Sometimes they come back: New and old spinal muscular atrophy adults in the era of nusinersen.

BACKGROUND AND PURPOSE: Following the commercial availability of nusinersen, there have been a number of new referrals of adults with spinal muscular atrophy (SMA) not regularly followed in tertiary-care centers or enrolled in any disease registry. METHODS: We compared demographics and disease characteristics, including assessment of motor and respiratory function, in regularly followed patients and newcomers subdivided according to the SMA type. RESULTS: The cohort included 166 adult patients (mean age: 37.09 years): one type I, 65 type II, 99 type III, and one type IV. Of these 166, there were 67 newcomers. There was no significant difference between newcomers and regularly followed patients in relation to age and disease duration. The Hammersmith Functional Motor Scale Expanded and Revised Upper Limb Module scores were higher in the regularly followed patients compared to newcomers in the whole cohort and in both SMA II and II. A difference was also found on ventilatory status (p = 0.013) and Cobb's angle >50° (p = 0.039) between the two subgroups. No difference was found in scoliosis surgery prevalence (p > 0.05). CONCLUSIONS: Our results showed differences between the two subgroups, even if less marked in the type III patients. In the type II patients, there was a higher proportion of newcomers who were in the severe end of the spectrum. Of the newcomers, only approximately a third initiated treatment, as opposed to the 51% in the regularly followed patients. The identification of patients who were not part of the registries will help to redefine the overall prevalence of SMA and the occurrence of different phenotypes.

Expanding the histopathological spectrum of CFL2-related myopathies.

Congenital myopathies (CMs) caused by mutation in cofilin-2 gene (CFL2) show phenotypic heterogeneity ranging from early-onset and rapid progressive forms to milder myopathy. Muscle histology is also heterogeneous showing rods and/or myofibrillar changes. Here, we report on three new cases, from two unrelated families, of severe CM related to novel homozygous or compound heterozygous loss-of-function mutations in CFL2. Peculiar histopathological changes showed nemaline bodies and thin filaments accumulations together to myofibrillar changes, which were evocative of the muscle findings observed in Cfl2-/- knockout mouse model.

Chronic inflammatory demyelinating polyneuropathy of childhood: clinical and neuroradiological findings.

INTRODUCTION: This study aims to report on serial magnetic resonance imaging (MRI) studies and clinical features in a cohort of children with chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Clinical, neuroradiological, and statistical investigations performed on nine children with CIDP were retrospectively reviewed. Pathological nerve root enhancement was categorized according to severity, extension, and morphology. A MRI score was thus obtained, and correlations with the clinical picture and disease course were explored. RESULTS: Intrathecal nerve root enhancement (NRE) of varying degrees was seen in a high percentage of patients. There was no significant correlation between the total MRI score at the first MRI study and either severity or course of the disease. However, we found a significant difference (p = 0.002) in NRE of patients with improving CIDP with respect to those with stable or progressing disease at the time of follow-up MRI. CONCLUSION: Contrast-enhanced MRI plays a pivotal role in children with CIDP, both for the initial diagnosis as well as a biomarker of clinical evolution, and should be performed in all children with suspected CIDP both at initial presentation and during follow-up. Further multicenter studies on larger cohorts are awaited to determine the ideal timing for follow-up MRI.

Clinical and neuroimaging features of the m.10197G>A mtDNA mutation: New case reports and expansion of the phenotype variability.

Complex I (CI) is the largest component of the mitochondrial respiratory chain (MRC) and it is made up of 7 mitochondrial DNA (mtDNA)-encoded and at least 38 nuclear DNA-encoded subunits. Isolated CI deficiency is the most common single enzyme deficiency in the heterogeneous group of MRC disorders and it is a relatively common etiology of Leigh-like syndrome (LS). With a few exceptions, descriptions of the clinical spectrum of specific mutations in CI are scarce. We here present three unrelated Italian children who harbored the homoplasmic m.10197G>A mutation in MT-ND3 associated with reduced enzyme activity of CI in muscle. Compared with the spectrum of phenotypes seen in 13 previously described families with the same mutation, these children showed some novel clinical features. Two of the boys presented with subacute onset of dystonia, which showed a remitting-relapsing clinical course in one of them. The third boy presented acute symptoms consisting of speech impairment, progressive left-sided hemiparesis, and also vertebral and arterial malformations. In all the children, molecular studies identified a similar mutation load in tissues, and neuroimaging findings were consistent with the features seen in LS. Functional investigations in cultured skin fibroblasts suggested low ATP production in homoplasmic cells. Our results confirm that the m.10197G>A mutation is relevant to these patients' clinical and biochemical phenotypes, which thus expand the array of phenotypes associated with this variant.

