P. Zaniol

Abnormal brain and muscle energy metabolism shown by 31P magnetic resonance spectroscopy in patients affected by migraine with aura

We studied brain and muscle energy metabolism by phosphorus 31 magnetic resonance spectroscopy (31P-MRS) in 12 patients affected by migraine with aura (classic migraine) in interictal periods. Brain 31P-MRS disclosed a low phosphocreatine content in all patients, accompanied by high adenosine diphosphate concentration, a high percentage of V/Vmax (adenosine triphosphate), and a low phosphorylation potential—features showing an unstable state of metabolism in classic migraine. Abnormal muscle mitochondrial function, in the absence of clinical signs of muscle impairment, was present in nine of the 12 patients examined.

Defective Brain Energy Metabolism Shown by in vivo 31P MR Spectroscopy in 28 Patients with Mitochondrial Cytopathies

We studied brain energy metabolism by phosphorus magnetic resonance spectroscopy (31P MRS) in 28 patients with mitochondrial cytopathies, and 20 normal control subjects. Fourteen patients had myopathy alone, six had only mild brain symptoms, and eight showed different degrees of brain involvement. Brain 31P MRS showed a low phosphocreatine content in all patients, accompanied by a high inorganic phosphate in 14 of 28 patients. The average value of the Pi concentration in the patient group was significantly (p = 0.009) different from the control group. The cytosolic pH was normal. From these data were derived a high concentration of ADP (calculated from the creatine kinase equilibrium), a high percent value of V/Vmax for ATP biosynthesis, and a low phosphorylation potential, all features showing a derangement of brain energy metabolism, in all patients with mitochondrial cytopathies. 31P MRS proved to be sensitive enough to disclose a deficit of mitochondrial functionality not only in the affected patients, but also in those without clinically evident brain symptoms.

Clinical and brain bioenergetics improvement with idebenone in a patient with Leber's hereditary optic neuropathy: a clinical and 31P-MRS study

We used phosphorus magnetic resonance spectroscopy (31P-MRS) to study in vivo brain and muscle bioenergetics in a male patient with Lebers hereditary optic neuropathy (LHON) and mtDNA mutation at 11,778 bp who developed spastic paraparesis with white matter lesions on brain MR imaging. The study was performed before and during treatment with idebenone (135 mg t.i.d.) and after withdrawal. Clinical amelioration and worsening were associated with parallel changes in brain and skeletal muscle bioenergetics following the administration or withdrawal of idebenone. Reversal of paraparesis by idebenone was paralleled by normalization of 31P-MRS, serum lactate and central motor conduction. Extra-ocular neurological dysfunction in LHON may be amenable to treatment by appropriate quinones.

Defective brain and muscle energy metabolism shown by in vivo 31P magnetic resonance spectroscopy in nonaffected carriers of 11778 mtDNA mutation

In vivo phosphorus magnetic resonance spectroscopy (31P-MRS) showed defective brain and muscle energy metabolism in three affected siblings in a family with Lebers hereditary optic neuropathy (LHON) with the 11778 mtDNA mutation. We studied 14 nonaffected members of the same pedigree by 31P-MRS and molecular genetics. Nine of 14 individuals studied had the 11778 mtDNA mutation, with various degrees of heteroplasmy. A decreased brain energy reserve, as shown by low phosphocreatine content and phosphorylation potential and high [ADP], was present in eight of these nine subjects with the 11778 mutation. A low rate of postexercise phosphocreatine recovery in muscle was present in six of the nine mutated individuals. Normal MRS findings in the brain of one and the muscle of three carriers were accompanied by a low percentage of mutated mtDNA. All subjects without mutation had normal brain and muscle MRS. 31P-MRS disclosed defective bioenergetics in the brain or muscle or both of all asymptomatic carriers studied from our pedigree.

Abnormal brain and muscle energy metabolism shown by 31P-MRS in familial hemiplegic migraine

Familial hemiplegic migraine (FHM) is a rare autosomal dominant disorder of unknown pathogenesis characterized by migraine and transitory hemiplegic attacks. We describe a kindred fulfilling the diagnostic criteria for FHM in which: (1) brain phosphorus magnetic resonance spectroscopy (31P-MRS) showed a reduced phosphocreatine content accompanied by high [ADP], high percentage of V/Vmax of ATP biosynthesis and decreased phosphorylation potential; (2) muscle 31P-MRS showed a reduced rate of phosphocreatine recovery after exercise; (3) blood lactate was increased after effort; (4) muscle biopsy showed, in one patient, rare ragged red fibers succinate-dehydrogenase positive and cytochrome c oxidase negative; (5) genetic analysis of muscle mitochondrial DNA did not show any of the two point mutations in the tRNA(Leu(UUR)) associated with the MELAS syndrome (Mitochondrial myopathy, Encephalopathy with Lactic Acidosis and Stroke-like episodes). The defective energy metabolism of brain and muscle found in this pedigree suggests a multisystemic disorder of mitochondrial function in this FHM pedigree.

