Three-dimensional analysis of pulmonary nodules by MSCT with Advanced Lung Analysis (ALA1) software.

PURPOSE: The purpose of this study was to test the reproducibility of the three-dimensional (3D) Advanced Lung Analysis software (3D-ALA, GE Healthcare) in the estimation of pulmonary nodule volume. MATERIALS AND METHODS: We retrospectively reviewed the unenhanced multislice CT scans (Lightspeed Pro 16 GE) of 77 patients with a solitary pulmonary nodule (n=71) or metastatic pulmonary disease (n=6). A total of 103 pulmonary nodules (19 well-circumscribed, 45 juxtavascular and 39 juxtapleural) were analysed grouped into five classes based on diameter: <5 mm, 10 nodules (9.7%); >or=5 to <10 mm, 25 nodules (24.2%); >or=10 mm to <15 mm, 41 nodules (39.8%); >or=5 to <18 mm, 14 nodules (13.6% ); >or=8 to <30 mm, 13 nodules (12.62%). The following acquisition parameters were used: slice thickness 0.625 mm, reconstruction interval 0.4 mm, pitch 0.562:1, 140 kV, 300 mAs, field of view 13 cm, bone kernel. For each of the 103 nodules three, 3D volume measurements were obtained by the 3D-ALA software. The reproducibility of nodule segmentation was evaluated according to a visual score (1=optimal, >or=95%; 2=fair, 90-95%; 3=poor, 0.05). CONCLUSIONS: Three-dimensional volume measurement with ALARiassunto 1 software is reproducible for all nodules as regards dimension and site. ALA-1 software provided a good and reproducible volume measurement in well-circumscribed and most juxtavascular nodules. Volumetric evaluation and reproducibility of volume estimation in juxtapleural pulmonary nodules, particularly those adjacent to diaphragmatic pleura, is inadequate, and software improvement is needed.

Ultrastructural findings in the peripheral nerve in a family with the intermediate form of Charcot-Marie-Tooth disease.

The authors describe here the ultrastructural findings in peripheral nerve biopsies from two affected members of a family with a previously undescribed intermediate form of Charcot-Marie-Tooth (CMT) disease. We found prevalent demyelinating features such as onion bulbs and myelin splits with uncompacted and irregularly enlarged lamellae, mostly at the Schmidt-Lantermann incisures and in paranodal region. Signs of a chronic axonopathy such as regeneration clusters, large fiber loss, Büngner's bands and unmyelinated fiber involvement were also seen. The presence of both demyelinating and axonal findings, not found in other genetically determined types of CMT disease, confirms the hypothesis of a new nosographic entity of intermediate type.

Autonomic nervous system and smooth muscle cell involvement in systemic sclerosis: ultrastructural study of 3 cases.

OBJECTIVE: To investigate morphological abnormalities in nerve and smooth muscle structures of the anorectal wall underlying gastrointestinal dysfunction in patients with systemic sclerosis (SSc). METHODS: We performed deep rectal biopsy in 3 patients with limited scleroderma of relatively recent onset and intestinal symptoms. RESULTS: We found ultrastructural signs of axonal degeneration and cytoskeletal abnormalities in the bundles of unmyelinated fibers. There was also focal degeneration of smooth muscle cells, often in association with the presence of partially degranulated mast cells. Many mast cells were also observed in close relation to nerve fibers and vessels. The enteric vessels often showed basal lamina reduplication and hypertrophied endothelial cells with obliterated lumen. No significant fibrosis was found. CONCLUSION: Our findings indicate early involvement of the autonomic nervous system and to a lesser extent of smooth muscle cells. We confirmed the presence of early vascular lesions and involvement of mast cells in the pathological process.

Type I sialidosis: a clinical, biochemical and neuroradiological study.

