Psychosocial impact of presymptomatic genetic testing for transthyretin amyloidotic polyneuropathy.

Presymptomatic genetic testing of an untreatable disease raises clinical, ethical, legal and psychosocial questions. Investigations in specific disorders are needed to help in understanding the motivation for and the impact of genetic testing in the lives of persons at risk for these diseases. Here, we performed a longitudinal study to investigate the psychological consequences of presymptomatic genetic testing on people at risk for transthyretin-related familial amyloidotic polyneuropathy (TTR-FAP). The aim of the present study was to provide possible guidelines for genetic counselling and psychosocial support. Impact of Event Scale Revised (IES-R), Hospital Anxiety and Depression Scale (HADS) and SF-36 questionnaires were administered to 18 asymptomatic subjects before, immediately after communication of the genetic test result and after 3, 6 and 26 months. Our findings showed evidence of anxiety, depression, avoidance of the disease, and psychological distress, especially for women, including those with a negative genetic test result ("survivor guilt"). A psychological support has to be provided before and continued at long term after presymptomatic genetic testing for TTR-FAP in people with positive result as well as in those with negative result.

Hypnic headache responsive to low-dose topiramate: a case report.

This is a clinical report of a 63-year-old woman, with a 3-year history of severe episodes of hypnic headache responding to low-doses of topiramate (25 mg at bedtime). Topiramate has been used at the dosage of 100 mg/day for hypnic headache prevention in one recent case report with benefit. This report confirms the efficacy of topiramate in hypnic headache even using low-dose regimen therapy.

Evidence of cardiovascular autonomic impairment in mitochondrial disorders.

OBJECTIVE: To investigate autonomic nervous system (ANS) function in mitochondrial disorders (MD). BACKGROUND: MD are characterized by a wide range of clinical features, including heart abnormalities and peripheral and central nervous systems involvement. Rarely autonomic symptoms have been reported. METHODS: 22 patients with MD underwent a battery of cardiovascular reflex tests including five tests of parasympathetic function and four tests of sympathetic function. Power spectral analyses (PSA) of heart rate variability in the supine and upright positions were also evaluated. Plasma levels of adrenaline, noradrenaline and dopamine were determined in the standing and lying positions. RESULTS: Only 4/22 patients referred symptoms related to ANS dysfunction. 46% of patients had a definite autonomic damage (i. e. an autonomic score >/= 4). 36% showed moderate alterations with an autonomic score in the range 2-3 and 18 % had a normal autonomic function. MD patients had a significantly (p <0.03) lower increase of adrenaline level after standing. CONCLUSIONS: Our data indicate an autonomic dysfunction in more than 80% of MD patients, even in the absence of a clinically manifested autonomic involvement. Cardiovascular autonomic investigation might be systematically employed in the characterization of MD.

Correlation between fatigue and brain atrophy and lesion load in multiple sclerosis patients independent of disability.

BACKGROUND: Fatigue is a major problem in multiple sclerosis (MS), and its association with MRI features is debated. OBJECTIVE: To study the correlation between fatigue and lesion load, white matter (WM), and grey matter (GM), in MS patients independent of disability. METHODS: We studied 222 relapsing remitting MS patients with low disability (scores or=5; n=197) and low-fatigue groups (FSS

Motor cortex abnormalities in amyotrophic lateral sclerosis with transcranial direct-current stimulation.

The aim of this study was to identify a neurophysiological marker of upper motoneuron involvement in patients with sporadic amyotrophic lateral sclerosis (ALS). For this purpose we evaluated the after-effects of transcranial direct-current stimulation (tDCS) on excitability of the motor cortex of eight ALS patients and eight healthy controls. Healthy controls showed a transient polarity-specific change in corticospinal excitability of about +/-45%, with anodal tDCS inducing facilitation and cathodal tDCS leading to inhibition, whereas no change could be induced in ALS patients after either type of tDCS. It is likely that the lack of tDCS after-effects in ALS is the result of alterations of the motoneuronal membrane or, alternatively, may represent an electrophysiological correlate of disordered glutamate neurotransmission. Further studies are warranted to confirm these results. The present findings may lead to a new, reliable electrophysiological marker of upper motoneuronal involvement in ALS.

