Design and simulation of losses in Ge/SiGe terahertz quantum cascade laser waveguides.

The waveguide losses from a range of surface plasmon and double metal waveguides for Ge/Si1-xGex THz quantum cascade laser gain media are investigated at 4.79 THz (62.6 µm wavelength). Double metal waveguides demonstrate lower losses than surface plasmonic guiding with minimum losses for a 10 µm thick active gain region with silver metal of 21 cm-1 at 300 K reducing to 14.5 cm-1 at 10 K. Losses for silicon foundry compatible metals including Al and Cu are also provided for comparison and to provide a guide for gain requirements to enable lasers to be fabricated in commercial silicon foundries. To allow these losses to be calculated for a range of designs, the complex refractive index of a range of nominally undoped Si1-xGex with x = 0.7, 0.8 and 0.9 and doped Ge heterolayers were extracted from Fourier transform infrared spectroscopy measurements between 0.1 and 10 THz and from 300 K down to 10 K. The results demonstrate losses comparable to similar designs of GaAs/AlGaAs quantum cascade laser plasmon waveguides indicating that a gain threshold of 15.1 cm-1 and 23.8 cm-1 are required to produce a 4.79 THz Ge/SiGe THz laser at 10 K and 300 K, respectively, for 2 mm long double metal waveguide quantum cascade lasers with facet coatings.

Amyotrophic lateral sclerosis causes small fiber pathology.

BACKGROUND AND PURPOSE: Our aim was to address the correlation between small fiber loss and amyotrophic lateral sclerosis (ALS) for disease onset, phenotype, genotype, duration, severity and sensory findings. METHODS: Consecutive patients referred for suspected ALS were screened. Exclusion criteria were possible ALS and previous diagnosis or known risk factors for small fiber neuropathies. A sural nerve conduction study (NCS) was bilaterally recorded. The ALS functional rating scale revised was administered and loss of functions were calculated using the Milano-Torino staging (MITOS) system. Sensory symptoms and signs were recorded. Genetic analysis was performed by the next-generation sequencing approach. Skin biopsy was performed at the distal leg and intraepidermal nerve fiber (IENF) density was quantified in three non-consecutive sections following published guidelines. Findings were referred to age- and sex-adjusted normative values. RESULTS: Fifty-seven patients including six with facial onset sensory and motor neuronopathy (FOSMN) were enrolled. Eight (15.7%) pure ALS patients and five (83%) FOSMN patients complained of sensory disturbances with different distributions. Sural NCS was normal in all except two patients. IENF density was reduced in 75.4% of pure ALS and 50% of FOSMN patients, without correlation with any disease features. IENF density was similarly reduced in bulbar (78.5%), flail limb (87.5%), pyramidal (100%), and spinal (68.2%) onset, as well as in genetic (83.3%) and sporadic (82%) ALS. There was no correlation with genotype, disease duration and severity. CONCLUSIONS: Intraepidermal nerve fiber loss is a feature of most ALS patients. It does not correlate with onset, phenotype, course and severity of the disease, and cannot be considered a clinical or prognostic biomarker.

Giant SEPs and SEP-recovery function in Unverricht-Lundborg disease.

OBJECTIVE: To evaluate the relationship between sensory hyperexcitability as revealed by giant SEPs and the SEP recovery function (SEP-R) in a series of patient with progressive myoclonic epilepsy of Unverricht-Lundborg type, identified as epilepsy, progressive myoclonic 1A (EPM1A), MIM #254800. METHODS: We evaluated SEPs by applying median nerve stimuli and SEP-R using paired stimuli at inter-stimulus intervals (ISIs) of between 20 and 600 ms in 25 patients and 20 controls. The SEPs were considered "giant" if the N20P25 and P25N33 amplitudes exceeded normal mean values by +3SD. RESULTS: During the paired-stimulus protocol, the SEPs elicited by the second stimulus (S2) were detectable at all ISIs but consistently suppressed in the 13 patients with giant SEPs reflecting a significantly delayed SEP-R. Maximal suppression roughly corresponded to the plateau of a broad middle latency (>100 ms) wave pertaining to the S1 response. CONCLUSIONS: The cortical processing dysfunction generating giant SEPs in EPM1A patients consistently combines with a long-lasting suppression of hyperexcitability that leads to a delayed giant SEP-R without obstructing the response to incoming stimuli. SIGNIFICANCE: The delayed SEP-R is not due to true inhibition but the suppression of aberrant hyper-synchronisation sustaining giant SEPs. A broad middle latency SEP component adds a significantly suppressive effect. This suggests that cortico-subcortical circuitries contribute to both the gigantism and the delayed SEP-R.

