Cortical Thinning of Motor and Non-Motor Brain Regions Enables Diagnosis of Amyotrophic Lateral Sclerosis and Supports Distinction between Upper- and Lower-Motoneuron Phenotypes.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder clinically characterized by muscle atrophy and progressive paralysis. In addition to the classical ALS affecting both the upper and lower motoneurons (UMN and LMN), other subtypes with the predominant (or even exclusive) affection of the UMN or LMN have been identified. This work sought to detect specific patterns of cortical brain atrophy in the UMN and LMN phenotypes to distinguish these two forms from the healthy state. METHODS: Using high-resolution structural MRI and cortical thickness analysis, 38 patients with a diagnosis of ALS and predominance of either the UMN (n = 20) or the LMN (n = 18) phenotype were investigated. RESULTS: Significant cortical thinning in the temporal lobe was found in both the ALS groups. Additionally, UMN patients displayed a significant thinning of the cortical thickness in the pre- and postcentral gyrus, as well as the paracentral lobule. By applying multivariate analyses based on the cortical thicknesses of 34 brain regions, ALS patients with either a predominant UMN or LMN phenotype were distinguished from healthy controls with an accuracy of 94% and UMN from LMN patients with an accuracy of 75%. CONCLUSIONS: These findings support previous hypothesis that neural degeneration in ALS is not confined to the sole motor regions. In addition, the amount of cortical thinning in the temporal lobe helps to distinguish ALS patients from healthy controls, that is, to support or discourage the diagnosis of ALS, while the cortical thickness of the precentral gyrus specifically helps to distinguish the UMN from the LMN phenotype.

Excitability in somatosensory cortex correlates with motoric impairment in amyotrophic lateral sclerosis.

Objective: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative motoneuron disease. As previous studies reported alterations in motor cortex excitability, we evaluate excitability changes in somatosensory system. Methods: We examined 15 ALS patients and 15 healthy controls. Cortical excitability was assessed using paired somatosensory evoked potentials of median nerves. To determine disease severity and functional impairment, we assessed muscle strength and revised ALS-Functional Rating Scale (ALSFRS-R). Results: We found significantly reduced bilateral paired-stimulation inhibition in the ALS-group (both p < 0.05). Additionally, paired-stimulation ratios significantly correlated with ALSFRS-R (left somatosensory cortex: r= -orte; right somatosensory cortex: r= -ort4; both p < 0.05) and contralateral muscle strength (left somatosensory cortex: r= -orte, p = 0.007; right somatosensory cortex: r= -ortex p = 0.003). Conclusions: The results indicate disinhibition of the somatosensory cortex in ALS. It remains open if central somatosensory disinhibition is a primary characteristic of ALS as one element of a multisystem neurodegenerative disorder or a compensatory up-regulation due to functional motoric impairment. Longitudinal studies are necessary to categorize these findings.

Muscle imaging data in late-onset Pompe disease reveal a correlation between the pre-existing degree of lipomatous muscle alterations and the efficacy of long-term enzyme replacement therapy.

BACKGROUND: Late-onset Pompe disease (LOPD) is a metabolic myopathy caused by mutations in GAA and characterized by proximal muscle weakness and respiratory insufficiency. There is evidence from clinical studies that enzyme replacement therapy (ERT) with human recombinant alpha-glucosidase improves motor performance and respiratory function in LOPD. OBJECTIVE: We analyzed quantitative muscle MRI data of lower limbs to evaluate the effects of long-term ERT on muscle parameters. METHODS: Three symptomatic LOPD patients who received ERT for five years and four untreated presymptomatic LOPD patients were included in the study. T1-weighted MRI images were used to determine volumes of thigh and lower leg muscles. In addition, mean gray values of eight individual thigh muscles were calculated to assess the degree of lipomatous muscle alterations. RESULTS: We detected a decrease in thigh muscle volume of 6.7% (p < 0.001) and an increase in lower leg muscle volume of 8.2% (p = 0.049) after five years of ERT. Analysis of individual thigh muscles revealed a positive correlation between the degree of lipomatous muscle alterations at baseline and the increase of gray values after five years of ERT (R(2) = 0.68, p < 0.001). Muscle imaging in presymptomatic patients showed in one case pronounced lipomatous alteration of the adductor magnus muscle and mild to moderate changes in further thigh muscles. CONCLUSIONS: The results demonstrate that fatty muscle degeneration can occur before clinical manifestation of muscle weakness and suggest that mildly affected muscles may respond better to ERT treatment than severely involved muscles. If these findings can be validated by further studies, it should be discussed if muscle alterations detected by muscle MRI may be an objective sign of disease manifestation justifying an early start of ERT in clinically asymptomatic patients in order to improve the long-term outcome.

Increased risk of suicide under intrathecal ziconotide treatment? - a warning.

Despite some other known psychiatric adverse effects, ziconotide is recommended for intrathecal pain treatment with a good efficacy and safety. Although some hints in previous studies are apparent, a higher suicidality has not been accepted as a treatment risk of ziconotide treatment by the investigators in the former randomized controlled trials so far. We present two cases supporting the suspicion of ziconotide-induced suicidality. Both showed no depressive symptoms at the time of treatment initiation. One patient performed suicide under low-dose (cumulative dosage: 779µg) 4 weeks after the onset of intrathecal ziconotide treatment despite sufficient pain relief. Another female patient with a history of depression, but free of symptoms under antidepressive medication since more than 15 years, developed severe suicidal ideation 2 months after ziconotide treatment (cumulative dosage: about 2900µg) with rapid recovery after drug discontinuation. The patient, who has completed suicide, had earlier given rise to discuss a potential depressive disorder, however, this diagnosis was scrapped, but the second patient had a clear history of depression. These cases substantiate the suspicion of a causal relationship between ziconotide and suicidality even in symptom-free patients with a history of depression. Therefore, a comprehensive psychiatric evaluation is unavoidable before and during ziconotide treatment.

VE-cadherin and ACE: markers for sepsis in post mortem examination?

Altered expression of endothelial markers - especially adhesion molecules - is diagnostically helpful for diagnosis of ante mortal undiagnosed sepsis. Up to now it is unclear whether (1) expression of Angiotensin converting enzyme (ACE) and/or VE-cadherin (VEC) plays a comparable role, (2) whether expression intensity correlates with post mortem interval. Fifty-nine lung specimens (20 lung specimens with regular morphology from tumour lobectomies, 39 from patients who died of septic ARDS due to microbiologically proven Gram-negative sepsis) were stained with an antibody against ACE (1:80) resp. VEC (1:100). All specimens showed vessel type specific expression patterns for ACE and VEC which was dramatically reduced in sepsis. ACE staining intensity did not correlate with time between death and autopsy. VEC staining was slightly but statistically not significantly reduced with increasing time interval. Pulmonary VEC and ACE expression are reduced in septic ARDS. However, as neither ACE nor VEC expression correlates with time interval between death and post mortem, expression intensities of VEC or ACE are no reliable indices for time elapsed since death.