Osteosclerotic myeloma with spinal leptomeningitis and severe polyneuropathy: A case report.

Osteosclerotic myeloma is a rare plasma cell disorder often associated with a polyneuropathy. We describe a young patient with progressive polyneuropathy associated with vertebral bone marrow lesions and unusual meningeal infiltration at cauda level. The diagnosis of osteosclerotic myeloma was confirmed by bone marrow biopsy findings including the chromosome 13q14 deletion in 37% of the cells. Leptomeningeal involvement was demonstrated by spine magnetic resonance imaging with gadolinium administration and fat-suppression technique.

Diffuse metabolic changes in the brain of patients with familial amyloid polyneuropathy. A proton MRSI study.

OBJECTIVES: To assess brain metabolic abnormalities in patients with familial amyloid polyneuropathy (FAP) due to the transthyretin (TTR) gene mutations. BACKGROUND: The TTR-FAP has variable phenotypic expression, which includes abnormalities of the central nervous system (CNS). Several conventional MRI studies have shown brain abnormalities, probably secondary to amyloid accumulation in leptomeningeal and subarachnoid vessels. However, TTR-related amyloid deposits do not seem to significantly affect the brain parenchyma and a prominent CNS impairment is considered to be rare in TTR amyloidosis. METHODS: We performed proton MR spectroscopic imaging (1H-MRSI) in the central brain of four unrelated TTR-FAP patients with either minimal or no signs of neurological involvement and eight age- and sex-matched normal controls (NC). Metabolic changes were assessed in the entire volume of interest (VOI) and in the frontal, periventricular and posterior white matter (WM). RESULTS: Conventional MRI was normal in 2 patients and showed minimal WM lesions in the remaining 2 patients. 1H-MRSI showed N-acetylaspartate to creatine ratio (NAA/Cr) decreases in the central brain VOI in all TTR-FAP patients (p < 0.005). These NAA/Cr decreases were homogeneous in all WM regions (p < 0.05 for all). CONCLUSIONS: 1H-MRSI findings suggest that diffuse metabolic changes, probably related to axonal damage, are present in brains of TTR-FAP patients even when they have no or minimal clinical and MRI signs of CNS involvement. The mechanism leading to sub-clinical metabolic brain changes needs to be identified.

Corticospinal excitability during motor imagery of a simple tonic finger movement in patients with writer's cramp.

Motor imagery (MI) is the mental rehearsal of a motor act without overt movement. Using transcranial magnetic stimulation (TMS), we tested the effect of MI on corticospinal excitability in patients with writer's cramp. In 10 patients with writer's cramp and 10 healthy controls, we applied focal TMS over each primary motor area and recorded motor evoked potentials (MEPs) from contralateral hand and arm muscles while participants imagined a tonic abduction of the index finger contralateral to the stimulated hemisphere. In healthy controls and patients, the MEP amplitude in the relaxed first dorsal interosseus muscle (FDI) showed a muscle-specific increase during MI; however, the increase was less pronounced in patients than in healthy controls. In addition, in patients but not in controls, the MEP amplitude also increased in hand and forearm muscles not involved in the imagined movement. This abnormal spread of facilitation was observed in the affected and unaffected upper limb. MI of simple hand movements is less efficient and less focussed in patients with writer's cramp than it is in normal subjects.

