Progressive brachial plexus enlargement in hereditary transthyretin amyloidosis.

Axonal polyneuropathy is the main feature of hereditary transthyretin amyloidosis (ATTRv). Nerve morphological abnormalities have been reported, but longitudinal changes have never been assessed. We performed a prospective widespread nerve ultrasound evaluation and nerve cross-sectional area (CSA) was compared with baseline data in both ATTRv patients and pre-symptomatic carriers. Thirty-eight subjects were evaluated (mean follow-up 17.1 months), among them 21 had polyneuropathy while 17 were pre-symptomatic carriers. CSA significantly increased at brachial plexus in both groups (p = 0.008 and p = 0.012) pointing to progressive brachial plexus enlargement as a longitudinal biomarker of both disease progression and disease occurrence in pre-symptomatic carriers.

Neurological involvement in Ile68Leu (p.Ile88Leu) ATTR amyloidosis: not only a cardiogenic mutation.

BACKGROUND: Ile68Leu transthyretin-related amyloidosis (ATTR) is known as a mainly or exclusively cardiogenic variant. We hypothesized that an accurate specialized neurological evaluation could reveal a consistent frequency of mixed phenotypes. METHODS: Forty-six consecutive subjects with transthyretin (TTR) Ile68Leu (p.Ile88Leu) mutation (29 patients and 17 unaffected carriers) underwent an in-depth cardiac and neurologic evaluation at a single center. RESULTS: All 29 patients showed cardiac involvement. In 20 (69%) cases, it was associated with neurological abnormalities (i.e. a mixed phenotype): 10 (35% of the total) had signs and symptoms of neuropathy, 5 (17%) had abnormalities at the neurologic specialist examination but without symptoms, and 5 (17%) had abnormal nerve conduction study only. None of the asymptomatic carriers showed neurological abnormalities or cardiac involvement. The Neuropathy Impairment Score was > 5 in seven patients at baseline, and became >5 in six more patients during follow-up. The probability of experiencing a major adverse cardiac event (MACE) during follow-up was higher in the mixed than cardiologic phenotype (p = 0.026). Age and phenotype were independent prognostic predictors of MACE. CONCLUSION: At least two-thirds of patients with Ile68Leu ATTR and amyloidotic cardiomyopathy show an associated - definite or probable - neurologic impairment of variable degree if accurately evaluated in a neurologic setting. This proportion can rise during follow-up. The mixed phenotype carries a worse prognosis compared to the exclusively cardiologic one. These observations show that more patients could be eligible for treatment with gene silencers than currently indicated and highlight the need for an in-depth and continuous multidisciplinary evaluation of Ile68Leu ATTR patients.

Nerve ultrasound in hereditary transthyretin amyloidosis: red flags and possible progression biomarkers.

BACKGROUND: Diagnostic delay of hereditary transthyretin amyloidosis (ATTRv, v for variant) prevents timely treatment and, therefore, concurs to the mortality of the disease. The aim of the present study was to explore with nerve ultrasound (US) possible red flags for early diagnosis in ATTRv patients with carpal tunnel syndrome (CTS) and/or polyneuropathy and in pre-symptomatic carriers. METHODS: Patients and pre-symptomatic carriers with a TTR gene mutation were enrolled from seven Italian centers. Severity of CTS was assessed with neurophysiology and clinical evaluation. Median nerve cross-section area (CSA) was measured with US in ATTRv carriers with CTS (TTR-CTS). One thousand one hundred ninety-six idiopathic CTS were used as controls. Nerve US was also performed in several nerve trunks (median, ulnar, radial, brachial plexi, tibial, peroneal, sciatic, sural) in ATTRv patients with polyneuropathy and in pre-symptomatic carriers. RESULTS: Sixty-two subjects (34 men, 28 women, mean age 59.8 years ± 12) with TTR gene mutation were recruited. With regard to CTS, while in idiopathic CTS there was a direct correlation between CTS severity and median nerve CSA (r = 0.55, p < 0.01), in the subgroup of TTR-CTS subjects (16 subjects, 5 with bilateral CTS) CSA did not significantly correlate with CTS severity (r = - 0.473). ATTRv patients with polyneuropathy showed larger CSA than pre-symptomatic carriers in several nerve sites, more pronounced at brachial plexi (p < 0.001). CONCLUSIONS: The present study identifies nerve morphological US patterns that may help in the early diagnosis (morpho-functional dissociation of median nerve in CTS) and monitoring of pre-symptomatic TTR carriers (larger nerve CSA at proximal nerve sites, especially at brachial plexi).

