Giovanni Rizzo

Idebenone Treatment In Leber's Hereditary Optic Neuropathy

Sir, We have read with great interest the results presented by Klopstock et al. (2011) concerning the RHODOS study on a clinical trial with idebenone in Lebers hereditary optic neuropathy (LHON) and we would like to share our own experience of idebenone therapy in LHON. Idebenone has been an approved drug (Mnesis®, Takeda Italia Farmaceutici) in Italy since the early 1990s and, after the initial report by Mashima et al . (1992) on its possible efficacy in LHON, we offered this therapeutic option to all of our new consecutive patients with LHON, almost all of whom accepted treatment. Idebenone was given after informed consent following the regulation for ‘off-label’ drug administration and was provided for free by the National Health Service, under the legislation for certified rare disorders. Patients were initially treated with 270 mg/day (Cortelli et al ., 1997; Carelli et al ., 1998 a , b ), but following the reports on idebenone treatment in Friedreich ataxia, the dosages were increased to 540–675 mg/day (Rustin et al ., 1999; Kearney et al ., 2009). To evaluate retrospectively the efficacy of idebenone therapy, we reviewed all of our patients with LHON, idebenone treated and untreated, after approval of the institutional Internal Review Board. Inclusion criteria for treated patients were the initiation of therapy within 1 year after visual loss in the second eye, and for all patients (treated and untreated) age at onset of at least 10 years and a follow-up of at least 5 years. We included only patients treated within 1 year after onset because this is the time frame to reach the nadir of the visual loss and the probability of spontaneous recovery of vision is highest in the following 5 years (Nikoskelainen et al ., 1983; Barboni et al ., 2005, 2010; …

Diffusion-weighted brain imaging study of patients with clinical diagnosis of corticobasal degeneration, progressive supranuclear palsy and Parkinson's disease

Corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are two neurodegenerative disorders within the category of tauopathies, which must be considered in differential diagnosis of Parkinsons disease. Although specific clinical and neuroradiological features help to guide the clinician to a likely diagnosis of Parkinsons disease, CBD or PSP, differential diagnosis remains difficult. The aim of our study was to analyse apparent diffusion coefficient (ADC(ave)) maps from patients with clinical diagnosis of CBD (corticobasal syndrome, CBS), classical phenotype of PSP (Richardsons syndrome, RS) and Parkinsons disease (PD) in order to identify objective markers to discriminate between these groups. Thirteen Parkinsons disease patients, 10 RS patients, 7 CBS patients and 9 healthy volunteers were recruited and studied in a 1.5 T MR scanner. Axial diffusion-weighted images were obtained and the ADC(ave) map was generated. Regions of interest (ROIs) included mesencephalon, corpus callosum and left and right superior cerebellar peduncle (SCP), thalamus, caudate, putamen, pallidus, posterior limb of internal capsule, frontal and parietal white matter. Histograms of ADC(ave) were generated for all voxels in left and right cerebral hemispheres and in left and right deep grey matter regions separately, and the 50th percentile values (medians) were determined. The ratio of the smaller to the larger median value (symmetry ratio) was calculated for left and right hemispheres and for left and right deep grey matter regions (1 = perfect symmetry). Putaminal ADC(ave) values in CBS and RS were significantly greater than those in Parkinsons disease and healthy volunteers, but could not distinguish CBS from RS patients. In CBS patients, the values of the medians of cerebral hemispheres histograms were significantly higher than those in RS, Parkinsons disease and healthy volunteers, while the hemispheric symmetry ratio in CBS (0.968, range 0.952-0.976) was markedly reduced compared with RS (0.993, range 0.992-0.994), Parkinsons disease (0.991, range 0.988-0.993) and healthy controls (0.990, range 0.988-0.993). The hemispheric symmetry ratio differentiated CBS patients from RS and Parkinsons disease patients with a sensitivity and specificity of 100%. In RS patients, the ADC(ave) values of the SCPs were significantly greater than those in Parkinsons disease and healthy volunteers. Our findings confirm that putaminal ADC(ave) values evaluation provides a good discrimination between Parkinsons disease and atypical parkinsonisms, including RS and CBS. Furthermore, diffusion-weighted imaging, by detecting the brain microstructural correlates of the typical asymmetric signs and symptoms in CBS and the SCP involvement in RS, was shown to aid characterization and differentiation of atypical parkinsonism.

Visual system involvement in patients with Friedreich's ataxia

Optic neuropathy is common in mitochondrial disorders, but poorly characterized in Friedreichs ataxia (FRDA), a recessive condition caused by lack of the mitochondrial protein frataxin. We investigated 26 molecularly confirmed FRDA patients by studying both anterior and posterior sections of the visual pathway using a new, integrated approach. This included visual field testing and optical coherence tomography (OCT), pattern visual evoked potentials (P-VEPs) and diffusion-weighted imaging. The latter was used to study optic radiation by calculating water apparent diffusion coefficients (ADC). All patients suffered optic nerve involvement with their disorder. Different patterns of visual field defects were observed and a variably reduced retinal nerve fiber layer thickness was seen by OCT in all cases. P-VEPs were abnormal in approximately half of the patients. Decreased visual acuity and temporal optic disc pallor were present in advanced stages of the disease, but only five patients were symptomatic. Two of these patients suffered a sudden loss of central vision, mimicking Lebers hereditary optic neuropathy (LHON), and of the other three symptomatic patients two were noted to be compound heterozygotes. ADC values of optic radiations in patients were significantly higher than controls (P < 0.01). Retinal nerve fiber layer thickness at OCT and P-VEPs correlated with age at onset and ICARS total score. ADC values correlated with age at onset, disease duration, GAA triplet expansion size, ICARS total score and P-VEPs. Visual pathway involvement is found consistently in FRDA, being previously underestimated, and we here document that it also involves the optic radiations. Occasional LHON-like cases may occur. However, optic neuropathy in FRDA substantially differs from classic mitochondrial optic neuropathies implying a different pathophysiology of visual system degeneration in this mitochondrial disease.

