Alice Todeschini

The role of mitochondria in neurodegenerative diseases

Mitochondria are implicated in several metabolic pathways including cell respiratory processes, apoptosis, and free radical production. Mitochondrial abnormalities have been documented in neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s diseases, and amyotrophic lateral sclerosis. Several studies have demonstrated that mitochondrial impairment plays an important role in the pathogenesis of this group of disorders. In this review, we discuss the role of mitochondria in the main neurodegenerative diseases and review the updated knowledge in this field.

Efficacy and Safety of Levetiracetam in Patients With Glioma: A Clinical Prospective Study

OBJECTIVE To evaluate the efficacy and safety of levetiracetam in the management of epilepsy in patients with glioma. DESIGN A prospective study in hospitalized patients with a new diagnosis of glioma. SETTING Department of Neurological Sciences and Visions, Spedali Civili of Brescia. PATIENTS From March 1, 2006, until January 1, 2009, 176 consecutive patients (101 men and 75 women) with a first diagnosis of glioma were enrolled in the study. All patients with a diagnosis of epilepsy were treated with levetiracetam. MAIN OUTCOME MEASURES Clinical, histological, and magnetic resonance imaging findings were analyzed. RESULTS Age at the diagnosis of glioma ranged from 22 to 79 years (mean [SD], 57 [15] years; median, 59 years). Duration of the disease ranged from 27 days to 2(1/2) years (mean [SD], 13.7 [7.8] months; median, 13 months). Eighty-two patients received levetiracetam because of a diagnosis of epilepsy. At the last evaluation (May 1, 2009), 75 of 82 patients (91%) treated with levetiracetam were seizure free; in 2 of these patients, levetiracetam was withdrawn because of intolerable adverse effects. Prompt and long-lasting control of seizures was obtained in 49 of 82 patients (60%) with a dose of levetiracetam that ranged from 1500 to 3000 mg/d, and 9 (11%) of the treated patients needed an increase of levetiracetam dosage to 4000 mg/d to become seizure free. No laboratory abnormalities were observed in patients with concomitant chemotherapy. CONCLUSION The results of this study provide good evidence that levetiracetam is efficacious and safe in patients with epilepsy due to glioma.

Glutamine synthetase expression as a valuable marker of epilepsy and longer survival in newly diagnosed glioblastoma multiforme

BACKGROUND Glutamine synthetase (GS) is an astrocytic enzyme catalyzing the conversion of glutamate and ammonia to glutamine. Its up-regulation has been related to higher tumor proliferation and poor prognosis in extra-cerebral tumors. We have previously reported a GS deficiency in patients with glioblastoma multiforme (GBM) who also developed epilepsy, which is a favorable prognostic factor in glioma. Here, we investigated the prognostic value of GS expression in patients with GBM with or without epilepsy and its correlation with survival. METHODS We conducted a clinical and histopathological study on 83 (52 males) consecutive patients with newly diagnosed GBM. Immunohistochemical expression of GS was scored semi-quantitatively on the basis of cell number, staining intensity, and distribution of immunoreactive cells. Several clinical and neuropathological variables were analyzed in relation to survival and GS expression. RESULTS Median age at diagnosis was 62 years. At the last evaluation, with a median follow-up of 11.5 months (range, 1.5-58 months), 5 patients (6%) were still alive and 78 (94%) were dead. GS expression patterns in neoplastic cells were inversely correlated to the presence of epilepsy (P < .0001 for intensity and P < .009 for homogeneity of GS distribution, respectively). Univariate analysis showed that RPA score, epilepsy, O6-methylguanine-DNA methyltransferase (MGM)T status, application of Stupp protocol, and GS intensity pattern had a significant impact on survival. Absent/low intensity of GS expression was significantly associated with a longer survival in both uni- (19 vs 8 months; P < .0005) and multivariate (P = .003) analyses. CONCLUSIONS Absent/low-intensity GS expression pattern represents a valuable biomarker of both epilepsy and overall survival in GBM.

