Francesca Pastorelli

Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types.

Background— Most studies of amyloidotic cardiomyopathy consider as a single entity the 3 main systemic cardiac amyloidoses: acquired monoclonal immunoglobulin light-chain (AL); hereditary, mutated transthyretin-related (ATTRm); and wild-type transthyretin-related (ATTRwt). In this study, we compared the diagnostic/clinical profiles of these 3 types of systemic cardiac amyloidosis. Methods and Results— We conducted a longitudinal study of 233 patients with clear-cut diagnosis by type of cardiac amyloidosis (AL, n=157; ATTRm, n=61; ATTRwt, n=15) at 2 large Italian centers providing coordinated amyloidosis diagnosis/management facilities since 1990. Average age at diagnosis was higher in AL than in ATTRm patients; all ATTRwt patients except 1 were elderly men. At diagnosis, mean left ventricular wall thickness was higher in ATTRwt than in ATTRm and AL. Left ventricular ejection fraction was moderately depressed in ATTRwt but not in AL or ATTRm. ATTRm patients less often displayed low QRS voltage (25% versus 60% in AL; P<0.0001) or low voltage-to-mass ratio (1.1±0.5 versus 0.9±0.5; P<0.0001). AL patients appeared to have greater hemodynamic impairment. On multivariate analysis, ATTRm was a strongly favorable predictor of survival, and ATTRwt predicted freedom from major cardiac events. Conclusions— AL, ATTRm, and ATTRwt should be considered 3 different cardiac diseases, probably characterized by different pathophysiological substrates and courses. Awareness of the diversity underlying the cardiac amyloidosis label is important on several levels, ranging from disease classification to diagnosis and clinical management.

Status dissociatus after surgery for tegmental ponto‐mesencephalic cavernoma: A state‐dependent disorder of motor control during sleep

After surgery for a tegmental ponto‐mesencephalic cavernoma, a patient developed sleep‐related excessive fragmentary myoclonus, diffuse myoclonic jerks, simple quasipurposeful movements of the limbs, and rapid eye movement (REM) sleep behaviour disorder as motor features of status dissociatus, a condition in which elements of one state of being (wake, NREM and REM sleep) pathologically intrude into another.

Gender-related risk of myocardial involvement in systemic amyloidosis

To investigate associations between gender and myocardial involvement in systemic amyloidosis, we reviewed all patients presenting between 1994 and September 2006 in our institutional network (100 AL and 98 familial transthyretin-related amyloidosis (ATTR) patients, plus 12 elderly men with senile systemic amyloidosis). We focused on echocardiographic descriptors of myocardial involvement (height-indexed mean left ventricular (LV) wall thickness, LV mass index), and baseline LV function. Among familial ATTR patients, female prevalence was lower within the highest tertile of either echocardiographic indicator of myocardial involvement. Gender was independently associated with height-indexed mean LV wall thickness (as were gene mutations). Female prevalence appeared rather similar across the different neurological stages. Within the subgroup of familial ATTR patients with amyloidotic cardiomyopathy, women tended to display a considerably less severe morphological and functional echocardiographic profile. We explored the possible role of female sex hormones by considering menopausal status: women in the highest tertile of mean LV wall thickness index were more often postmenopausal than those in the other two tertiles and had a much higher (∼15 years) mean age; analogous age-related associations were not observable for men. In conclusion, these findings raise the hypothesis that some biological characteristic associated with female gender protects against myocardial involvement in familial ATTR.

Phenotypic and genotypic heterogeneity in transthyretin-related cardiac amyloidosis: Towards tailoring of therapeutic strategies?

Transthyretin-related hereditary amyloidosis (ATTR) is genotypically/phenotypically heterogeneous. We investigated myocardial involvement in ATTR in a cohort of patients with a wide range of mutations. Clinical/echocardiographic follow-up of 41 consecutive symptomatic ATTR patients from a single referral center was analyzed according to TTR mutation. Diagnosis was based on histology, immunohistochemistry and genotyping. Median follow up was 40 months (range 8–120). Among the 12 different mutations identified, Val30Met was found in 10 patients and Glu89Gln in seven. Compared with Val30Met, Glu89Gln was associated with higher LV mass index, lower left ventricular ejection fraction and shorter E-wave deceleration time. All Glu89Gln carriers had cardiomyopathy, which was more severe (for left ventricular thickness, left ventricular mass and restrictive pathophysiology) than in the six affected Val30Met patients. Glu89Gln was independently associated with higher risk of major cardiovascular events among cardiomyopathy patients. This follow-up study of ATTR patients carrying a wide range of mutations indicates that (1) cardiac involvement is a very important component of phenotypic expression; and (2) genotype is an important source of heterogeneity in myocardial involvement, with Glu89Gln being associated with a severe, heart-driven prognosis. We think that combined heart–liver transplantation could be considered for Glu89Gln carriers with established, morphologically severe cardiomyopathy.