Deficit of brain and skeletal muscle bioenergetics and low brain magnesium in juvenile migraine : An in vivo 31P magnetic resonance spectroscopy interictal study

We used phosphorus magnetic resonance spectroscopy (31P MRS) to investigate in vivo the brain and skeletal muscle energy metabolism of 15 children with migraine with aura in interictal periods. Brain 31P MRS disclosed low phosphocreatine and high inorganic phosphate contents, and high intracellular pH in all patients. Calculated [ADP] and the relative rate of mitochondrial oxidation were higher in the brain of patients than in control subjects, whereas the phosphorylation potential was lower. Brain intracellular free Mg2+ concentration was reduced by 25% in patients. Abnormal skeletal muscle mitochondrial respiration was also disclosed in 7 of 15 patients as shown by the slow rate of phosphocreatine postexercise recovery. The multisystem bioenergetic failure found in patients with juvenile migraine is comparable to that found in adults with different types of migraine.

31P-NMR spectroscopy of skeletal muscle in Becker dystrophy and DMD/BMD carriers: Altered rate of phosphate transport

Muscle energy metabolism was studied by phosphorus nuclear magnetic resonance spectroscopy (31P-NMR) in 6 patients with Becker dystrophy, and in 24 female DMD/BMD carriers (n = 18) and non-carriers (n = 6). At rest all patients showed a high Pi/PCr ratio due to low PCr and high Pi contents, and a high intracellular IpH. 31P-NMR of carriers and non-carriers did not differ from controls. In patients and carriers in-magnet exercise revealed a reduced ability to perform work and Pi/PCr ratios higher than controls for comparable relative levels of steady-state work. Post-exercise Pi recovery was found abnormal in patients and in carriers. The 31P-NMR abnormalities found in the working muscle of both BMD patients and female DMD/BMD carriers indicate a defect of phosphate metabolism that, be it primary or secondary, reflects a deficit of energy metabolism.

Phosphorus Magnetic Resonance Spectroscopy in Cluster Headache

We performed in vivo MR spectroscopy phosphorus (sup 31 P-MRS) on the brain and skeletal muscles of 14 patients affected with cluster headache (CH). We examined patients in interictal periods, and also examined nine of them during the cluster period, although not during the attack. Brain31 P-MRS showed reduced phosphocreatine (PCr) levels, an increased ADP concentration (calculated from the creatine kinase equilibrium), a reduced phosphorylation potential, and a high relative rate of ATP biosynthesis (V/Vmax %). The inorganic phosphate (Pi) content was increased during the cluster period. Ten of 13 patients also showed a slow rate of PCr recovery in muscle after the exercise.31 P-MRS in CH patients showed abnormalities of brain and skeletal muscle energy metabolism comparable with those seen in various types of migraine, thus leading us to suggest a similarity in biochemical pathogenic mechanisms between CH and migraine. NEUROLOGY 1997;48: 113-118

Epilepsia partialis continua associated with NADH-coenzyme Q reductase deficiency

We report the clinical, neuroradiological and biochemical features of a patient with epilepsia partialis continua (EPC). MRI studies disclosed multiple cortico-subcortical areas of abnormal signal intensity. The activity of complex I of the mitochondrial respiratory chain was markedly reduced in skeletal muscle. The biochemical defect was reflected in vivo by a failure of brain and skeletal muscle bioenergetics, as shown by exercise and phosphorus magnetic resonance spectroscopy (31P-MRS) studies. Muscle morphology was repeatedly normal, and molecular genetic analysis of mitochondrial DNA was not informative. On the basis of in vivo and in vitro findings, the observed defect of the mitochondrial respiratory chain was considered the underlying biochemical pathogenesis of the disease. The observation of an oxidative defect in the brain and skeletal muscle of a patient with EPC emphasizes the importance of studying mitochondrial energy metabolism in patients with EPC not associated with primary CNS lesions when clinical and morphological findings suggesting a mitochondrial disorder are lacking. 31P-MRS can be a useful method to uncover deficits of CNS mitochondrial function and provide the indication for further biochemical studies.

Further impairment of muscle phosphate kinetics by lengthening exercise in DMD/BMD carriers

We used phosphorus magnetic resonance spectroscopy (31P-MRS) to study the effect of exercise-induced muscle injury in the calf muscle of 7 DMD/BMD carriers and 6 non-carrier females. All subjects performed 50-80 lengthening contractions with the right calf muscles. 48 h after lengthening exercise non-carriers showed increased sensitivity to pressure in their gastrocnemius accompanied by increased T2 relaxation times and by elevated Pi/PCr ratios at rest. DMD/BMD carriers did not show any effect of lengthening exercise on these measurements. In-magnet exercise revealed in all carriers a reduced initial rate of Pi recovery and an increased time to fully recovery the resting value of intracellular pH. Lengthening exercise further decreased the initial rate of Pi recovery. Non-carriers did not show any variation attributable to lengthening exercise either during in-magnet work or during recovery from exercise. We found that lengthening exercise contractions causes: (1) less muscle injury in carriers compared to non-carriers, (2) even slower rate of Pi recovery, but (3) no effect on Pi recovery in non-carriers. The use of lengthening exercise and measurements of Pi recovery may be a useful method to evaluate the disease process in DMD/BMD.