Oxidative stress in myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy affecting adults. The genetic basis of DM1 consists of a mutational expansion of a repetitive trinucleotide sequence (CTG). The number of triplets expansion divides patients in four categories related to the molecular changes (E1, E2, E3, E4). The pathogenic mechanisms of multi-systemic involvement of DM1 are still unclear. DM1 has been suspected to be due to premature aging, that is known to be sustained by increased free radicals levels and/or decreased antioxidants activities in neurodegenerative disorders. Recently, the gain-of-function at RNA level hypothesis has gained great attention, but oxidative stress might act in the disease progression. We have investigated 36 DM1 patients belonging to 22 unrelated families, 10 patients with other myotonic disorders (OMD) and 22 age-matched healthy controls from the clinical, biochemical and molecular point of view. Biochemical analysis detected blood levels of superoxide dismutase (SOD), malonilaldehyde (MDA), vitamin E (Vit E), hydroxyl radicals (OH) and total antioxidant system (TAS). Results revealed that DM1 patients showed significantly higher levels of SOD (+40%; MAL (+57%; RAD 2 (+106%; and TAS (+20%; than normal controls. Our data support the hypothesis of a pathogenic role of oxidative stress in DM1 and therefore confirm the detrimental role played by free radicals in this pathology and suggest the opportunity to undertake clinical trials with antioxidants in this disorder.

Asymptomatic hyperCKemia in a case of Danon disease due to a missense mutation in Lamp-2 gene.

Primary lysosome-associated membrane protein-2 (LAMP-2) deficiency is an X-linked disease, characterized by the clinical triad of cardiomyopathy, vacuolar myopathy and mental retardation, previously known as Danon disease. Mutations of lamp-2 gene have been reported so far in about 20 patients, one of whom was Italian. We describe a new Italian case with persistent hyperCKemia, exercise intolerance and hypertrophic cardiomyopathy but with no muscle weakness or mental impairment. Muscle biopsy revealed a vacuolar myopathy with mild glycogen storage, and immunohistochemical studies detected LAMP-2 deficiency. A new nucleotide substitution (T961C) on exon 8 of lamp-2 gene was identified as responsible for the protein deficiency. This is the first missense mutation so far described. LAMP-2 deficiency should be considered as a cause of recurrent hyperCKemia and hypertrophic cardiomyopathy.

Autonomic function in elderly uremics studied by spectral analysis of heart rate.

BACKGROUND: Aging determines an altered response of the autonomic nervous system (ANS) to physiologic stresses. A widespread autonomic damage is well recognized in chronic renal failure (CRF). METHODS: We studied 30 CRF patients, aged 19 to 85 years, who were on bicarbonate hemodialysis. Surface electrocardiogram was recorded on lying and 65 degrees head-up tilt standing positions. A dedicated software, using an autoregressive modeling technique, allowed to calculate power spectral analysis (PSA) of heart rate variability, assessing a low-frequency band in the range 0.03 to 0.15 Hz, and a high-frequency band in the range 0.15 to 0.33 Hz. Low-frequency and high-frequency components are regarded, but not invariably, as specific markers of sympathetic and parasympathetic activities, respectively, and the low-frequency/high frequency ratio as an index of sympathovagal balance. RESULTS: In normal controls, low-frequency band value and low-frequency/high-frequency ratio on standing resulted significantly reduced in the group older than 65 years when compared with those younger than 65 years; an opposite finding was seen in high-frequency band value on standing. In uremic patients, low-frequency band on lying resulted significantly lower only in elderly uremics when compared with elderly controls, whereas low-frequency band on standing was significantly lower in elderly than in younger uremics. Regression analysis showed a significant inverse relationship between aging and most low-frequency band values, especially in uremics. The comparison of linear regression models confirmed that a sympathetic autonomic derangement is greatly present in older uremics, in particular after 50 years of age. CONCLUSION: Our data support assertion that combination of aging and CRF increases the chance of autonomic derangement being present.

Distinct changes in cortical and spinal excitability following high-frequency repetitive TMS to the human motor cortex.