High-dose Ig VENA is well tolerated and efficacious in patients with multifocal motor neuropathy.

Multifocal motor neuropathy (MMN) is a rare, chronic, motor neuropathy that progressively impairs physical functioning and quality of life. Randomised controlled trials have shown that high-dose intravenous immunoglobulin (IVIg) is superior to placebo in improving muscle strength and disability, but many patients require periodic infusions to maintain long-term improvement. This observational, multicentre, retrospective study investigated the efficacy and tolerability of human normal immunoglobulin (Ig VENA) at high intravenous infusion rates in 20 MMN patients (14 male, 6 female). Thirty days after the first infusion, there was an improvement of at least 1 point in two muscles compared to baseline on the Medical Research Council (MRC) scale and of 1 point in the ONLS (Overall Neuropathy Limitation Scale) scale in 15 patients (75%) and 10 patients (50%), respectively; 45% improved on both scales. At 6 months, 100% of 12 patients had improved on the MRC and 79% of 14 patients had improved on the ONLS scale; 83% improved on both scales. All reported adverse drug reactions (ADR) were mild, transient and possibly related to the study drug. Four patients (20%) reported ADRs, three reported headache and one fever. There were no serious or unexpected ADRs. By confirming that high-dose Ig VENA is efficacious and well tolerated, this study adds to the evidence base for IVIg in MMN and potentially increases clinicians' and patients' choice of therapy.

Brain Microbleeds 12 Years after Orthotopic Liver Transplantation in Val30Met Amyloidosis.

Unexplained focal neurologic episodes (FNEs) can occur in patients with transthyretin-related familial amyloidotic polyneuropathy (TTR-FAP) after orthotopic liver transplantation (OLT). A patient with Val30Met FAP underwent OLT at age 34 years. Twelve years after transplantation, she presented with recurrent FNEs lasting from 10 minutes to 8 hours each, with nonuniform deficitary clinical features and variably associated with headache. Magnetic resonance imaging showed multiple brain microbleeds and diffuse contrast enhancement of the craniospinal leptomeninges consistent with amyloid deposits. Our observation suggests that microbleeds associated with meningovascular amyloidosis can underlie FNEs in TTR-FAP. Moreover, it confirms that OLT does not halt progression of leptomeningeal and vascular amyloid deposition due to TTR production in the choroid plexuses. Such a progression might compromise the good long-term prognosis of patients with TTR-FAP due to increased risk of intracranial hemorrhages. Pharmacologic therapies targeting brain TTR production may modify this scenario.

Mild Lafora disease: clinical, neurophysiologic, and genetic findings.

We report clinical, neurophysiologic, and genetic features of an Italian series of patients with Lafora disease (LD) to identify distinguishing features of those with a slowly progressive course. Twenty-three patients with LD (17 female; 6 male) were recruited. Mean age (± SD) at the disease onset was 14.5 ± 3.9 years and mean follow-up duration was 13.2 ± 8.0 years. NHLRC1 mutations were detected in 18 patients; EPM2A mutations were identified in 5. Patients who maintained >10 years gait autonomy were labeled as "mild" and were compared with the remaining LD patients with a typical course. Six of 23 patients were mild and presented significantly delay in the age at onset, lower neurologic disability score at 4 years after the onset, less severe seizure phenotype, lower probability of showing both photoparoxysmal response on electroencephalography (EEG) and giant somatosensory evoked potentials, as compared to patients with typical LD. However, in both mild and typical LD patients, EEG showed disorganization of background activity and frequent epileptiform abnormalities. Mild LD patients had NHLRC1 mutations and five of six carried homozygous or compound heterozygous D146N mutation. This mutation was found in none of the patients with typical LD. The occurrence of specific NHLRC1 mutations in patients with mild LD should be taken into account in clinical practice for appropriate management and counseling.

Quality of life in patients with craniocervical dystonia: Italian validation of the "Cervical Dystonia Impact Profile (CDIP-58)" and the "Craniocervical Dystonia Questionnaire (CDQ-24)".