Supratentorial and pontine MRI abnormalities characterize recessive spastic ataxia of Charlevoix-Saguenay. A comprehensive study of an Italian series.

BACKGROUND AND PURPOSE: The autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disorder caused by mutations in the SACS gene. The disease, first described in Canadian families from Québec, is characterized by cerebellar ataxia, pyramidal tract involvement and peripheral neuropathy. METHODS: Analysis of SACS gene allowed the identification of 14 patients with ARSACS from 13 unrelated Italian families. Clinical phenotype, gene mutations and magnetic resonance imaging (MRI) findings were analysed. RESULTS: We found 16 novel SACS gene mutations, including a large in-frame deletion. The age at onset was in infancy, but one patient presented the first symptoms at age 32. Progression of the disease was variable, and increased muscle tone was mostly recognized in later stages. Structural MRI showed atrophy of the superior cerebellar vermis, a bulky pons exhibiting T2-hypointense stripes, identified as the corticospinal tract (CST), thinning of the corpus callosum and a rim of T2-hyperintensity around the thalami in 100% of cases. The presence of iron or other paramagnetic substances was excluded. Diffusion tensor imaging (DTI) revealed grossly over-represented transverse pontine fibres (TPF), which prevented reconstruction of the CST at this level (100% of cases). In all patients, significant microstructural alterations were found in the supratentorial white matter of forceps, cingulum and superior longitudinal fasciculus. CONCLUSIONS: Our findings further enlarge the genetic spectrum of SACS mutations and widen the study of clinical phenotype. MRI characteristics indicate that pontine changes and supratentorial abnormalities are diagnostic. The over-representation of TPF on DTI suggests a developmental component in the pathogenesis of the disease.

Polymyography in the diagnosis of childhood onset movement disorders.

UNLABELLED: We report on the results of a clinical and polymyographic retrospective study of 61 paediatric patients with tremor, dystonia and/or myoclonus. Aim of the study was to verify the contribution of polymyography in the classification of these movement disorders and in their aetiological definition. METHODS: The movement disorders were clinically classified by two experts, based on clinical and videotape recordings evaluation; all patients underwent standardized polymyographic evaluation; aetiological diagnosis was performed according to diagnostic protocols for dystonia, myoclonus, tremor and psychogenic movement disorders. The polymyographic features were summarized in five different patterns (dystonia, subcortical myoclonus, myoclonic dystonia, tremor, normal) and compared with the clinical classification and with aetiological diagnosis. RESULTS: In more than 70% of the patients the polymyographic features were in accordance with the clinical classification; in 31% the polymyographic features allowed to identify a clinically unclassified movement disorder and in 19.6% disclosed a not clinically evident associated movement disorder. The polymyographic study did not contribute to the aetiological diagnosis, but was useful in supporting the clinical diagnosis of psychogenic movement disorder.

POEMS syndrome: relapse after successful autologous peripheral blood stem cell transplantation.

We report a patient with POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, Skin changes) treated with high dose chemotherapy and auto-Peripheral Blood Stem Cell Transplantation (auto-PBSCT) who had a very good response with complete clinical remission. Seven years later, she relapsed and a new sclerotic bone lesion was found. To our knowledge, this is the first POEMS syndrome relapse after successful auto-PBSCT.

Movement-related desynchronization-synchronization (ERD/ERS) in patients with Unverricht-Lundborg disease.

We studied changes in event-related desynchronization/synchronization (ERD/ERS) patterns in patients with Unverricht-Lundborg disease (ULD), presenting with prominent action myoclonus. We analyzed the movement-related ERD/ERS in alpha and beta frequency bands in 15 patients using self-paced finger extension as a motor paradigm and we compared the results with those obtained in 12 healthy volunteers. In all ULD patients, alpha- and beta-ERD regularly occurred with onset and location similar to that found in healthy controls, but the desynchronization of alpha activity was significantly greater than in controls (C3: -64.4+/-9.8% vs. -49.7+/-14.8%; p=0.004). Moreover, in the patients, both alpha- and beta-ERD spread toward frontal electrodes. In controls, the post-movement beta-ERS regularly occurred; it was absent in eight patients with severe action myoclonus, while, in seven patients with mild or moderate myoclonus, the beta-peak was significantly smaller with respect to that measured in controls (55.6+/-15.1% vs. 153.9+/-99.8%, p=0.006). The failure of beta-ERS well-correlated with motor impairment resulting from action myoclonus, whereas SSEPs and long-loop reflexes performed to detect signs of cortical hyperexcitability showed inconsistent changes. In ULD patients, ERD/ERS changes indicate an increased activation of motor cortex during movement planning and a great reduction of post-excitatory inhibition of motor cortex. The changes involving beta-ERS had a significant relationship with the functional disability in individual patients and might play a pathogenic role in the motor dysfunction.