MYH7-related myopathies: clinical, histopathological and imaging findings in a cohort of Italian patients.

BACKGROUND: Myosin heavy chain 7 (MYH7)-related myopathies are emerging as an important group of muscle diseases of childhood and adulthood, with variable clinical and histopathological expression depending on the type and location of the mutation. Mutations in the head and neck domains are a well-established cause of hypertrophic cardiomyopathy whereas mutation in the distal regions have been associated with a range of skeletal myopathies with or without cardiac involvement, including Laing distal myopathy and Myosin storage myopathy. Recently the spectrum of clinical phenotypes associated with mutations in MYH7 has increased, blurring this scheme and adding further phenotypes to the list. A broader disease spectrum could lead to misdiagnosis of different congenital myopathies, neurogenic atrophy and other neuromuscular conditions. RESULTS: As a result of a multicenter Italian study we collected clinical, histopathological and imaging data from a population of 21 cases from 15 families, carrying reported or novel mutations in MYH7. Patients displayed a variable phenotype including atypical pictures, as dropped head and bent spine, which cannot be classified in previously described groups. Half of the patients showed congenital or early infantile weakness with predominant distal weakness. Conversely, patients with later onset present prevalent proximal weakness. Seven patients were also affected by cardiomyopathy mostly in the form of non-compacted left ventricle. Muscle biopsy was consistent with minicores myopathy in numerous cases. Muscle MRI was meaningful in delineating a shared pattern of selective involvement of tibialis anterior muscles, with relative sparing of quadriceps. CONCLUSION: This work adds to the genotype-phenotype correlation of MYH7-relatedmyopathies confirming the complexity of the disorder.

[Sensory processing could be temporally organized by ultradian brain rhythms]. / El procesamiento sensorial podría estar organizado en el tiempo por ritmos cerebrales ultradianos.

INTRODUCTION: Neuronal activity of sensory systems depends on input from the environment, the body and the brain itself. Various rhythms have been shown to affect sensory processing, such as the waking-sleep cycle and hippocampal theta waves, our aim in this revision. The hippocampus, known as a structure involved in learning and memory processing, has the theta rhythm (4-10 Hz), present in all behavioural states. This rhythm has been temporally related to automatic, reflex and voluntary movements, both during wakefulness and sleep, and in the autonomic control of the heart rate. On the other hand theta rhythm has been considered as a novelty detector expressing different level of attention, selecting the information and protecting from interference. DEVELOPMENT AND CONCLUSIONS: Our research is based on the hypothesis that sensory processing needs a timer to be processed and stored, and hippocampal theta rhythm could contribute to the temporal organization of these events. We have demonstrated that auditory and visual unitary discharges in guinea pigs show phase-locking to the hippocampal theta rhythm. This temporal correlation appears during both spontaneous and specific sensory stimulation evoked discharges. Neuronal discharges fluctuate between phase-locked and uncorrelated firing modes relative to the theta rhythm. This changing state depends on known and unknown situations. We have provoked, changing the visual stimuli, a power theta rhythm increment and the phase-locking between this rhythm and the lateral geniculate neurone discharge during wakefulness. In slow wave sleep results were different demonstrating that the ways of the inputs processing have changed.

[The auditory system in sleep]. / El sistema auditivo en el ciclo sueño-vigilia.

INTRODUCTION: The sensory information that the central nervous system receives represents an enormous amount of data coming from the outer world and from the body itself. This constitutes a set of influences that affects the general brain developing as well as on the sleep-waking organization. DEVELOPMENT: We have proposed changes in the auditory information processing throughout the sleep-wakefulness cycle may be at least partially evidenced by single neurons extracellular recordings. We introduce the concept that the neural network organization during sleep vs that of wakefulness is different and can be modulated by sensory signals, and vice versa, the sensory input may be influenced by the central nervous system asleep or awake. During sleep the evoked firing of auditory units increases, decreases or remains similar to that observed during quiet wakefulness. There has been no auditory unit yet that stopped firing as the guinea pig enters sleep. Approximately half of the cortical neurons studied did not change firing rate when passing into sleep while others increased or decreased. Thus, the system is continuously aware of the environment. CONCLUSIONS: We postulate that those neurons that changed their evoked firing during sleep, increasing or decreasing, are part of active sleep processes. Thus, the continuous sensory information input to the brain during sleep may serve to 'sculpt', modulate, the brain by activity-dependent mechanisms of neural development as has been postulated for wakefulness.

Disruption of muscle basal lamina in congenital muscular dystrophy with merosin deficiency.

