Incidental cardiac uptake of 99mTc-diphosphonates is predictive of poor outcome: data from 9616 bone scintigraphies.

BACKGROUND: Bone scintigraphy (BS) is highly diagnostic for amyloid transthyretin (ATTR) cardiomyopathy. Prevalence and prognostic value of BS cardiac uptake is not well established. Our aim was to assess the prevalence of subclinical cardiac ATTR amyloidosis in patients undergoing [99mTc]MDP/DPD scintigraphy and to define their phenotype and prognosis. METHODS AND RESULTS: BS scans performed for any clinical indications from 2009 to 2020 were reviewed. Patients were stratified according to Perugini visual score of cardiac uptake. Follow-up data were collected. Among 9616 BS scans, 0.7% (n = 67) showed cardiac uptake. In 47 (70%) patients, Perugini score was 1 and in 20 (30%) patients uptake was ≥ 2, suggesting cardiac ATTR amyloidosis. Forty subjects (61%) died during the follow-up (mean 47 ± 30 months). Compared with patients with Perugini score 1, those Perugini score ≥ 2 showed increased death rate (P = .018). Two (2/67) subjects were investigated for TTR gene mutations resulting negative. CONCLUSIONS: In patients undergoing BS for different clinical indications, cardiac uptake suggesting cardiac ATTR amyloidosis is a rare, but still neglected finding, thus preventing possible diagnosis of ATTR cardiomyopathy. Importantly, cardiac uptake negatively affects the survival. Physicians should be aware of this rare, but crucial finding for timely diagnosis and treatment.

Obinutuzumab, a new anti-CD20 antibody, and chlorambucil are active and effective in anti-myelin-associated glycoprotein antibody polyneuropathy.

BACKGROUND AND PURPOSE: Rituximab, a chimeric anti-CD20 monoclonal antibody, has been used in polyneuropathy associated with anti-myelin-associated glycoprotein (anti-MAG) antibody polyneuropathy with controversial results. Herein, two patients with anti-MAG antibody neuropathy and concurrent chronic lymphocytic leukemia (CLL) are reported, who dramatically responded to obinutuzumab, a novel glycoengineered humanized anti-CD20 monoclonal antibody. METHODS: Patient 1 was an 82-year-old man with severe demyelinating sensory-motor neuropathy. He was wheelchair-bound, with loss of sensation up to the knees. He had a CLL, immunoglobulin M (IgM) lambda monoclonal gammopathy, with anti-MAG antibodies >70 000 Bühlmann titer units (BTU). Patient 2 was an 84-year-old woman with demyelinating neuropathy, paresthesias and gait instability. She had CLL and IgM kappa paraprotein with anti-MAG antibodies >70 000 BTU. Both patients were treated with obinutuzumab intravenously at 100 mg on day +1, 900 mg +2, then at 1000 mg on days 8 and 15 of cycle 1 and day 1 of cycles 2-6; chlorambucil was given orally at 0.5 mg/kg on days 1 and 15 of cycles 1-6. RESULTS: Patient 1 at cycle 6 was able to stand, gait was possible with monolateral support, hypoesthesia and strength improved. M-protein and IgM level decreased. In patient 2, already after three cycles, the monoclonal component disappeared and there was dramatic improvement of symptoms and gait normalization. At the end of therapy anti-MAG antibody titer decreased to 5462 BTU. Neurophysiology also improved. CONCLUSIONS: In our patients, obinutuzumab was effective as a first-line treatment of anti-MAG antibody polyneuropathy. CLL might have had a role in the response to therapy, but the associations might be considered in future trials.

Acute amnestic syndrome in isolated bilateral fornix stroke.

BACKGROUND AND PURPOSE: Acute onset of amnestic syndrome may represent a challenging diagnostic issue. In addition to non-vascular etiology, thalamic strokes or infarction involving several temporal lobe structures have been reported. METHODS: We describe three patients in whom an isolated bilateral anterior fornix infarction presented with an acute amnestic syndrome. Clinical presentation, differential diagnosis and magnetic resonance images are discussed for each patient and vascular anatomy of the involved brain regions is also considered. RESULTS: Bilateral anterior columns of the fornix showed cytotoxic edema and bilateral narrowing of anterior cerebral artery was demonstrated. CONCLUSIONS: We suggest that bilateral fornix infarction should always be considered in the diagnostic work-up of an amnestic syndrome with acute onset.

Anti-sulfatide/galactocerebroside antibodies in immunoglobulin M paraproteinemic neuropathies.