Childhood-onset multifocal motor neuropathy with conduction blocks.

Multifocal motor neuropathy (MMN) is an acquired disorder with onset in adulthood. The authors describe a patient with a slowly progressing distal upper limb motor neuropathy since age 6 years, in whom definite conduction blocks in upper limbs, outside common entrapment sites, and no sensory involvement were consistent with MMN. IV immunoglobulin treatment produced marked muscle strength improvement and conduction block disappearance. MMN diagnosis should also be considered in childhood.

Sequential antibodies to potassium channels and glutamic acid decarboxylase in neuromyotonia.

A patient with thymoma-associated neuromyotonia and voltage-gated potassium channel (Kv1.2 and Kv1.6) antibodies by immunoprecipitation and rat brain immunolabeling was treated successfully with immunoadsorption and cyclophosphamide. Curiously, glutamic acid decarboxylase antibodies, absent at onset, appeared later. Stiff-person syndrome was absent, but fast blink reflex recovery suggested enhanced brainstem excitability. The range of antibodies produced in thymoma-associated neuromyotonia is richer, and the timing of antibody appearance more complex, than previously suspected.

Sensorimotor cortex excitability in Unverricht-Lundborg disease and Lafora body disease.

OBJECTIVE: To investigate whether Unverricht-Lundborg disease (ULD) and Lafora body disease (LBD) can be differentiated on the basis of their neurophysiologic profiles. METHODS: Somatosensory evoked potentials (SSEPs), long-loop reflexes (LLRs), and the influence of conditioning nerve stimulation on the motor potentials evoked by transcranial stimulation in 8 patients with LBD and 10 patients with ULD were investigated. RESULTS: Both groups showed sensorimotor cortex hyperexcitability, but their electrophysiologic profiles were different. Enlarged P25 to N33 SSEP components and enhanced LLRs were common in the ULD patients, whereas medium-latency "giant" SSEP components and less consistently enhanced LLRs were more frequently found in the patients with LBD. Cortical relay time was extremely brief in ULD but varied in LBD. Conditioning somatosensory stimuli differently affected motor cortex excitability, leading to early facilitation in ULD and delayed and prolonged facilitation in LBD. CONCLUSIONS: Patients with Unverricht-Lundborg disease (ULD) and Lafora body disease (LBD) have different electrophysiologic profiles. The ULD findings point to an aberrant subcortical or cortical loop (possibly short-cutting the somatosensory cortex) that is involved in generating the prominent action myoclonus characterizing the disorder. The LBD findings highlight sustained hyperexcitability of the sensorimotor cortex in response to afferent stimuli, which fit with a more severe impairment of inhibitory mechanisms.

Progressive dysarthria: definition and clinical follow-up.

Progressive dysarthria is a common sign of several degenerative disorders of the central nervous system; it may also be a distinct nosographic entity. We identified nine patients in which progressive dysarthria remained the sole neurological sign for at least 2 years after onset. At least a year after hospital admission, the following diagnoses were made: two cases of corticobasal degeneration, one of frontotemporal dementia, one of primary progressive aphasia, one of motor neuron disease (MND)-dementia, one of ALS, and one of ALS-aphasia. In the remaining two patients progressive dysarthria remained the only neurological sign at latest examination. We conclude that in most cases progressive dysarthria is the presenting sign of an established neurodegenerative disease (generally degenerative dementia or motor neuron disease), although the possibility that progressive dysarthria is a distinct entity cannot be excluded. To clarify this issue, studies (probably multicenter) on more patients with longer clinical follow-up and pathological confirmation are required.

Movement-activated myoclonus in genetically defined progressive myoclonic epilepsies: EEG-EMG relationship estimated using autoregressive models.

OBJECTIVE: To study electroencephalography-electromyography (EEG-EMG) relationships in patients with different forms of progressive myoclonic epilepsies (PME). METHODS: EEG-EMG auto-spectra, coherence and phase functions were estimated by means of bivariate and time varying autoregressive (AR) models in 15 patients: 8 with Unverricht-Lundborg, 4 with Lafora body disease, and 3 with sialidosis. RESULTS: The coherence spectra of the EMG epochs including action myoclonus and contralateral frontocentral EEG derivations showed a main beta peak (average coherence: 0.60-0.79) in all patients, regardless of the type of PME. The time lag from cortex to muscle was 13.0-21.3 ms. Significantly, coherent gamma activity was consistently found only in the 3 patients with sialidosis; the most heterogeneous results were obtained in the patients with Lafora disease, who showed a more complex coherence profile. Periods of normal muscle contractions, which could be recorded in patients with Unverricht-Lundborg PME, were characterised by the presence of an EEG-EMG beta coherence peak on the same frequency as in the case of action myoclonus, but with a lower coherence value. CONCLUSIONS: AR models were capable of describing EEG-EMG relationships in patients with PME, and indicated that coherent cortical and EMG beta oscillations are crucially involved in the generation of myoclonus. Moreover, they could detect the uneven spectral profiles characterising the different forms of PME.