Dystonia is a disabling and disfiguring disorder that can often affect many aspects of patients' daily lives, and lower their self-esteem. To date, quality of life (QoL) has been assessed in dystonic patients using generic measures that do not address the specific problems of this diagnostic group. Recently, two disease-specific scales "The Cervical Dystonia Impact Profile (CDIP-58)" and the "Craniocervical Dystonia Questionnaire (CDQ-24)" were validated for measuring QoL in craniocervical dystonia patients. No disease-specific scales for QoL for dystonic patients are currently available in Italian. The aim of our study was to produce and validate the Italian version of the CDIP-58 and CDQ-24. We obtained the Italian version of CDQ-24 and CDIP-58 with a back-translation design. Both scales were applied to a population of 94 craniocervical dystonia patients along with the Short Form 36 health-survey questionnaire (SF-36), both before and 4 weeks after botulinum toxin therapy. A group of 65 controls matched for sex, age and comorbidity underwent the SF-36. Internal consistency was satisfactory for all subscales. Both the CDIP-58 and CDQ-24 showed moderate to high correlations with similar items of the SF-36. Sensitivity to change was confirmed by highly significant improvements in all CDQ-24 subscales and by moderate improvements in three out of eight CDIP-58 subscales and total score. This is the first Italian study on QoL in dystonia patients. We validated the Italian version of two disease-specific questionnaires to evaluate QoL in craniocervical dystonia patients. These scales could be useful for both clinical practice and clinical trials.

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.

A novel T137A SOD1 mutation in an Italian family with two subjects affected by amyotrophic lateral sclerosis.

Mutations in the superoxide dismutase-1 (SOD1) gene occur in some forms of familial amyotrophic lateral sclerosis (ALS). To date about 150 mutations are known to involve this gene. Here we describe a novel missense mutation in exon 5 of the SOD1 gene in an Italian family with two members affected by ALS. Sequencing of the SOD1 gene was performed on 11 members of the family and 75 healthy controls. Electron microscopy was also performed on one ALS patient. We identified a heterozygous mutation in codon 137 leading to substitution of threonine by alanine. Further studies are needed to clarify the role of this alteration in ALS aetiopathogensis; nevertheless, T137A seems to represent a new missense mutation of the SOD1 gene in ALS patients.

Validation of the Italian version of the Neuropathic Pain Symptom Inventory in peripheral nervous system diseases.

The aim of this study was to validate the Italian version of the Neuropathic Pain Symptom Inventory (NPSI) in patients with neuropathic pain due to peripheral nerve diseases, and also to evaluate the validity of a new NPSI score: a frequency weighted NPSI score (NPSI-FW). First, the original version of the NPSI was translated into Italian. Then the validity and reliability of the Italian NPSI (I-NPSI) were tested in 392 Italian patients consecutively referred to 16 Italian outpatient services for peripheral nerve diseases, by correlating the I-NPSI scores with other pain scales. The repeatability and responsiveness were assessed. A significant correlation between the I-NPSI scores and all the other pain measures was seen. Reproducibility and responsiveness were good. Our study shows the validity of the I-NPSI and demonstrates its reliability for assessing neuropathic pain in patients with peripheral nerve diseases. The I-NPSI scores represent reliable measurements to assess neuropathic symptoms and effectiveness of treatment on them.

Brain white matter damage in SCA1 and SCA2. An in vivo study using voxel-based morphometry, histogram analysis of mean diffusivity and tract-based spatial statistics.

BACKGROUND AND PURPOSE: Neurodegeneration in spinocerebellar ataxia type 1(SCA1) and 2(SCA2) is associated with white matter(WM) damage. Voxel-Based Morphometry(VBM), histogram analysis of mean diffusivity(MD) and Tract-Based Spatial Statistics(TBSS) enable an in vivo quantitative analysis of WM volume and structure. We assessed with these 3 techniques the whole brain WM damage in SCA1 and SCA2. PATIENTS AND METHODS: Ten patients with SCA1, 10 patients with SCA2 and 10 controls underwent MRI with acquisition of T1-weighted and diffusion tensor images. The results were correlated with severity of clinical deficit. RESULTS: VBM showed atrophy of the brainstem and cerebellar WM without significant differences between SCA1 and SCA2. Focal atrophy of the cerebral subcortical WM was also present. Histogram analysis revealed increased MD in the brainstem and cerebellum in patients with SCA1 and SCA2 which in SCA2 was more pronounced and combined with mild increase of the MD in the cerebral hemispheres in SCA2. In SCA1 and SCA2 TBSS revealed decreased fractional anisotropy(FA) in the inferior, middle and superior cerebellar peduncles, pontine transverse fibres, medial and lateral lemnisci, spinothalamic tracts, corticospinal tracts and corpus callosum. The extent of tract changes was greater in SCA2 patients who also showed decreased FA in the short intracerebellar tracts. In both diseases VBM, histogram and TBSS results correlated with clinical severity. CONCLUSIONS: Brain WM damage featuring a pontocerebeellar atrophy is similar in SCA1 and SCA2 but more pronounced in SCA2. In both diseases it correlates with severity of the clinical deficit.

