Paolo Ambrosetto

Celiac disease, posterior cerebral calcifications and epilepsy†

Ten patients (5 males) affected by epilepsy with cerebral calcifications of unknown etiology mainly located in the posterior regions were subjected to a battery of tests including an intestinal biopsy. Our aim was to establish whether or not the patients also suffered from celiac disease. Celiac diseases was found in 6 patients. This result and the individual cases reported in the literature suggest that this triad of diseases (celiac disease, posterior cerebral calcifications and epilepsy) are casually related. The same HLA phenotype was found in all 10 patients, i.e., including the cases without celiac disease, suggesting an underlying disorder of the immune system. Our results emphasize that particular attention should be paid to a search for celiac disease in all patients with epilepsy and posterior cerebral calcifications.

Sturge-Weber syndrome without port-wine facial nevus: report of 2 cases studied by CT

2 cases of Sturge-Weber syndrome without facial nevus are reported. The patients presented different forms of epilepsy. The diagnosis was made by computed tomography (CT) which showed typical intracranial calcifications in both occipital regions. The problems concerning the atypical and incomplete forms of the syndrome are briefly discussed. The importance of CT as a diagnostic procedure for this disease is emphasized.

A combined a-EEG and MR spectroscopy study in term newborns with hypoxic–ischemic encephalopathy

OBJECTIVES Brain damage following a perinatal hypoxic-ischemic (HI) insult has been documented by different diagnostic techniques. The aim of the present study was to relate a-EEG time course during the first 24h of life to brain metabolic changes detected by proton MR spectroscopy ((1)H-MRS) at 7-10days of life and to evaluate their correlation with outcome. METHODS Thirty-two patients with any grade HI encephalopathy were studied. Thirty-one out of 32 patients survived and underwent (1)H-MRS examination at 7-10days of life; a-EEG was recorded during the first 24h of life in 27/32 newborns; 26 patients underwent both examinations. Griffiths test, evaluation of motor skills, visual and hearing function were performed at regular intervals until the age of 2years. RESULTS a-EEG at 6, 12 and 24h of life showed a significant correlation with outcome. N-acetyl-aspartate/creatine (Cr), Lactate/Cr and myo-inositol differed significantly between patients with normal or poor outcome. a-EEG time course during the first 24h of life showed improvement in newborns with normal (1)H-MRS and good outcome and a deterioration in those with abnormal (1)H-MRS and poor outcome. CONCLUSIONS a-EEG time course may be able to document the severity and the evolution of the cerebral damage following an HI event. a-EEG is related to the severity of cerebral injury as defined by (1)H-MRS and both examinations showed a good correlation with outcome. These data, obtained in non-cooled infants, may represent reference data for future investigations in cooled infants.

Computed Tomography and Magnetic Resonance Imaging Findings in Ophthalmoplegic Migraine

A patient with ophthalmoplegic migraine is described, and his computed tomography and magnetic resonance imaging findings are discussed. According to our results, triad migraine, third nerve palsy, and focal enhancement of an enlarged third cranial nerve at the root exit zone should be considered pathognomonic of the disease, and further examinations should be avoided. Pathogenetic theories of the disease are discussed, and we suggest a new pathogenetic theory.

Primary empty sella: differences and similarities between children and adults.

To identify possible differences between empty sella in children and adults we studied 43 subjects (age 13.6 ±5.4 years, range 4.1–27 years) with hypothalamic‐pituitary disorders and empty sella at magnetic resonance imaging. Pituitary function, presence of non‐endocrine symptoms, perinatal history, sellar volume, pituitary height, midline or intrasellar anatomical abnormalities were evaluated. Twenty subjects had isolated growth hormone deficiency, 17 multiple pituitary hormone deficiency and 6 puberty disorders (3 precocious puberty, 2 idiopathic delayed puberty, 1 Kallmann syndrome). The group with multiple pituitary hormone deficiency had a higher percentage of subjects with complete empty sella, i.e pituitary height < 2 mm (p= 0.016), or intrasellar anatomical abnormalities (p = 0.0002) than the other groups. The subjects with puberty disorders had a mean sellar volume higher than the other groups (p < 0.05). Apart from pituitary dysfunction, symptoms of the empty sella syndrome were infrequent (9.3% of cases) in our subjects. The age of our subjects, the frequent association between empty sella and pituitary dwarfism and the non‐enlarged sellae suggest a different aetiology, perhaps congenital, for empty sella in our subjects. As in adults, empty sella may be associated with both pituitary hypo‐ and hyperfunction.