Diffusion-weighted imaging study of patients with essential tremor

The pathophysiology of essential tremor (ET) is unknown. PET and fMRI studies have revealed bilateral activation and 1H‐MRS studies metabolic abnormalities in the cerebellum and other functionally related brain structures in ET. Diffusion‐weighted imaging (DWI) was used to search for evidence of tissue integrity abnormalities in these areas in ET patients and 10 matched controls by calculating water apparent diffusion coefficients (ADCs). Regions of interest included the left and right cerebellum, red nucleus, thalamus, caudate, putamen, pallidum, and frontal white matter. Histograms of ADCs were generated for all pixels in the infratentorial compartment and manually segmented areas corresponding to brainstem, vermis, and cerebellar hemispheres. ADC values were similar in all brain areas in patients and controls. Our study did not detect changes affecting the investigated brain regions in ET patients. These findings argue against major structural damage in the ET brain, although more subtle neurodegenerative changes cannot be ruled out.

Magnetic resonance diagnostic markers in clinically sporadic prion disease: a combined brain magnetic resonance imaging and spectroscopy study

The intra vitam diagnosis of prion disease is challenging and a definite diagnosis still requires neuropathological examination in non-familial cases. Magnetic resonance imaging has gained increasing importance in the diagnosis of prion disease. The aim of this study was to compare the usefulness of different magnetic resonance imaging sequences and proton magnetic resonance spectroscopy in the differential diagnosis of patients with rapidly progressive neurological signs compatible with the clinical diagnosis of sporadic prion disease. Twenty-nine consecutive patients with an initial diagnosis of possible or probable sporadic prion disease, on the basis of clinical and electroencephalography features, were recruited. The magnetic resonance protocol included axial fluid-attenuated inversion recovery-T2- and diffusion-weighted images, and proton magnetic resonance spectroscopy of the thalamus, striatum, cerebellum and occipital cortex. Based on the clinical follow-up, genetic studies and neuropathology, the final diagnosis was of prion disease in 14 patients out of 29. The percentage of correctly diagnosed cases was 86% for diffusion-weighted imaging (hyperintensity in the striatum/cerebral cortex), 86% for thalamic N-acetyl-aspartate to creatine ratio (cutoff ≤1.21), 90% for thalamic N-acetyl-aspartate to myo-inositol (mI) ratio (cutoff ≤1.05) and 86% for cerebral spinal fluid 14-3-3 protein. All the prion disease patients had N-acetyl-aspartate to creatine ratios ≤1.21 (100% sensitivity and 100% negative predictive value) and all the non-prion patients had N-acetyl-aspartate to myo-inositol ratios >1.05 (100% specificity and 100% positive predictive value). Univariate logistic regression analysis showed that the combination of thalamic N-acetyl-aspartate to creatine ratio and diffusion-weighted imaging correctly classified 93% of the patients. The combination of thalamic proton magnetic resonance spectroscopy (10 min acquisition duration) and brain diffusion-weighted imaging (2 min acquisition duration) may increase the diagnostic accuracy of the magnetic resonance scan. Both sequences should be routinely included in the clinical work-up of patients with suspected prion disease.

Clinical and neuroimaging evidence of interictal cerebellar dysfunction in FHM2

We used multimodal magnetic resonance (MR) techniques [brain diffusion-weighted magnetic resonance imaging, diffusion-weighted imaging (DWI), proton MR spectroscopy (MRS), 1H-MRS; and skeletal muscle phosphorous MRS, 31P-MRS] to investigate interictal brain microstructural changes and tissue energy metabolism in four women with genetically determined familial hemiplegic migraine type 2 (FHM2), belonging to two unrelated families, compared with 10 healthy women. Brain DWI revealed a significant increase of the apparent diffusion coefficient median values in the vermis and cerebellar hemispheres of FHM2 patients, preceding in two subjects the onset of interictal cerebellar deficits. 31P-MRS revealed defective energy metabolism in skeletal muscle of FHM2 patients, while brain 1H-MRS showed a mild pathological increase in lactate in the lateral ventricles of one patient and a mild reduction of cortical N-acetyl-aspartate to creatine ratio in another one. Our MRS results showed that a multisystem energy metabolism defect in FHM2 is associated with microstructural cerebellar changes detected by DWI, even before the onset of cerebellar symptoms.

Sleep and temperature rhythms in two sisters with P102L Gerstmann-Sträussler-Scheinker (GSS) disease

BACKGROUND Sleep disorders are increasingly recognized in the symptomatology of many neurodegenerative diseases. Gerstmann-Sträussler-Scheinker (GSS) disease is a hereditary prion disease featuring cerebellar ataxia, akinetic parkinsonism, pyramidal signs and cognitive decline. METHODS We performed a polysomnographic study (PSG) of sleep and body core temperature (BcT degrees ) in two sisters with GSS. RESULTS Our study showed protracted nocturnal awakenings, reduced sleep efficiency and brief daytime naps but also qualitatively preserved slow-wave and REM sleep and substantially normal arousal and periodic limb movements in sleep indices and BcT degrees rhythm. CONCLUSIONS These findings conflict with those in multiple system atrophy and other prion diseases such as fatal familial insomnia, which enter the differential diagnosis of GSS and are characterized by prominently disrupted sleep-wake and BcT degrees cycles.