We report biochemical, morphological and neuroradiological findings in a 40-year-old woman affected with type I sialidosis. The clinical symptoms, consisting of a cerebellar syndrome, were first noted at the age of 17 years. The macular cherry-red spot was first observed after 23 years of disease. A CT scan performed at 21 years of age showed enlargement of the fourth ventricle. Nuclear magnetic resonance imaging of the brain performed at the age of 40 showed severe atrophy of the cerebellum and pontine region; atrophy of cerebral hemispheres and of the corpus callosum was also observed. We emphasize the prolonged course of illness in this patient, observed over a long period of time. Of particular interest is the neuroradiological study showing our findings both at the beginning of the disease and after 20 years.

Inheritance of a 38-kb fragment in apparently sporadic facioscapulohumeral muscular dystrophy.

Facioscapulohumeral dystrophy (FSHD) is an autosomal-dominant muscular disorder associated with a short (<35 kb) EcoRI/BlnI fragment resulting from deletion of an integral number of units of a 3.3-kb repeat located at 4q35. In this study, we determined fragment sizes separated by pulsed-field gel electrophoresis in a patient with an apparently sporadic case of FSHD and in his healthy family members. A 38-kb fragment was detected in the proband, in his older brother, and in their father. This finding prompted a clinical reevaluation of the father and brother. A subclinical phenotype restricted to abdominal muscle weakness was detected, and serum creatine kinase values were found to be elevated in both. The proband's brother also showed evidence of an independently occurring subtelomeric rearrangement of 4q35, which normally occurs in about 20% of the population. The identification of a "borderline" 38-kb EcoRI/BlnI fragment in an affected subject and his very mildly affected relatives extends the size range of disease alleles and expands existing data on the variable intrafamilial expressivity of FSHD. This study highlights the importance of a careful molecular and clinical analysis extended to family members of apparently sporadic cases with larger EcoRI/BlnI fragments for accurate diagnosis and appropriate genetic counseling in FSHD.

Early synthesis and correlation of serum anti-thyroid antibodies with clinical parameters in multiple sclerosis.

A high frequency of anti-thyroid antibodies has been demonstrated in multiple sclerosis (MS), but there is a lack of data on the possible association of thyroid autoimmunity with disease activity. To assess whether anti-thyroid antibodies are synthesized early in MS or are induced over the course of the disease and whether or not they are correlated with clinical findings, we assayed serum anti-peroxidase and anti-thyroglobulin antibodies in 129 relapsing-remitting MS patients at the time of diagnosis and prior to any immunosuppressive or immunomodulatory treatment. Anti-peroxidase antibodies were detected in 28/129 (21.7%) MS patients, compared to 12/130 (9.2%) neurological controls (P=0.006) and 8/152 (5.3%) normal healthy subjects (P<0.0001). High titres of anti-thyroglobulin antibodies were detected in 11/129 (8.5%) MS patients compared to 6/130 (4.6%) patients with other neurological diseases (P=0.22) and 5/152 (3.3%) normal healthy subjects (P=0.07). Anti-peroxidase antibodies were associated with initial relapse in 14 of 28 (50%) of the patients compared to 18/101 (18%) without antibodies (P=0.001). Similarly, anti-thyroglobulin antibodies were associated with first relapse in 8/11 (73%) of the patients compared to 11/118 (9.3%) of those without (P<0.0001). However, there was no correlation between anti-thyroid antibody titres and disease duration or CSF IgG index values. By contrast, a significant inverse correlation was found between anti-thyroglobulin antibody titres and EDSS score (r(s)=-0. 75; P=0.008). Our findings demonstrate that anti-peroxidase and anti-thyroglobulin antibodies are synthesized early in relapsing-remitting MS and are associated with early clinical disease activity. Furthermore, high titres of anti-thyroglobulin antibodies are associated with low disability scores, suggesting a possible protective role of these antibodies that deserves further investigation.

Detection of beta-A4 amyloid and its precursor protein in the muscle of a patient with juvenile neuronal ceroid lipofuscinosis (Spielmeyer-Vogt-Sjögren).