Small Nerve Fiber Pathology in Critical Illness

Background Degeneration of intraepidermal nerve fibers (IENF) is a hallmark of small fiber neuropathy of different etiology, whose clinical picture is dominated by neuropathic pain. It is unknown if critical illness can affect IENF. Methods We enrolled 14 adult neurocritical care patients with prolonged intensive care unit (ICU) stay and artificial ventilation (≥ 3 days), and no previous history or risk factors for neuromuscular disease. All patients underwent neurological examination including evaluation of consciousness, sensory functions, muscle strength, nerve conduction study and needle electromyography, autonomic dysfunction using the finger wrinkling test, and skin biopsy for quantification of IENF and sweat gland innervation density during ICU stay and at follow-up visit. Development of infection, sepsis and multiple organ failure was recorded throughout the ICU stay. Results Of the 14 patients recruited, 13 (93%) had infections, sepsis or multiple organ failure. All had severe and non-length dependent loss of IENF. Sweat gland innervation was reduced in all except one patient. Of the 7 patients available for follow-up visit, three complained of diffuse sensory loss and burning pain, and another three showed clinical dysautonomia. Conclusions Small fiber pathology can develop in the acute phase of critical illness and may explain chronic sensory impairment and pain in neurocritical care survivors. Its impact on long term disability warrants further studies involving also non-neurologic critical care patients.

Pitfalls in diagnosing mitochondrial neurogastrointestinal encephalomyopathy

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in the gene encoding thymidine phosphorylase and is characterized by external ophthalmoparesis, gastrointestinal dysmotility, leukoencephalopathy, and neuropathy. The availability of new therapeutic options (peritoneal dialysis, allogeneic stem cell transplantation, enzyme replacement) makes it necessary to diagnose the disease early, which is not always achieved due to the difficulty in recognizing this disorder, especially in case of atypical presentation. We describe three MNGIE patients with atypical onset of the disease. In the first patient the main symptoms were long-standing chronic fever, recurrent acute migrant arthritis, and gastrointestinal disorders mimicking autoimmune or inflammatory intestinal diseases; the second patient complained only of exercise intolerance and muscle cramps, and the third patient had a CIDP-like polyneuropathy. This study stresses the insidious heterogeneous clinical onset of some cases of MNGIE, expands the spectrum of the phenotype, and suggests considering MNGIE in the differential diagnosis of enteropathic arthritis, isolated exercise intolerance, and inflammatory polyneuropathies not responsive to the usual treatment. A better understanding of the clinical heterogeneity of MNGIE is necessary in order to diagnose atypical cases and promote early diagnosis, which is now absolutely necessary in view of the new available therapies.

Current Options in the Treatment of Mitochondrial Diseases

Mitochondrial diseases (MD) are disorders caused by an impairment of the mitochondrial respiratory chain function. They are usually progressive, isolated or multi-system diseases and have variable times of onset. Because mitochondria have their own DNA (mtDNA), MD can be caused by mutations in both mtDNA and nuclear DNA (nDNA). The complexity of genetic control of mitochondrial function is in part responsible for the intra- and inter-familiar clinical heterogeneity of this class of diseases. Despite the remarkable progress in understanding of the molecular bases of these disorders, therapy of MD is quite inadequate. Present options of treatment mainly include physical, pharmacological and gene therapy approaches. Aerobic exercise and physical therapy is useful to prevent or correct deconditioning and may improve exercise tolerance. Pharmacological approach is based on removing noxious metabolites, using reactive oxygen species scavengers and administrating vitamins and cofactors which is especially important in case of primary deficiencies of specific compounds such as Coenzyme Q10. Gene therapy is fascinating but it is difficult to apply because of polyplasmy and heteroplasmy. Experimental methods include gene shifting, allotopic expression, mitochondrial transfection or correcting mtDNA mutations with specific restriction endonucleases. Here, we discussed some recent patents. Progresses in each of these fields may open interesting perspectives for the future.

