Cristina Cuccagna

Peripheral neuropathy is a common manifestation of mitochondrial diseases: a single-centre experience

Peripheral neuropathy in mitochondrial diseases (MDs) may vary from a subclinical finding in a multisystem syndrome to a severe, even isolated, manifestation in some patients.

Mitochondrial neuropathy: considerations on pathogenesis

Inspired by the letter of Finsterer & Frank [1] we further analysed our cohort of patients with mitochondrial diseases (MDs), providing additional data. Nerve conduction studies revealed a neuropathy in 40 patients without symptoms or signs (9 mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS), 10 myoclonic epilepsy with ragged-red fibers (MERRF), 4 mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), 13 progressive external ophthalmoplegia (PEO) and 4 other MDs). These data confirm the importance of always screening patients with MD for neuropathy. Neuropathy was defined as indicated in Luigetti et al. [2] and we used normative data from our laboratory obtained with the same electromyography (EMG) apparatus (Dantec Keypoint). Conversely, in 12 patients (two MERRF, nine PEO and one other MD) with neuropathic symptoms or signs (absence or reduction of distal tendon reflexes that are normally spared in myopathies), nerve conduction studies proved normal. Longitudinal neurophysiological followup will elucidate whether nerve involvement will occur also in these cases. As in our previous article [2], diabetes was reported in 15 cases, seven with neuropathy and eight without. All patients with diabetes were in treatment and the mean HbA1c value was 57.67 mmol/mol (range 46.0–85.0; normal value < 42.0), again excluding any correlation of diabetes or treatment with the presence of neuropathy. Other conditions predisposing to a neuropathy occurred in six patients (two hepatitis C virus (HCV), one hepatitis B virus (HBV), one with rheumatoid arthritis, one with chronic renal failure and one with previous assumption of chemotherapies). Neuropathy occurred only in half of those (one PEO with HCV, one MELAS with HBV and one MELAS with chronic renal failure). Furthermore, seven patients (one MELAS, one MERRF, four PEO and one other MD) suffered from hypothyroidism and all disclosed a polyneuropathy. All of these patients were in longlasting substitutive therapy with normal values of circulating hormones and therefore we do not believe that this condition could have influenced the neuropathy onset. In fact, neuropathy is a rare event in hypothyroidism and has been reported only in severely affected and untreated patients [3]. No patients suffered from parathyroid dysfunction. Hearing impairment, as we indicated previously [2], was reported in 84 patients (12 MELAS, 14 MERRF, one MNGIE, 50 PEO and seven other MDs) but none reported dizziness or other symptoms suggesting involvement of vestibular nerve. No patients suffered from autonomic system dysfunction. The mutation load in PEO associated with mitochondrial DNA (mtDNA) single deletion was available in muscle for 40 patients (from 20% to 91%). Heteroplasmy levels of the A8344G mutation were available in muscle for 12 patients (mutation load from 10% to 88%) and in blood for seven patients (mutation load from 0% to 76%). The mutation load for A3243G was available in muscle for four patients (from 50% to 80%) and in blood for six patients (from 14% to 67%). No clear relationship was observed between the mutation load and the presence of neuropathy. In summary, we believe that these new data strengthen and confirm the conclusion of our previous work that neuropathy is a common feature of mitochondrial disorders specifically related to the MD [2].

Resolution of Muscle Inflammation After Tumor Removal in a Woman with Paraneoplastic Dermatomyositis

The paraneoplastic association of dermatomyositis (DM) and underlying breast cancer is well established1,2. This report confirms the diagnostic and therapeutic value of searching for malignancy in patients with DM3,4. A 33-year-old woman developed subacute severe proximal muscle weakness, dysphagia, respiratory failure, skin lesions on the forehead, and purplish discoloration around the upper eyelid, with ulcerating nodules in …