Ophthalmoplegic migraine: From questions to answers

Introduction The International Classification of Headache Disorders classifies ophthalmoplegic migraine (OM) under “cranial neuralgias and central causes of facial pain.” OM is diagnosed when all the following criteria are satisfied: At least two attacks fulfilling criterion B. Migraine-like headache accompanied or followed within four days of its onset by paresis of one or more of the III, IV and/or VI cranial nerves. Parasellar orbital fissure and posterior fossa lesions ruled out by appropriate investigations. In children the syndrome is rare and magnetic resonance (MR) shows strongly enhancing thickened nerve at the root entry zone (REZ). Method The authors review the literature focusing on pathogenesis theories. Results The authors suggest that ischemic reversible breakdown of the blood-nerve barrier is the most probable cause of OM and to include MR findings in the hallmarks of the disease. Conclusion OM is the same disease in adulthood and childhood, even if in adults the MR imaging findings are negative. In the authors’ opinion, OM should be classified as migraine.

Wernicke's encephalopathy in a child: case report and MR findings.

Abstract We report a child affected by Wernickes encephalopathy (WE), which was unsuspected clinically. MRI suggested the correct diagnosis and prompted appropriate thiamine replacement. WE is a difficult condition to recognise, especially in children, and MRI may be useful in the diagnosis of the disease.

MR findings in Seckel's syndrome: report of a case

Abstract The cranial MR findings in a patient with Seckels syndrome are presented. The examination demonstrated osseous anomalies of the face, but, unlike previous reports, the brain and cerebellum were normal. The authors emphasise the importance of further reports on MR findings in patients affected by Seckels syndrome.

MR findings in pituitary haemosiderosis

Abstract A girl with Diamond-Blackfan syndrome and hypopituitarism was suspected of having pituitary haemosiderosis because of the clinical picture and the long history of blood transfusions. On T1-weighted MR images the pituitary exhibited a markedly hypointense anterior lobe (mimicking the empty sella), suggesting iron deposition, while on T2W MRI the low signal of the pituitary was surrounded by the high signal of the CSF. MR may be considered the examination of choice for detecting iron overload in the pituitary.

A case of fragile X premutation tremor/ataxia syndrome with evidence of mitochondrial dysfunction