Brain structural damage in spinocerebellar ataxia type 1 : a VBM study.

BACKGROUND AND OBJECTIVE: Neuropathological description of the brain in spinocerebellar ataxia type 1(SCA1) is limited to a few cases. Voxel-based morphometry (VBM) enables an unbiased in vivo whole-brain quantitative analysis of regional differences in gray matter (GM) and white matter (WM) volume. We assessed with VBM the structural damage in patients with genetically confirmed SCA1. METHOD: Fifteen SCA1 patients and 15 age-matched healthy controls underwent MR examination with acquisition of high-resolution T1-weighted images. The results were correlated with the disease duration and severity of the clinical deficit assessed with the International Cerebellar Ataxia Rating Scale (ICARS) and Inherited Ataxia Clinical Rating Scale (IACRS). RESULTS: As compared to controls, patients with SCA1 showed a significant (p < 0.05 corrected for multiple comparison) symmetric loss of volume of the GM in the rostral cerebellar vermis and paramedian portions of the anterior cerebellar lobes. WM was decreased in the peridentate region and middle cerebellar peduncles but not in the pons. No GM or WM volume loss was found in the cerebral hemispheres. The cerebellar and brainstem GM and WM volume loss correlated with disease duration and the ICARS and IACRS scores. CONCLUSIONS: VBM confirms that atrophy predominantly involves the brainstem and cerebellum in SCA1. The correlation with the clinical features indicates that VBM might be useful to monitor disease progression.

The Total Neuropathy Score as an assessment tool for grading the course of chemotherapy-induced peripheral neurotoxicity: comparison with the National Cancer Institute-Common Toxicity Scale.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a major side effect of several antineoplastic drugs. However, despite its clinical importance, there is no agreement as to the best way to assess the severity and changes in CIPN. We have previously demonstrated a correlation between the severity of CIPN, assessed using the Total Neuropathy Score (TNS) or its reduced versions, and several common toxicity scales. In this study, we investigated two series of patients (total number = 173) who were evaluated at baseline and during chemotherapy with the TNS (n= 122) or the TNSc (the TNS version based exclusively on the clinical evaluation of the patients, n= 51) and with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) 2.0, with the aim of comparing the sensitivity to the changes in CIPN severity. In both series, the TNS and the TNSc had a significant correlation with the NCI-CTC in scoring the severity of CIPN, confirming the results of previous studies. Moreover, both the TNS and the TNSc showed a higher sensitivity to CIPN changes. We, therefore, propose the TNSc as a reliable method for assessing not only the severity but also the changes in CIPN.

Multi-center assessment of the Total Neuropathy Score for chemotherapy-induced peripheral neurotoxicity.

The aim of this multi-center study was to assess with reduced versions of the Total Neuropathy Score (TNS), the severity of chemotherapy-induced peripheral neurotoxicity (CIPN), and to compare the results with those obtained with common toxicity scales. An unselected population of 428 cancer patients was evaluated at 11 different centers using a composite (clinical + neurophysiological, TNSr) or clinical (TNSc) examination and with the National Cancer Institute - Common Toxicity Criteria (NCI-CTC) 2.0 and Eastern Cooperative Oncology Group (ECOG) scores. A highly significant correlation was demonstrated between the TNSr and the NCI-CTC 2.0 and ECOG scores; but the TNSr evaluation was more accurate in view of the more extended score range. Also, the simpler and faster TNSc (based only on the clinical neurological examination) allowed to grade accurately CIPN and correlated with the common toxicity scores. The correlation tended to be closer when the sensory items were considered, but also the TNSr motor items, which were not specifically investigated in any other previous study, significantly correlated with the results of the common toxicity scales. In conclusion, this study suggests that the TNSr is a reliable tool for accurately grading and reporting CIPN, with the additional and so far unique support of a formal comparison with known and widely used common toxicity scales. The TNSc is a valid alternative if neurophysiological examination is not feasible. The longer time needed to calculate the TNSr and TNSc in comparison to the ECOG or the NCI-CTC 2.0 scales is offset by the more detailed knowledge of the CIPN characteristics.