Muscle biopsy tissue from a patient affected by the juvenile form of neuronal ceroid lipofuscinosis (NCL) was studied immunohistochemically using antibodies to beta-amyloid peptide and amyloid precursor protein. Positive reaction in muscle was specifically localized to autophagic vacuoles and blood vessel walls. Increased acid phosphatase reaction suggested enhanced lysosomal activity. We hypothesize that beta-amyloid is deposited in NCL muscle by a lysosomal mechanism similar to that proposed in other disorders involving beta-amyloid.

A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia.

OBJECTIVE: To search for mutations in the calcium channel gene CACNA1A and to study the genotype-phenotype correlation in a family with a severe familial hemiplegic migraine (FHM) phenotype and a slowly progressive cerebellar ataxia. BACKGROUND: CACNA1A gene mutations on chromosome 19 are involved in approximately 50% of FHM families. The association of FHM and cerebellar ataxia has been reported in a small number of FHM families, all linked to chromosome 19. METHODS: The proband, in addition to typical hemiplegic migraine attacks, experienced severe episodes during which hemiplegia was associated with acutely altered consciousness and fever lasting several days. She, as well as her affected sister, developed a permanent, late-onset cerebellar ataxia and cerebellar atrophy evident on MRI. Linkage analysis was performed and the whole CACNA1A gene, 47 exon-intron boundaries, was analyzed by double gradient-denaturing gradient gel electrophoresis (DG-DGGE). RESULTS: Genetic studies suggested linkage to chromosome 19p13, and DG-DGGE analysis detected a heteroduplex fragment in exon 13 of the CACNA1A gene. By direct sequencing, a G-to-A substitution resulting in an arginine to glutamine change at codon 583 in the second putative voltage sensor domain of the channel alpha1A-subunit, was identified, possibly representing the disease-causing mutation. The proband and her affected sister were treated with acetazolamide, reporting freedom from new FHM attacks but no benefit in the progression of ataxia. CONCLUSIONS: The combination of episodic dysfunction and permanent deficit could depend on the variety of functions of calcium channels and their distribution in the nervous system.

Ultrastructural study of enteric ganglia in three patients with Rett syndrome.

In order to verify whether a pseudo-obstruction syndrome was associated with morphological changes in enteric ganglia, we performed an ultrastructural study on rectal biopsy specimens in three patients with Rett syndrome. Features of enteric neurons, detected to a different extent in all three biopsy specimens, included an abnormal dilatation of endoplasmic reticulum with a disorganization of cisternae of the Golgi apparatus, and masses of unidentified electron-dense granulo-filamentous material, probably of lipidic origin, observed in the perikaryon. Large electron-lucent membrane-bound vacuoles were found mostly within satellite glial cells. Sometimes, the axon terminals were swollen and showed intraxonal vacuolization. We conclude that the reported findings do not represent a specific sign of degeneration and do not constitute a significant morphological marker of disease.

Neuronal intranuclear inclusion disease: neuropathologic study of a case.

We report neuropathological findings in a 22-year-old man affected with neuronal intranuclear inclusion disease. The inclusions affected to different extents the various structures of the central nervous system, being more numerous in cerebral cortex, inferior olives, hypoglossal and oculomotor nuclei. They ultrastructurally differed from Marinesco bodies. In the neurons of the substantia nigra, we occasionally observed intranuclear inclusions resembling the so-called rodlets of Roncoroni. We did not observe inclusions in the extraneuronal tissues. There was no apparent correlation between frequency of the inclusions and neuronal loss. Intranuclear inclusions were found in many morphologically normal neurons. We suggest that the intranuclear inclusions are the marker of a distinctive disorder, even though their role in neuronal degeneration remains to be clarified.

CAG repeat expansion in an italian family with spinocerebellar ataxia type 2 (SCA2): a clinical and genetic study.