Neurophysiological features in relation to clinical signs in clinically diagnosed corticobasal degeneration.

We investigated the association between clinical and neurophysiological characteristics in patients with a clinical diagnosis of probable corticobasal degeneration (CBD), and searched for neurophysiological features supporting the diagnosis in life. Ten patients with clinically probable CBD underwent comprehensive neurological evaluation and brain MRI. Long latency reflexes (LLR), upper limb somatosensory (SEP) and motor evoked (MEP) potentials were recorded. The mini-mental state examination (MMSE), the phonemic verbal fluency test (PVFT) and the De Renzi ideomotor apraxia test were also performed. Polygraphic EEG was performed in the six patients with myoclonus. The SEP N30 frontal component was absent bilaterally in four patients, was absent on the left side in one, and had increased latency in other three. MEPs were abnormal in four patients (three had prolonged central motor conduction time, one of whom also had increased MEP threshold, and one had increased MEP threshold). All six patients with myoclonus had enhanced LLRs at rest, which were also of abnormally increased amplitude during motor activation; latencies were generally shorter than in classic cortical reflex myoclonus. On back-averaging, no EEG spikes time-locked to EMG activity were found in any myoclonus patient. Five patients were demented by MMSE, eight had ideomotor apraxia scores in the ideomotor apraxia range and five had defective verbal fluency. Brain MRI revealed asymmetric cortical atrophy in all patients, particularly evident frontoparietally. Neurophysiological techniques, particularly LLR, can assist CBD diagnosis especially in patients with myoclonus. Patients with evident parkinsonism had greater SEP N30 (frontal) abnormalities, while most patients with marked paresis had slower MEP times.

Cell volume-dependent phosphorylation of proteins of the cortical cytoskeleton and cell-cell contact sites. The role of Fyn and FER kinases.

Cell volume affects diverse functions including cytoskeletal organization, but the underlying signaling pathways remained undefined. We have shown previously that shrinkage induces Fyn-dependent tyrosine phosphorylation of the cortical actin-binding protein, cortactin. Because FER kinase was implicated in the direct phosphorylation of cortactin, we investigated the osmotic responsiveness of FER and its relationship to Fyn and cortactin. Shrinkage increased FER activity and tyrosine phosphorylation. These effects were abolished by the Src family inhibitor PP2 and strongly mitigated in Fyn-deficient but not in Src-deficient cells. FER overexpression caused cortactin phosphorylation that was further enhanced by hypertonicity. Exchange of tyrosine residues 421, 466, and 482 for phenylalanine prevented cortactin phosphorylation by hypertonicity and strongly decreased it upon FER overexpression, suggesting that FER targets primarily the same osmo-sensitive tyrosines. Because constituents of the cell-cell contacts are substrates of Fyn and FER, we investigated the effect of shrinkage on the adherens junctions. Hypertonicity provoked Fyn-dependent tyrosine phosphorylation in beta-catenin, alpha-catenin, and p120(Cas) and caused the dissociation of beta-catenin from the contacts. This process was delayed in Fyn-deficient or PP2-treated cells. Thus, FER is a volume-sensitive kinase downstream from Fyn, and the Fyn/FER pathway may contribute to the cell size-dependent reorganization of the cytoskeleton and the cell-cell contacts.

Chronic inflammatory demyelinating polyradiculoneuropathy: long-term course and treatment of 60 patients.

The objective of this study was to assess the long-term course and treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We evaluated, according to a predefined protocol, a series of 60 CIDP patients who received a long-term course of steroids and immunosuppressants. Eighteen of them also had monoclonal gammopathy of undetermined significance (MGUS). Mean follow-up was 4.4 years and was similar for CIDP and CIDP-MGUS patients. At the end of the follow-up, improvement was ascertained in 60% of patients (69% CIDP, 39% CIDP-MGUS). Complete remission was achieved in 13%. Out of 26 patients receiving steroids as a monotherapy, 19 improved (73%). The following variables were predictive of a better outcome: female gender, younger age at onset, relapsing-remitting course, and absence of axonal damage at neurophysiologic study. In the multivariate analysis, younger age at onset and demyelination without axonal damage still retained an independent positive value.