Frank Lehmann-Horn

Comparative analysis of brain structure, metabolism, and cognition in myotonic dystrophy 1 and 2

Objective: Myotonic dystrophy type 1 and 2 (DM1/DM2) are multisystemic diseases with common cognitive deficits beside the cardinal muscular symptoms. We performed a comprehensive analysis of cerebral abnormalities to compare the neuropsychological defects with findings in different imaging methods in the same cohort of patients. Methods: Neuropsychological investigations, structural cerebral MRI including brain parenchymal fraction (BPF) and voxel-based morphometry (VBM), and 18F-deoxy-glucose PET (FDG-PET) were performed in patients (20 DM1 and 9 DM2) and matched healthy controls, and analyzed using statistical parametric mapping (SPM2). Results: DM1 and DM2 patients showed typical neuropsychological deficits with a pronounced impairment of nonverbal episodic memory. Both patient groups showed a reduction of the global gray matter (measured by BPF), which could be localized to the frontal and parietal lobes by VBM. Interestingly, VBM revealed a bilateral hippocampal volume reduction that was correlated specifically to both a clinical score and episodic memory deficits. VBM also revealed a pronounced change of thalamic gray matter. White matter lesions were found in >50% of patients and their extent was correlated to psychomotor speed. FDG-PET revealed a frontotemporal hypometabolism, independent of the decrease in cortical gray matter. All abnormalities were similar in both patient groups but more pronounced for DM1. Conclusions: Our results suggest that 1) some of the characteristic cognitive deficits of these patients are linked to specific structural cerebral changes, 2) decreases in gray matter and metabolism are independent processes, and 3) the widespread brain abnormalities are more pronounced in DM1.

7-T 35Cl and 23Na mr imaging for detection of mutationdependent alterations in muscular edema and fat fraction with sodium and chloride concentrations in muscular periodic paralyses

Purpose To determine whether altered sodium (Na(+)) and chloride (Cl(-)) homeostasis can be visualized in periodic paralyses by using 7-T sodium 23 ((23)Na) and chlorine 35 ((35)Cl) magnetic resonance (MR) imaging. Materials and Methods Institutional review board approval and informed consent of all participants were obtained. (23)Na (repetition time msec/echo time msec, 160/0.35) and (35)Cl (40/0.6) MR imaging of both lower legs was performed with a 7-T whole-body system in patients with genetically confirmed hypokalemic periodic paralysis (Cav1.1-R1239H mutation, n = 5; Cav1.1-R528H mutation, n = 8) and Andersen-Tawil syndrome (n = 3) and in 16 healthy volunteers. Additionally, each participant underwent 3-T proton MR imaging on the same day by using T1-weighted, short-tau inversion-recovery, and Dixon-type sequences. Muscle edema was assessed on short-tau inversion-recovery images, fatty degeneration was assessed on T1-weighted images, and muscular fat fraction was quantified with Dixon-type imaging. Na(+) and Cl(-) were quantified in the soleus muscle by using three phantoms that contained 10-, 20-, and 30-mmol/L NaCl solution and 5% agarose gel as a reference. Parametric data for all subpopulations were tested by using one-way analysis of variance with the Dunnett test, and correlations were assessed with the Spearman rank correlation coefficient. Results Median muscular (23)Na concentration was higher in patients with Cav1.1-R1239H (34.7 mmol/L, P < .001), Cav1.1-R528H (32.0 mmol/L, P < .001), and Kir2.1 (24.3 mmol/L, P = .035) mutations than in healthy volunteers (19.9 mmol/L). Median muscular normalized (35)Cl signal intensity was higher in patients with Cav1.1-R1239H (27.6, P < .001) and Cav1.1-R528H (23.6, P < .001) than in healthy volunteers (12.6), but not in patients with the Kir2.1 mutation (14.3, P = .517). When compared with volunteers, patients with Cav1.1-R1239H and Cav1.1-R528H showed increased muscular edema (P < .001 and P = .003, respectively) and muscle fat fraction (P < .001 and P = .017, respectively). Conclusion With 7-T MR imaging, changes of Na(+) and Cl(-) homeostasis can be visualized in periodic paralyses and are most pronounced in the severe phenotype Cav1.1-R1239H, with up to daily paralytic episodes. (©) RSNA, 2016 An earlier incorrect version of this article appeared online. This article was corrected on April 18, 2016.

Malignant Hyperthermia: An Inherited Disorder of Muscle Calcium Metabolism

Malignant hyperthermia (MH) is a rare pharmacogenetic disorder of skeletal muscle metabolism, inherited in an autosomal dominant manner. In the majority of cases, mutations are found in the gene encoding ryanodine receptor type 1 (RyR1), the calcium release channel in the sarcoplasmic reticulum. MH is typically triggered by volatile anesthetics; crises outside general anesthesia are extremely rare. More than half of reported adverse anesthetic MH events are allotted to children. Clinical crises are characterized by tachycardia, acidosis, generalized muscle stiffness, and high body temperature originating from unleashed calcium release from the sarcoplasmic reticulum. Life-threatening complications include cardiac arrhythmia, renal failure, disseminated intravascular coagulation, and rhabdomyolysis. Clinical treatment is based on rapid infusion of dantrolene, which inhibits myoplasmic calcium increase and might also be beneficial in other hypermetabolic MH-like events, especially when calcium turnover is augmented. Increasing knowledge on genetic causes and pathophysiologic pathways allows specific handling of these patients.