We report an Italian family in which molecular genetic analysis showed expansion of CAG repeats indicative of the SCA2 genotype. This family confirms that ataxia, ophthalmoparesis and sensory peripheral neuropathy are the salient features of the SCA2 phenotype. In the present cases, early onset and mental deterioration were important additional findings. Nerve biopsy findings were compatible with a chronic axonopathy. We found a direct correlation between length of triplet expansion and severity of the clinical symptoms. Of particular interest is the late-onset phenotypical expression in a patient with 34 repeats.

Juvenile Leigh syndrome with protracted course presenting as chronic sensory motor neuropathy, ataxia, deafness and retinitis pigmentosa: a clinicopathological report.

We herein describe a male patient who died at 37 years of age, after having suffered from a slowly progressive syndrome of chronic sensory motor neuropathy, deafness, retinitis pigmentosa and ataxia. The neuropathological study showed symmetric areas of necrosis and demyelination affecting the cerebellum and brainstem. The type of lesion was consistent with the characteristics of Leigh Syndrome. On the basis of the histology of the lesions, we believe that they appeared only a few months before the death of the patient. We underline the atypical clinical picture and suggest that, in certain cases, brain MRI may not be a reliable diagnostic tool.

Detection of Borrelia burgdorferi DNA and complement membrane attack complex deposits in the sural nerve of a patient with chronic polyneuropathy and tertiary Lyme disease.

We report a patient who developed a chronic sensory-motor polyneuropathy and a progressive myelopathy 4 years after a tick bite. An increased serum antibody titer to Borrelia burgdorferi suggested a diagnosis of Lyme neuroborreliosis, although a concomitant cervical spondylosis probably contributed to spinal cord damage. Treatment with ceftriaxone resulted in a marked improvement of neuropathic symptoms, providing indirect evidence of spirochetal infection. Search for B. burgdorferi DNA by polymerase chain reaction amplification on sural nerve confirmed the diagnosis, demonstrating that the spirochete localized in the peripheral nervous system. The presence of complement membrane attack complex deposits and macrophage infiltrates around epineurial vessels and within the endoneurium suggests that the neuropathy in our patient was immune-mediated.

Immunolocalization of several laminin chains in the normal human central and peripheral nervous system.

Using specific monoclonal antibodies against different subunits of laminin, we studied the differential distribution pattern of several laminin chains in the central (CNS) and peripheral (PNS) nervous system. Laminin chains alpha 1, beta 1 and gamma 1, were found in the basement membrane (BM) of blood vessels in both CNS and PNS. In contrast, laminin alpha 2 though present in the BM of capillaries in the CNS, was completely absent from PNS capillaries. Laminins alpha 2, beta 1, gamma 1 could be detected in peripheral nerve, in the BM of Schwann cells, which did not contain Laminin alpha 1. The possible importance of laminin alpha 2 for myelination in the PNS as well as in the function of the blood-brain barrier in the CNS, and its potential relevance to the pathology of congenital muscular dystrophy associated with deficiency of this laminin chain, is discussed.

High levels of cerebrospinal fluid IgM binding to myelin basic protein are associated with early benign course in multiple sclerosis.