Identification of TTR-Related Subclinical Amyloidosis With 99mTc-DPD Scintigraphy

We have previously documented that 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) has a high affinity for transthyretin (TTR)-infiltrated myocardium, allowing a differential diagnosis with light-chain cardiac amyloidosis [(1)][1] and other non-amyloidotic cardiomyopathies with a

Metabolic risk factor profile associated with use of second generation antipsychotics: a cross sectional study in a community mental health centre

BackgroundSecond generation antipsychotics (SGA) have demonstrated several advantages over first generation antipsychotics (FGA) in terms of positive, negative, cognitive, and affective symptoms and a lower propensity for extrapyramidal side effects. Despite these undeniable advantages, SGA have been associated with causing and exacerbating metabolic disorders, such as obesity, diabetes, and hyperlipidemia. This cross sectional study aimed to evaluate the metabolic risk factor profile associated with use of SGAs in comparison with non -treated control patients.MethodsThe study was carried out at a Community Mental Health Centre (CMHC) in Bologna. The study subjects were outpatients with serious mental disorders treated with SGA (clozapine, olanzapine, risperidone, quetiapine). A sample of adult men and women suffering from idiopathic hyperhydrosis, without psychiatric history or antipsychotic treatment, were randomly selected from outpatients of the Department of Neurology in Bologna as a reference group. We investigated differences among the treatment and reference groups for glycaemia, cholesterolaemia and triglyceridaemia levels.ResultsThe study sample was composed of 76 patients, 38 males and 38 females. The reference group was composed of 36 subjects, 19 females and 17 males. All patients treated with SGAs had higher mean glycaemia and triglyceridaemia and a significantly higher risk of receiving a diagnosis of hyperglycaemia and hypertriglyceridaemia than the reference group. We did not find any differences in mean glycaemia or mean triglyceridaemia levels among treatment groups. Patients with clozapine had a significantly higher mean BMI value and rate of obesity than patients treated with other SGAs.ConclusionThe rate of obesity and metabolic disorders observed in this study were higher than the prevalence in the control group and similar to that previously reported in psychiatric samples; these findings imply per se that more attention should be paid to the metabolic condition of psychiatric patients. In line with the International Consensus Conferences we recommend that monitoring of weight, fasting plasma glucose, cholesterol and triglyceride levels be obtained in routine clinical practice with all antipsychotics.

Adult Alexander's disease without leukoencephalopathy

poison control center consultation. Tamoxifen infrequently causes reversible neurotoxicity, but only at much higher doses ( 160mg/m daily). Recent investigations into the use of artemisinin compounds in cancer treatment have not been substantiated in clinical trials. Because of pervasive reports of animal brainstem toxicity, and the gradual emergence of similar patient cases, it becomes imperative to ascertain the safety of prolonged courses of artemisinin for cancer prophylaxis.

Genotypic and phenotypic correlation in an Italian population of hereditary amyloidosis TTR-related (HA-TTR): clinical and neurophysiological aids to diagnosis and some reflections on misdiagnosis

131 HA-TTR patients from a single referral centre presented at onset five major clinical syndromes: (1) the typical “Portuguese variant” axonal polyneuropathy with dissociated (syringomyelic like) sensory loss and autonomic dysfunction; (2) bilateral carpal tunnel syndrome; (3) restless leg syndrome with impotence and unexplained loss of weight; (4) pure motor neuropathy without autonomic abnormalities; (5) recurrent small brain or spinal cord ischemia or haemorrhages with leptomeningeal amyloid deposition (and late superficial siderosis of the central nervous system) and vitreous deposits. Some patients in our population presented a “pseudodemyelinating” onset of the somatic neuropathy, as well as atypical motor neuropathy simulating lower motor neuron disease. The five syndromes can overlap in advanced stages of the disease. Genetic screening of HA-TTR could be worthwhile in any idiopathic progressive axonal peripheral neuropathy, as well as in drug resistant demyelinating sensory-motor neuropathy or in pure motor neuropathy, when multi-organ involvement is present.

Early onset aggressive hereditary amyloidosis: report of an Italian family with TTR Arg47 mutation.

Arg47 is a rare transthyretin-related (TTR) amyloidosis variant that is characterised by polyneuropathy and autonomic failure. We describe an Italian family with this mutation whose members (two women and their father) showed a rapid progression of the peripheral nervous system involvement and died within 5 years of clinical onset. Patients with Arg47 or other aggressive TTR amyloidoses should be considered high priority patients for orthotopic liver transplantation.

Transthyretin RNA profiling in livers from transplanted patients affected by familial amyloidotic polyneuropathy, and identification of a dual transcription start point

Abstract: Mutations in the transthyretin (TTR) gene cause familial amyloidotic polyneuropathy (FAP), an autosomal dominant peripheral neuropathy, often associated with cardiomyopathy. Liver transplant currently represents a powerful therapeutic approach for FAP patients, although its efficacy is heavily dependent both on the disease severity and on the cardiac functionality.