Neurological involvement during legionellosis, look beyond the lung

Legionella represents the etiologic agent of a relevant number of cases of pneumonia in patients admitted to the Emergency Department and is still associated with a remarkable mortality rate. Among extrapulmonary legionellosis manifestations, central nervous system (CNS) involvement has been frequently documented. Main symptoms are confusion, obtundation, stupor, headache, and behavioral abnormalities; cerebellar dysfunction may rarely occur. Encephalopathic manifestations are frequently reversible within weeks or months, although ataxia and dysarthria may persist after years. Since the mechanisms of extrapulmonary manifestations, including neurological ones, still need to be clarified, no specific therapeutic strategies have been proposed to treat complicated patients so far [1–3]. A 36-year-old Caucasian man without any significant medical comorbidities was admitted to our hospital with fever and tachypnea. In the last 3 days he had presented fever, malaise, progressive dyspnea, abdominal pain and confusion. Chest X-ray showed a left median-inferior consolidation with consensual pleural effusion. The urinary antigen test for Legionella pneumophila serogroup one was positive. Lumbar puncture revealed normal protein and glucose levels, and 12 lymphocytes/mm; cerebrospinal fluid (CSF) bacterial cultures were negative. Antimicrobial therapy with intravenous levofloxacin and azitromicin was started. Within a few days, fever and respiratory distress progressively disappeared. However, on day 3 after admission, neurological examination showed severe dysarthria, limb and trunk ataxia, impaired finger-to-nose and heel-to-shin movement, nystagmus, and slight intentional tremor. Brain magnetic resonance imaging (MRI) showed a strongly increased signal of 12 mm in the splenium of the corpus callosum (SCC) on T2and diffusion-weighted

Hypoglossal palsy and coeliac disease: An uncommon presentation for a common disease?

Twelfth-nerve palsy, associated with other cranial neuopathies, is relatively common in clinical practice and is often an minous sign of malignant disease [1]. Isolated hypoglossal palsy IHP), rather, is rare. Tongue weakness and atrophy, sometimes ssociated with dysarthria, dysphagia and headache, are the only eatures of the clinical picture. Many disorders can be responsible for IHP. Neoplasia, once gain, is the most frequent cause but trauma, malformations, vasular, infectious and autoimmune diseases have been reported as ell. Searching for the correct etiological diagnosis requires the ystematic use of many radiological and laboratory investigations nd, above all, careful and prolonged follow-up. In spite of these easures, very rarely, the cause is not found and this condition is nown as idiopathic IHP. Coeliac disease (CD) is a chronic disorder caused by immune esponse to gluten, a protein present in wheat, rye and barley. This ondition produces inflammation, villous atrophy and crypt hyperlasia in the proximal part of the intestine. Clinically, the typical icture of CD as pediatric gastrointestinal disorder is now out of ate. The diagnosis is, in fact, often made in adults with extrainestinal symptoms.

Small fibre neuropathy in mitochondrial diseases explored with sudoscan

OBJECTIVE Polyneuropathy in mitochondrial diseases (MDs) is relatively common and widely investigated, but few data are instead reported about small fibres involvement. METHODS In order to investigate the involvement of small fibres in MDs we performed extensive neurophysiological test (nerve conduction studies; sympathetic skin response; sudoscan) in 27 patients with genetic diagnosis of MD (7 m.3243A > G; 4 m.8344A > G; 9 single mtDNA deletion; 7 multiple mtDNA deletions). RESULTS NCS showed a polyneuropathy in 11/27 cases (41%). The incidence was very high in POLG1 (100%), m.8344A > G (75%) and m.3243A > G (43%), while only 11% of patients with single deletion had evidence of large fibres involvement. Sympathetic skin response was abnormal only in three patients (one progressive external ophthalmoplegia with single mtDNA deletion; one patient with m.3243A > G mutation; one patient with POLG1 mutation). Sudoscan revealed the presence of an autonomic small fibres dysfunction in 9/27 cases (33%), most of them (7/9) carrying a single mtDNA deletion. Sudoscan data were also confirmed in a sub-group of patients by laser evoked potentials study. Considering only patients with single mtDNA deletion 7/9 (78%) showed abnormal results at sudoscan. CONCLUSIONS Small fibre neuropathy is another feature to investigate in mitochondrial diseases and seems specifically associated with the presence of single mtDNA deletion. SIGNIFICANCE The correct identification through specific neurophysiological tests of small fibres involvement in MDs represents another tile in this challenging diagnosis.