BACKGROUND AND PURPOSE: Anti-sulfatide antibodies have been observed in heterogeneous neuropathies and their clinical relevance is still controversial. Whether the combination of sulfatide with galactocerebroside would increase sensitivity or specificity of enzyme-linked immunosorbent assay testing compared to sulfatide alone was assessed. METHODS: Immunoglobulin M (IgM) antibodies to sulfatides, galactocerebroside and combined sulfatide and galactocerebroside (Sulf/GalC) were measured in 229 neuropathy patients, including 73 with IgM paraproteinemic neuropathy [62 with anti-myelin-associated glycoprotein (anti-MAG) antibody] and 156 with other neuropathies. Results from 27 patients with IgM monoclonal gammopathy without neuropathy and 28 healthy subjects served as control. RESULTS: Thirty-three patients showed increased titers of anti-sulfatide antibodies, 28 of whom had an IgM paraproteinemic neuropathy (P < 0.0001). When evaluating the reactivity for the combination Sulf/GalC, 57/229 patients were found to be positive, including 36/73 (49%) with IgM paraproteinemic neuropathy (P < 0.0001). Patients with known anti-sulfatide antibodies also showed anti-Sulf/GalC reactivity, with increased titers in 48.5% of the cases. Testing for anti-Sulf/GalC antibodies allowed 24 additional patients to be detected (eight with IgM paraproteinemic neuropathies), who had no reactivity to the individual glycolipids. Amongst the 11 subjects with IgM paraproteinemic neuropathy who were negative for anti-MAG antibodies, only two were reactive to sulfatide, whilst six (55%) were found to be positive when tested against the combination of sulfatide and galactocerebroside. CONCLUSIONS: Testing for both sulfatide and galactocerebroside in IgM paraproteinemic neuropathies seems to increase the sensitivity compared to anti-sulfatide antibodies alone (49% and 39%, respectively, with a slightly reduced specificity, from 97% to 87%), helping the characterization of otherwise undefined neuropathy that could benefit from immunomodulatory therapy.

Brain anatomical substrates of mirror movements in Kallmann syndrome.

Among male patients affected by Kallmann syndrome, a genetically determined disease due to defective neural migration leading to hypogonadropic hypogonadism and hypo/anosmia, about 40% present the peculiar phenomenon of mirror movements, i.e. involuntary movements mirroring contralateral voluntary hand movements. Several pathogenic hypotheses have been proposed, but the ultimate neurological mechanisms are still elusive. The aim of the present study was to investigate brain anatomical substrates of mirror movements in Kallmann syndrome by means of a panel of quantitative MRI analyses. Forty-nine male Kallmann syndrome patients underwent brain MRI. The study protocol included 3D-T1-weighted gradient echo, fluid attenuated inversion recovery and diffusion tensor imaging. Voxel-based morphometry, sulcation, curvature and cortical thickness analyses and tract based spatial statistics were performed using SPM8, Freesurfer and FSL. All patients underwent a complete physical and neurological examination including the evaluation of mirror movements (according to the Woods and Teuber criteria). Kallmann syndrome patients presenting with mirror movements (16/49, 32%) displayed the following brain changes: 1) increased gray matter density in the depth of the left precentral sulcus behind the middle frontal gyrus; 2) decreased cortical thickness in the precentral gyrus bilaterally, in the depth of right precentral sulcus and in the posterior portion of the right superior frontal gyrus; and 3) decreased fractional anisotropy in the left hemisphere involving the temporal lobe and peritrigonal white matter. No differences were shown by cortical curvature and sulcation analyses. The composite array of brain changes observed in Kallmann syndrome patients with mirror movements likely represents the anatomical-structural underpinnings leading to the peculiar derangement of the complex circuitry committed to unilateral hand voluntary movements.

Brain changes in Kallmann syndrome.

