hypothalamic and thalamic regions, while white matter was mainly reduced in corpus callosum. The reduced callosal size was highly significant and independently confirmed by different methods. Our data provide first evidence for grey and white matter loss along brain midline structures in DM2 patients. The reduced size of the corpus callosum further extends the spectrum of white matter changes in DM2 and may represent the morphological substrate of neuropsychological abnormalities previously described in this disorder.

Consensus on cerebral involvement in myotonic dystrophy: Workshop report: May 24–27, 2013, Ferrere (AT), Italy

Thirty-four clinicians, scientists and representatives from industries convened for a workshop on cerebral involvement in myotonic dystrophy (DM). The workshop was held in Ferrere (Asti) from May 24th to 27th 2013 and as the previous one [1] had the purpose to stimulate the research on CNS dysfunction in DM and to discuss major issues regarding CNS involvement. Classically viewed as a neuromuscular disease, for many years research on DM has been principally focused on muscular aspects. Therefore few data are available for CNS involvement. With new therapeutic developments with potential to affect pathophysiology across multiple tissues and organ systems it will be mandatory to increase our understanding of CNS pathophysiology in order to appropriately monitor whether or not there is beneficial effect in CNS. Indeed CNS dysfunction is one of the major issue affecting quality of life in DM patients thus it has to be appropriately considered in planning clinical trials. This workshop included different themes covering all the topics of DM CNS involvement. CNS research needs to proceed faster and consensus has to be established in the major themes of CNS study. The present report describes the major issues that emerged during the workshop, with the aim of updating and stimulating research in this critical field.