Strategies for treating mitochondrial disorders: An update

Mitochondrial diseases are a heterogeneous group of disorders resulting from primary dysfunction of the respiratory chain due to both nuclear and mitochondrial DNA mutations. The wide heterogeneity of biochemical dysfunctions and pathogenic mechanisms typical of this group of diseases has hindered therapy trials; therefore, available treatment options remain limited. Therapeutic strategies aimed at increasing mitochondrial functions (by enhancing biogenesis and electron transport chain function), improving the removal of reactive oxygen species and noxious metabolites, modulating aberrant calcium homeostasis and repopulating mitochondrial DNA could potentially restore the respiratory chain dysfunction. The challenge that lies ahead is the translation of some promising laboratory results into safe and effective therapies for patients. In this review we briefly update and discuss the most feasible therapeutic approaches for mitochondrial diseases.

Mitochondrial diseases: advances and issues

Mitochondrial diseases (MDs) are a clinically heterogeneous group of disorders caused by a dysfunction of the mitochondrial respiratory chain. They can be related to mutation of genes encoded using either nuclear DNA or mitochondrial DNA. The advent of next generation sequencing and whole exome sequencing in studying the molecular bases of MDs will bring about a revolution in the field of mitochondrial medicine, also opening the possibility of better defining pathogenic mechanisms and developing novel therapeutic approaches for these devastating disorders. The canonical rules of mitochondrial medicine remain milestones, but novel issues have been raised following the use of advanced diagnostic technologies. Rigorous validation of the novel mutations detected using deep sequencing in patients with suspected MD, and a clear definition of the natural history, outcome measures, and biomarkers that could be usefully adopted in clinical trials, are mandatory goals for the scientific community. Today, therapy is often inadequate and mostly palliative. However, important advances have been made in treating some clinical entities, eg, mitochondrial neuro-gastrointestinal encephalomyopathy, for which approaches using allogeneic hematopoietic stem cell transplantation, orthotopic liver transplantation, and carrier erythrocyte entrapped thymidine phosphorylase enzyme therapy have recently been developed. Promising new treatment methods are being identified so that researchers, clinicians, and patients can join forces to change the history of these untreatable disorders.

Clinical spectrum and evolution of monoclonal gammopathy-associated neuropathy: an observational study.

Background:Paraproteinemic neuropathy (PPN) is often under-diagnosed because of its clinical and electrophysiological variability. Progression of neuropathy is considered an alarm bell for possible malignant conversion of underlying monoclonal gammopathy (MG). Objective:To report clinical presentation, course, and evolution in a group of patients with PPN in order to identify findings useful for achieving the diagnosis, suspecting progression, and recognizing the underlying hematological conditions. Patients and Methods:Thirty-nine patients with PPN underwent clinical examination, electrodiagnostic studies, cerebrospinal fluid analysis, and laboratory tests. These parameters were compared between the different peak groups. Results:IgM MG was found in 51.4%, IgG MG in 33.3%, and IgA MG in 10.3% of our cohort. PPN appeared as mainly sensory, demyelinating, mildly progressive neuropathy, regardless of the type of peak or light chain. However, axonal findings were present in many IgG patients and in part of the IgM patients and a small number of the IgG patients may have presented with motor symptoms at the onset. The IgM patients had a significant tendency toward clinical worsening and IgG subjects had a more elevated rate of malignancy. IgA-related neuropathies were rare, heterogenous, and with a high tendency to evolution and malignancy. Conclusions:Most of PPN often present a relatively monomorphic clinical picture but they can be clinically heterogenous and must be suspected even if sensory impairment and demyelination are not the dominant features. Tendency to malignancy seems globally elevated and needs intensive follow-up. Diagnostic approach to patients presenting with peripheral neuropathy should always include the typing of monoclonal immunoglobulins in serum and urine. In contrast, patients presenting with MG should be submitted to nerve conduction study/electroneurography and neurological evaluation.

MR Neurography in Diagnosing Nondiabetic Lumbosacral Radiculoplexus Neuropathy

Here we describe the imaging findings in a 73‐year‐old woman who had pain in the right inguinal region, followed by progressive weakness of muscles innervated by the right femoral and obturator nerves, diagnosed as nondiabetic lumbosacral radiculoplexus neuropathy. Magnetic resonance neurography showed thickening and increase in signal intensity of the right femoral and obturator nerves.