The fragile X premutation tremor/ataxia syndrome (FXTAS) is a recently described adult-onset neurodegenerative disorder1 characterized by cerebellar ataxia and/or intention tremor and other documented symptoms such as short-term memory loss, executive function deficits, cognitive decline, Parkinsonism, peripheral neuropathy, lower limb proximal muscle weakness, and autonomic dysfunction in various combinations. Magnetic resonance imaging (MRI) findings in affected individuals include increased T2 signal intensity in the middle cerebellar peduncles and cerebellar peridentate white matter, cerebellar cortical atrophy, cerebral atrophy, and thinned corpus callosum.2,3 A 58-year-old man was referred to us because of rest and action tremor and ataxic gait. He had no family history of neuropsychiatric disorders, except a late-onset tremor in his maternal grandfather. At the age of 45, he developed major depression with severe anxiety and social phobia. He experienced onset of right arm tremor by the age of 48, followed by right leg tremor, intermittent tongue tremor, mild right bradykinesia, and gait instability by the age of 53. At the age of 56, tremor extended to the left side and he started complaining of memory loss. At the age of 58, he had developed severe ataxia with falls. Neurological examination showed bilateral rest, postural, and action tremor; mild right bradykinesia; left Babinski; reduced deep tendon reflexes at the patellae and absent at the ankles; and ataxic gait. Neuropsychological testing documented short-term and long-term memory loss and executive function deficits without dementia. IQ score was normal (total IQ 90). Copper; HIV markers; lysosomial enzymes studies; genetic testing for spinocerebellar ataxias type 2, 3, and 6; and cerebrospinal fluid investigations (including oligoclonal bands) were all normal. MRI scans showed symmetrically decreased T1 and increased T2 signal intensity in the middle cerebellar peduncles, peridentate white matter, and periventricular and subependymal cerebral white matter. Mild cerebral and cerebellar cortical atrophy and thin corpus callosum with hyperintense genu and splenium were also present (Fig. 1A–D). Genetic testing disclosed a CGG expansion in the FMR1 (fragile X mental retardation 1) gene in the 55to 200-repeat range (91 3 CGG repeats on Southern blot analysis), termed premutation. The diagnostic criteria proposed by Jacquemont and colleagues for definite FXTAS were fulfilled.2 Proton (1H-MRS) and phosphorus (31P-MRS) magnetic resonance spectroscopy (MRS) studies were performed in a 1.5T GE Medical Systems Signa Horizon LX whole-body scanner. Single voxel 1H-MRS spectra were acquired using the PRESS sequence in the left cerebellar hemisphere (including the dentate nucleus and the peridentate white matter with abnormal signal intensity on MRI), in the normalappearing left parieto-occipital white matter, in the midbrain parietal– occipital cortex (TE 35 msec; TR 4,000 msec) and in the lateral ventricles (TE 288 msec; TR 1,500 msec; Fig. 1E). Peak areas for N-acetylaspartate (NAA), creatine–phosphocreatine (Cr), choline (Cho), and lactate were calculated using the time domain fitting program AMARES/MRUI. 31P-MRS spectra were acquired at rest from the left calf muscles as previously described4 with a repetition time of 5 seconds (128 FIDs), and phosphocreatine, inorganic phosphate (Pi), and ATP were quantified using AMARES/MRUI. Ten healthy sexand age-matched subjects were also studied. Reduced cerebellar NAA/Cr (1.21; normal range, 1.31–1.68) and abnormally increased lactate in ventricles (Fig. 1F), undetectable in controls, were found in the patient. No metabolic alterations were found in the other cerebral regions studied. Muscle 31P-MRS in the patient detected an increase in Pi to ATP ratio (0.78; normal range, 0.44 – 0.62). Ventricular lactate accumulation and increased Pi to ATP ratio in the resting calf muscles found in our patient are typical findings in mitochondrial encephalomyopathies5–7 and point to a dysfunction of oxidative phosphorylation. Several findings indicate an RNA-mediated pathogenesis for FXTAS.8 The main molecular abnormality in this disease is the twoto fivefold increase in FMR1 mRNA with lownormal or mildly decreased levels of FMRP (fragile X mental retardation protein).9 Mechanisms of pathogenesis could be similar to that of myotonic dystrophy (DM), where abnormal RNAs with the CTG trinucleotide expansion accumulate in ribonuclear foci and alter the regulation or localization of different forms of RNA-binding protein, leading to aberrant splicing of several transcripts.10,11 Of interest, the 31P-MRS study of patients with DM disclosed an impairment of oxidative phosphorylation.12 In FXTAS, excess binding of some proteins to mRNA with CGG expansion has been hypothesized to trigger the accumulation or abnormal processing of proteins by the proteasomal degradation pathway, inducing intranuclear inclusion formation, and to deplete the protein cellular pool, leading to a loss of their normal functions in other regulatory processes.8 Unlike DM, no aberrant transcripts are known in FXTAS. In both, however, one of the final events due to RNA toxic gain-offunction could be a dysfunction of the respiratory chain. Our MRS findings in a single patient could be coincidental, but if further studies confirm mitochondrial dysfunction in FXTAS, as well as in DM, they would shed more light on all pathogenic mechanisms in these diseases.