Progressive axonal polyneuropathy in a mitochondrial disorder: an uncommon association with familial amyloid neuropathy

Mitochondrial diseases are inherited disorders of oxidative phosphorylation that present with a multitude of clinical features in different combinations and with various inheritance patterns. The occurrence and characteristics of peripheral nerve involvement vary considerably amongst syndromes and genetic background [1]. Transthyretin (TTR) amyloidosis is a rare, life-threatening, progressively debilitating, autosomal dominant condition characterized by extracellular deposition of TTRderived amyloid fibrils in peripheral and autonomic nervous system, heart and other organs, leading to tissue damage and organ failure [2]. Characteristic of polyneuropathy in TTR-amyloidosis may differ according to geographic area [2]. We report a 67-year-old man that came to our observation for a four-year history of numbness and tingling in lower limb associated with walking difficulties and exercise intolerance. After extensive diagnostic work-up (see Supplementary material) patient was discharged with a diagnosis of mitochondrial disorder with multi-system involvement (Figure 1(A–D)). He was stable for about two years and then markedly worsened. Neurological examination revealed unchanged bilateral ptosis, ambulation possible only for few meters with bilateral support, muscle weakness of lower limbs graded by Medical Research Council (MRC) scale 0–1 in distal and 4 in proximal muscles and of upper limbs graded 3 in distal and 4 in proximal muscles, hypoesthesia with stocking-gloves distribution, reduced tendon reflexes in upper and absent in lower limbs. In parallel with the clinical deterioration, nerve conduction studies demonstrated a worsening of the polyneuropathy (Supplementary Table S1). Suspecting a superimposed inflammation the patient underwent lumbar puncture that was unremarkable and a highdosage cycle of intravenous immunoglobulin (IVIg) without improvement. Serum and urine immunofixation was again unremarkable. Myocardial scintigraphy with bone tracer was normal.

P24.10 Sleep disordered breathing in progressive external ophthalmoplegia

frontal spindles observed in parietal region consisted of slower frequency, compared with those in centro-parietal region. The difference of propensities between slow spindles and fast spindles have been still under debate. Objectives: To clarify the properties of sleep spindles between healthy subjects and medicated depressive patients, including frequency range, spectra power and the pattern of propagation. Methods: Healthy comparison subjects (n = 20) and medicated depressive patients (n = 15) were recruited. Subjects were recorded during all night with 32 channels EEG. Recordings were analyzed for changes in EEG power spectra, power topography. In addition, we graphically demonstrated the pattern of propagation of each type of spindle, divided into fast spindle 12.5 16 Hz and slow spindle 10.5 12.5 Hz. Ethical committee of Tokyo Medical and Dental University approved this study and written informed consent was obtained from each subject. Results: Sleep EEG of depressive subjects exhibited significant higher amplitude of slow spindle in frontal region, compared with that of comparison normal groups (p < 0.05). Slow spindles were generally dominant in whole cerebral regions in depressive patients, while fast spindles were prominent within frontal region in normal groups. Conclusions: Sleep spindles are generated by the thalamic reticular nucleus and are modulated by corticothalamic and thalamocortical connections. The alteration in sleep spindles in medicated depressive subjects may reflect dysregulation in thalamic-reticular and thalamocortical mechanisms and could represent a recovery process on neural network, involving pharmacological modulation on synaptic function.

W12.2 Mitochondrial encephalomyopathies: central nervous system involvement

Methods: fMRI during a hand-grip task was performed in 10 ALS patients (age range 42 82 years). Image pre-processing and statistical analysis was performed using SPM8. A second level random effects analysis was used with a cluster-level significance p < 0.05 (corrected). A range of disease measures was tested in regression models: age, disease duration, functional rating scales, hand function tests, handedness index, upper motor neuron burden and electrophysiological markers. Results: Group fMRI activations included contralateral primary sensorimotor cortex, lateral premotor cortex, posterior parietal cortex and supplementary motor area. Disease duration, ALS Functional Rating Scale, hand function tests and electrophysiological measures showed some statistically significant correlations with fMRI activity. The pattern of correlations was inconsistent across the functional measures. There was no effect of age, handedness and upper motor neuron burden on fMRI activations. Conclusions: Cortical fMRI activity in ALS patients correlates to a certain extent with some of the disease measures. The pattern of these correlations is, however, rather complex and inconsistent. Using fMRI as a biomarker for ALS disease progression seems a possibility but there are many methodological issues to be considered. Longitudinal studies of larger groups of patients at different stages of the disease are warranted.