We assessed human myelin basic protein (MBP) binding IgM levels in CSF. MBP is the most studied putative antigen in multiple sclerosis (MS) and immune responses against it may be involved in the demyelination process. We also correlated these levels with EDSS score and other parameters of disease progression and prognosis, both at the time of CSF analysis and during follow-up. CSF IgM anti-MBP levels were assayed by measuring total IgM levels with solid-phase ELISA in CSF samples from 66 patients with relapsing-remitting MS, 11 subjects without neurological diseases, 20 patients with non-inflammatory neurological diseases and 7 patients with lymphocytic meningitis, before and after immunoabsorption with human MBP. Confirmation of IgM binding specificity was performed by immunoblotting of positive CSF samples onto MBP coated-nitrocellulose sheets. Clinical evaluation (disability score, number and time of attacks) was performed during a mean follow-up of 2.7 +/- 1.1 years. 23 of the 66 relapsing-remitting MS patients (33.8%) had elevated IgM anti-MBP levels. In this patient subgroup, IgM anti-MBP levels correlated with the IgM index (r = 0.71; P = 0.0001), but not with CSF/serum albumin (r = 0.08; P = 0.72). In the first year of follow-up, patients with low IgM anti-MBP suffered from more numerous attacks than those with elevated levels (0.86 +/- 0.63 versus 0.43 +/- 0.58; P = 0.017). Patients with high IgM binding to MBP had a first attack during follow-up in a significantly higher time than those with low binding (28.87 +/- 4.7 versus 17 +/- 2.6 months, respectively; P = 0.005) and reached a decrease of 0.5 EDSS point significantly faster than those with low IgM (16.17 +/- 1.2 versus 29.7 +/- 2.6 months, respectively; P = 0.0002). A similar significant finding was observed when the time to reach low disability score (EDSS < or = 2.0) was analyzed (10.7 +/- 2.57 +/- 3.3 months, respectively; P = 0.014). These findings demonstrate that in a subgroup of MS patients, elevated CSF levels of IgM anti-MBP are associated with early favorable course and therefore suggest that IgM binding to MBP could be a possible prognostic marker in relapsing-remitting MS to select early MS patients for future trials.

Unusual clinical features and early brain MRI lesions in a family with cerebral autosomal dominant arteriopathy.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a recently described inherited disorder. The pathologic gene maps on chromosome 19. The clinical spectrum of the disease consists of recurrent strokes, migraine, transient ischemic attacks, mood changes, and dementia. We report a genetically assessed CADASIL family with atypical clinical presentations of epileptic seizures. In two asymptomatic family members there were early brain abnormalities on MRI. Our report expands the clinical spectrum of CADASIL and suggests that it is possibly an undiagnosed disorder.

[High-resolution ultrasonography in the study of carpal tunnel syndrome]. / L'ecografia con alta risoluzione nello studio della sindrome del tunnel carpale.

We investigated the reliability of some US signs in the diagnosis of the carpal tunnel syndrome. We carried out a single-blind study with 13-MHz high resolution probes and electromyography on 132 patients with clinical evidence of the carpal tunnel syndrome; a control group of 20 asymptomatic patients was also submitted to US. Eighty-six of 107 patients with US signs of the carpal tunnel syndrome were then submitted to surgical decompression (resection of the transverse carpal ligament), while the extant 21 patients underwent conservative treatment and clinical follow-up. To diagnose the carpal tunnel syndrome, we considered the following US patterns: median nerve changes (swelling before its entrance into the carpal tunnel and flattening in the tunnel itself), palmar bowing of the flexor retinaculum, thickening of the transverse carpal ligament and increased depth of the carpal tunnel, as measured from the apex of the transverse carpal ligament convexity to the underlying carpal bone. Median nerve changes were unreliable signs and were missing in many cases: only 45 of 107 patients exhibited median nerve swelling before and/or its flattening in the carpal tunnel (42%). Such indirect signs as the thickening of the transverse carpal ligament in chronic cases were demonstrated in 94 of 107 patients with the carpal tunnel syndrome (88%) and canal deepening in all unilateral carpal tunnel syndromes was shown in 92 of 107 patients (87%); both these signs proved to be much more reliable. The palmar bowing of the flexor retinaculum was also difficult to demonstrate in surgical patients or in those with connective tissue fibrosis within the tunnel: this sign was demonstrated in 80 of 107 patients with the carpal tunnel syndrome confirmed with electromyography (75%). Tanzer and Rietze reported median nerve changes observed at surgery in 43% and 66% of their patients, respectively. Recent MR findings in asymptomatic wrists have demonstrated that the normal median nerve has an elliptical shape inside the carpal tunnel. To conclude, high resolution US exhibited 96% sensitivity, 95% specificity and 93% diagnostic accuracy and proved to play a major role in the diagnosis of the carpal tunnel syndrome.