It has been shown that high-frequency repetitive transcranial magnetic stimulation (rTMS) to the human primary motor hand area (M1-HAND) can induce a lasting increase in corticospinal excitability. Here we recorded motor evoked potentials (MEPs) from the right first dorsal interosseus muscle to investigate how sub-threshold high-frequency rTMS to the M1-HAND modulates cortical and spinal excitability. In a first experiment, we gave 1500 stimuli of 5 Hz rTMS. At an intensity of 90% of active motor threshold, rTMS produced no effect on MEP amplitude at rest. Increasing the intensity to 90% of resting motor threshold (RMT), rTMS produced an increase in MEP amplitude. This facilitatory effect gradually built up during the course of rTMS, reaching significance after the administration of 900 stimuli. In a second experiment, MEPs were elicited during tonic contraction using weak anodal electrical or magnetic test stimuli. 1500 (but not 600) conditioning stimuli at 90% of RMT induced a facilitation of MEPs in the contracting FDI muscle. In a third experiment, 600 conditioning stimuli were given at 90% of RMT to the M1-HAND. Using two well-established conditioning-test paradigms, we found a decrease in short-latency intracortical inhibition (SICI), and a facilitation of the first peak of facilitatory I-waves interaction (SICF). There was no correlation between the relative changes in SICI and SICF. These results demonstrate that subthreshold 5 Hz rTMS can induce lasting changes in specific neuronal subpopulations in the human corticospinal motor system, depending on the intensity and duration of rTMS. Short 5 Hz rTMS (600 stimuli) at 90% of RMT can selectively shape the excitability of distinct intracortical circuits, whereas prolonged 5 Hz rTMS (> or =900 stimuli) provokes an overall increase in excitability of the corticospinal output system, including spinal motoneurones.

Immunolocalization and activation of transcription factor nuclear factor kappa B in dysimmune neuropathies and familial amyloidotic polyneuropathy.

BACKGROUND: Recently, immunoreactivity of transcription factor nuclear factor kappaB (NF-kappaB) was found in peripheral nerves from patients with Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), and familial amyloidotic polyneuropathy (FAP), suggesting a role in their pathogenesis. OBJECTIVE: To investigate expression and activation of NF-kappaB in nerve biopsy specimens from patients with peripheral neuropathies of different origins. PATIENTS: Nerve biopsies from 17 patients (5 with CIDP, 3 with vasculitis, 4 with Charcot-Marie-Tooth disease, and 5 with FAP) and 3 normal sural nerves were studied by immunocytochemistry and Western blot of nuclear extracts for the activated form of NF-kappaB. Nuclear factor kappaB DNA-binding activity was studied by electrophoretic mobility shift assay. RESULTS: Immunobinding for the activated form p65 of NF-kappaB was found in 2% to 5% of endoneurial vessel walls, in the external myelin of 5% to 10% of fibers, and in a few axons in CIDP specimens. It was also found in 5% to 15% of epineurial and endoneurial vessels in vasculitis specimens and at the level of amyloid deposits in FAP nerves. Nuclear factor kappaB immunoreactivity was not correlated to type of inflammatory cells, but it often corresponded to the deposition of the terminal complement complex C5b9. Western blot analysis of nuclear extracts showed a single band corresponding to 65 kDa in all affected nerves. Nuclear factor kappaB DNA-binding activity was revealed by electrophoretic mobility shift assay in specimens from patients with CIDP, vasculitis, and FAP. CONCLUSION: Our novel findings suggest a crucial role of NF-kappaB in inflammatory neuropathies and FAP.

Long lasting effects of transcranial direct current stimulation on motor imagery.

Transcranial magnetic stimulation (TMS) was employed to probe the modulatory effects of transcranial direct current stimulation of motor cortex on motor evoked responses (MEPs) produced during motor imagery. MEP amplitudes at rest and during motor imagery were assessed before and for a period of 60 min after transcranial direct current stimulation (tDCS) applied over the primary motor cortex at 1 mA for 5 min. Cathodal stimulation induced a decrease of about 30% of MEP amplitude at rest and a 50% reduction of MEP size during imagery. Ten minutes after tDCS, MEPs at rest returned to baseline values while MEPs during motor imagery were suppressed for up to 30 min. No changes in MEP amplitude during imagery were found after anodal stimulation. tDCS could represent a powerful tool to modulate the excitability of motor areas involved in mental practice and motor imagery.