Neurological toxicity of long-term (>1 yr) thalidomide therapy in patients with multiple myeloma.

OBJECTIVE: Thalidomide is remarkably active in advanced relapsed and refractory multiple myeloma (MM), so that its use has been recently proposed either in newly diagnosed patients or as maintenance treatment after conventional or high-dose therapy. This latter therapeutic approach has risen the concern of side-effects of long-term therapy with this drug. METHODS: We analysed long-term toxicity of 40 patients (27 M, 13 F, median age = 61.5 yr) who received salvage therapy with thalidomide +/- dexamethasone for longer than 12 months (median 15, range 12-44) at our centre. All the patients had achieved at least a stable disease upon treatment with thalidomide alone (200-400 mg/d, n = 20) or thalidomide (200 mg/d) and dexamethasone (40 mg/d for 4 d every 4 wk) (n = 20). RESULTS AND CONCLUSIONS: Neurotoxicity was the most troublesome and frequent toxic effect that was observed after long-term treatment, the incidence averaging 75%. Among these 30 patients symptoms included paraesthesias, tremor and dizziness. Neurotoxicity was grade 1 in six patients (15%); grade 2 in 13 patients (32.5%), thus determining thalidomide dose reduction to 100 mg/d; and grade 3 in 11 patients (27.5%) who had subsequently to interrupt therapy despite their response. Electromyographic study, performed in patients with grade >/=2 neurotoxicity, revealed a symmetrical, mainly sensory peripheral neuropathy, with minor motor involvement. The severity of neurotoxicity was not related to cumulative or daily thalidomide dose, but only to the duration of the disease prior to thalidomide treatment, although no patients presented neurological symptoms at study entry. These results suggest that long-term thalidomide therapy in MM may be hampered by the remarkable neurotoxicity of the drug, and that a neurological evaluation should be mandatory prior to thalidomide treatment, in order to identify patients at risk of developing a peripheral neuropathy.

Proton MR spectroscopy of the cerebellum and pons in patients with degenerative ataxia.

PURPOSE: To investigate whether proton magnetic resonance (MR) spectroscopy is a useful complement to MR imaging in patients with degenerative ataxia. MATERIALS AND METHODS: Brain MR imaging and single-voxel proton MR spectroscopy of the right cerebellar hemisphere and pons were performed in 30 patients with sporadic (n = 16) or inherited (n = 14) degenerative ataxia and in 20 healthy control subjects. Several indexes of brainstem and cerebellar atrophy were measured on MR images, as well as the N-acetylaspartate/creatine (NAA/Cr), choline/Cr (Cho/Cr), and myo-inositol/Cr (mI/Cr) ratios in the MR spectra. Differences between patients and subjects were evaluated with the Kruskal-Wallis and Mann-Whitney tests, whereas correlation of clinical, MR imaging, and spectroscopic data was assessed with nonparametric Spearman rank correlation. RESULTS: Measurements of brainstem and cerebellar atrophy obtained from MR images revealed patients had olivopontocerebellar atrophy (OPCA) (n = 11), spinal atrophy (SA) (n = 8), or corticocerebellar atrophy (CCA) (n = 4). Seven patients did not fulfill the criteria for any group and were considered undefined. In patients with OPCA, the pontine and cerebellar NAA/Cr and Cho/Cr ratios were significantly decreased when compared with those of the control subjects. Pontine and cerebellar NAA/Cr ratios were also significantly reduced in patients with SA and CCA. Five patients with undefined ataxia had a substantial decrease of pontine or cerebellar NAA/Cr ratio when compared with that of the control subjects. In patients with OPCA, the pontine NAA/Cr ratio (but not the atrophy measurements) showed a correlation (P =.04) with disability. CONCLUSION: MR spectroscopy is a useful complement to MR imaging in patients with degenerative ataxia.