BACKGROUND AND PURPOSE: Kallmann syndrome is a rare inherited disorder due to defective intrauterine migration of olfactory axons and gonadotropin-releasing hormone neurons, leading to rhinencephalon hypoplasia and hypogonadotropic hypogonadism. Concomitant brain developmental abnormalities have been described. Our aim was to investigate Kallmann syndrome-related brain changes with conventional and novel quantitative MR imaging analyses. MATERIALS AND METHODS: Forty-five male patients with Kallmann syndrome (mean age, 30.7 years; range, 9-55 years) and 23 age-matched male controls underwent brain MR imaging. The MR imaging study protocol included 3D-T1, FLAIR, and diffusion tensor imaging (32 noncollinear gradient-encoding directions; b-value=800 s/mm2). Voxel-based morphometry, sulcation, curvature, and cortical thickness analyses and tract-based spatial statistics were performed by using Statistical Parametric Mapping 8, FreeSurfer, and the fMRI of the Brain Software Library. RESULTS: Corpus callosum partial agenesis, multiple sclerosis-like white matter abnormalities, and acoustic schwannoma were found in 1 patient each. The total amount of gray and white matter volume and tract-based spatial statistics measures (fractional anisotropy and mean, radial, and axial diffusivity) did not differ between patients with Kallmann syndrome and controls. By specific analyses, patients with Kallmann syndrome presented with symmetric clusters of gray matter volume increase and decrease and white matter volume decrease close to the olfactory sulci; reduced sulcal depth of the olfactory sulci and deeper medial orbital-frontal sulci; lesser curvature of the olfactory sulcus and sharper curvature close to the medial orbital-frontal sulcus; and increased cortical thickness within the olfactory sulcus. CONCLUSIONS: This large MR imaging study on male patients with Kallmann syndrome featured significant morphologic and structural brain changes, likely driven by olfactory bulb hypo-/aplasia, selectively involving the basal forebrain cortex.

First Report of Fusarium proliferatum Causing Rot on Garlic and Onion in Argentina.

In October 2001 and January 2002, in onion fields (Allium cepa L. cv Valencianita) in the Provinces of San Juan (SJ) and Mendoza (MZ), Argentina, plants were observed with chlorosis, dry leaf tips, and bulbs showing discoloration and rot. During the summer of 2002, a tan rot with white mycelium in rot cavities was also observed in stored garlic bulbs (Allium sativum) in MZ. Four monosporic cultures obtained with a micro punch adapted microscope (three from onion CSJ1, CMZ1, CMZ2 and one from garlic AMZ1) were characterized by morphology on PDA and carnation leaf agar (2). The isolates were deposited in the fungal collection of the Plant Mycosis Laboratory of the Integrated Unit Balcarce. The isolates produced abundant aerial white mycelium and a violet to vinaceous pigmentation. Club-shaped microconidia were abundant, in chains on both mono- and polyphialides. Slender, thin-walled and relatively straight macroconidia were produced only under black light and were mostly 3-septate. Chlamydospores were absent. The isolates were identified as Fusarium proliferatum. Crosses to confirm mating populations and to identify mating types were made in triplicate on carrot agar (3) with standard tester strains D-04853 (MATD-2) and D-04854 (MATD-1) as female parents and the field isolates as male parents. Crosses were examined weekly and were scored positive only if perithecia were seen oozing a cirrhus of ascospores. The identities of these isolates were confirmed as showing positive crosses with standard tester strains of Gibberella intermedia. Pathogenicity tests were conducted with healthy 45-day-old onion seedlings (cv. Valcatorce INTA). The roots of the onion seedlings were soaked in a conidial suspension (5 × 106 conidia/ml) of each isolate (CSJ1, CMZ1, CMZ2) for 2 h; the control was soaked in sterile water (SW). Seedlings were transplanted to pots in a sterile mixture of soil and sand (v/v). Five plants were used for each of 3 replications. The plants were placed in a greenhouse and irrigated with SW. After 3 weeks, symptoms were evaluated. All inoculated plants exhibited symptoms similar to those observed in the bulbs from which the pathogen was isolated and a brown rot appeared on the basal plate of the onion, later becoming dark brown. In garlic, the inoculation consisted of a wound 4.5 mm deep and 2 mm wide in superficially sterilized garlic cloves (cv. Nieve INTA). Inside the cavity, a drop (50 µl) was placed from a suspension of 5 × 106 conidia/ml (AMZ1), then covered with a drop of paraffin. Controls used SW. The garlic cloves were incubated in hermetically sealed trays at 22 ± 3°C in darkness for 3 weeks (1). Garlic showed tan rot and white mycelium in the wound. F. proliferatum was reisolated from inoculated onion seedlings and garlic cloves. The controls did not exhibit symptoms nor were any fungi recovered when tissue was excised from the inoculation points and plated on agar. F. proliferatum was previously reported in Argentina on asparagus (4) with symptoms similar to those of onion and garlic. To our knowledge, this is the first report of F. proliferatum attacking onion and garlic in Argentina. This pathogen has the potential risk of mycotoxin accumulation in contaminated bulbs. References: (1) F. M. Dugan et al. J. Phytopathol. 155:437, 2007. (2) W. Gerlach and H. Nirenberg. The genus Fusarium - A Pictorial Atlas. Mitt. Biol. Bundesanst. Land. Forstwirsch. Berl.-Dahlem, 1982. (3) C. J. R. Klittich and J. F. Leslie. Genetics 118:417, 1988. (4) G. Lori et al. Plant Dis. 82:1405, 1998.