Cardiovascular autonomic control in myotonic dystrophy type 1: a correlative study with clinical and genetic data.

The autonomic nervous system has been evaluated in myotonic dystrophy with contradictory results and its relationship with heart disturbances remains unclear. Twenty-three patients with myotonic dystrophy type 1 were investigated by a battery of six cardiovascular autonomic tests and power spectral analysis of heart rate variability. Although 15 patients (65%) revealed abnormal or borderline results in some tests, only one patient had a definite autonomic damage, as indicated by two or more abnormal tests. As a group, myotonic dystrophy type 1 patients showed a significant reduction of heart rate variability during deep breathing (P < 0.0001). The exclusive involvement of parasympathetic tests suggests that a mild vagal dysfunction occurs in some myotonic dystrophy type 1 patients. The results indicate that such autonomic abnormalities are not: (1) part of a peripheral neuropathy; (2) related to cytosine-thymine-guanine repeat size or breathing pattern. Power spectral analysis showed a reduction of supine low-frequency band, which is, but not exclusively, a marker of sympathetic activity. It was inversely correlated to disease duration (P < 0.04), suggesting a progression as the disease advances. A low-frequency power, recorded after standing, was significantly associated (P < 0.02) with presence of heart involvement. Our findings suggest that a mixed, especially parasympathetic, autonomic dysfunction may occur in myotonic dystrophy type 1, although it is not a major finding. It could play a role in the occurrence of cardiac abnormalities, or increase the risk of sudden cardiovascular events.

Apoptosis and apoptosis-related proteins in thyroid myopathies.

DNA fragmentation and apoptosis-related proteins have been investigated in thyroid cells and there is evidence that Fas-mediated apoptosis is inhibited by thyroid stimulating hormone (TSH). We investigated DNA fragmentation by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and Bcl-2 and Fas antigen expression by immunocytochemistry in skeletal muscles from 12 patients with hypothyroid myopathy and 5 patients with hyperthyroid myopathy. The finding of very few TUNEL-positive muscle fibers in both conditions suggests that apoptosis does not play a role in the pathogenesis of thyroid myopathies. Bcl-2 expression increased significantly in hypothyroid myopathy, correlating with high serum TSH levels, and not with either triiodothyronine (T3) or thyroxine (T4) serum levels. By contrast, Fas antigen was overexpressed in hyperthyroid myopathy, correlating with low TSH levels. These findings suggest an anti-apoptotic role for TSH itself in skeletal muscle.

Multifocal motor neuropathy and asymptomatic Hashimoto's thyroiditis: first report of an association.

Motor neuropathy with multifocal conduction blocks represents a recently identified autoimmune disorder of the peripheral nerve myelin. Association of motor neuropathies or neuronopathies with thyroid disorders, such as hyperthyroidism, hypothyroidism or thyroid neoplasms has been rarely described. We studied a 61-year-old man with a 2-year-history of slowly progressive weakness of the left limbs with atrophy and fasciculations. Nerve conduction velocity studies revealed multifocal motor conduction blocks. Serum IgM titer of antibodies against GM1 was elevated (1:1280; n.v. up to 1:640). Thyroid studies were compatible with Hashimoto's thyroiditis. Therapy with high dose intravenous immunoglobulins was followed by a prompt clinical recovery. Then the disease assumed an intravenous immunoglobulins dependent course with a full clinical, but transient, recovery. This is the first observation of an association of multifocal motor neuropathy with high titers of GM1 and Hashimoto's thyroiditis and reinforces the multifocal motor neuropathy autoimmune origin as well as the repeated clinical recoveries after intravenous immunoglobulins. This case also suggests to deeply investigate the thyroid function in patients with multifocal motor neuropathy.