We studied three new cases of congenital muscular dystrophy (CMD) with homogeneous clinical and laboratory features, represented by congenital muscle hypotonia and weakness, early contractures, elevated serum CK, and dystrophic pattern at muscle biopsy, without clinical impairment of CNS. Merosin, the laminin isoform that contains the alpha 2 heavy chain, was absent in muscle fibers of all the patients by immunohistochemistry and by immunoblot. By electron microscopy, we found a severe disruption of muscle fiber basal lamina, but not of blood vessel basal lamina, which contains the laminin alpha 1 heavy chain isoform. This disruption may play a key role in the degeneration of muscle fibers and in the abnormal proliferation of connective tissue seen in CMD.

Clinical and genetic heterogeneity in autosomal recessive nemaline myopathy.

Autosomal recessive nemaline (rod) myopathy is clinically and genetically heterogeneous. A clinically distinct, typical form, with onset in infancy and a non-progressive or slowly progressive course, has been assigned to a region on chromosome 2q22 harbouring the nebulin gene Mutations have now been found in this gene, confirming its causative role. The gene for slow tropomyosin TPM3 on chromosome 1q21, previously found to cause a dominantly inherited form, has recently been found to be homozygously mutated in one severe consanguineous case. Here we wished to determine the degree of genetic homogeneity or heterogeneity of autosomal recessive nemaline myopathy by linkage analysis of 45 families from 10 countries. Forty-one of the families showed linkage results compatible with linkage to markers in the nebulin region, the highest combined lod scores at zero recombination being 14.13 for the marker D2S2236. We found no indication of genetic heterogeneity for the typical form of nemaline myopathy. In four families with more severe forms of nemaline myopathy, however, linkage to both the nebulin and the TPM3 locus was excluded. Our results indicate that at least three genetic loci exist for autosomal recessive nemaline myopathy. Studies of additional families are needed to localise the as yet unknown causative genes, and to fully elucidate genotype-phenotype correlations.

In vivo intracellular characteristics of inferior colliculus neurons in guinea pigs.

Intracellular in vivo recordings of physiologically identified inferior colliculus central nucleus (ICc) auditory neurons (n = 71) were carried out in anesthetized guinea pigs. The neuronal membrane characteristics are described showing mainly quantitative differences with a previous report [Nelson, P.G. and Erulkar, S.D., J. Neurophysiol., 26 (1963) 908-923]. The spontaneous spike activity was consistent with the discharge pattern of most extracellularly recorded units. The action potentials showed different spike durations, short and long, and some of them exhibited hyperpolarizing post-potentials. There were also differences in firing rate. The ICc neurons exhibited irregular activity producing spike trains as well as long silent periods (without spikes). Intracellular current injection revealed membrane potential adaptation and shifts that outlasted the electrical stimuli by 20-30 ms. Both evoked synaptic potentials and the spike activity in response to click and tone-burst stimulation were analyzed. Depolarizing-hyperpolarizing synaptic potentials were found in response to contralateral and binaural sound stimulation that far outlasted the stimulus (up to 90 ms). When ipsilaterally stimulated, inhibitory responses and no-responses were also recorded. Although few cells were studied, a similar phenomenon was observed using tone-burst stimulation; moreover, a good correlation was obtained between membrane potential shifts and the triggered spikes (input-output relationship). These in vivo results demonstrate the synaptic activity underlying many of the extracellularly recorded discharge patterns. The data are consistent with the known multi-synaptic ascending pathway by which signals arrive at the ICc as well as the descending corticofugal input that may contribute to the generation of long duration post-synaptic potentials.

Membrane and circuit properties of lateral septum neurons: relationships with hippocampal rhythms.

The lateral septum receives the most important afferents from the hippocampus, has been proposed to contribute to theta (theta) rhythm generation. Our aim was to study the membrane and circuital properties of lateral septum neurons and their relationship with hippocampal rhythms. Extra- and intracellular recordings (n=81) were obtained in urethane-anesthetized rats. Two neuronal populations were found, one of them with hippocampal theta; rhythm dependence (theta-D, 68%), and the other group independent of hippocampal theta; rhythm (theta-I, 32%). Other differences were spontaneous firing rate (theta-D=13.20+/-2.09, theta-I=6.99+/-1.18; p<0.005) with a bursting pattern in the theta-D group and single discharges in the theta-I group. Intracellular recordings showed higher synaptic activity in theta-D than in theta-I neurons. Both groups showed fast spikes while only theta-D neurons had high-threshold and low-threshold slow spikes. theta-D neurons had theta-oscillations in their membrane potential. Stimulation of the contralateral lateral septum resets the hippocampal theta rhythm and the theta rhythm recorded intracellularly in the lateral septum neurons. Some neurons (10.6%) showed rhythmic oscillations lasting a few seconds, at a higher frequency than those of the simultaneously recorded hippocampal EEG. This high frequency appeared spontaneously or could be evoked by stimulations of the fornix and reticularis pontis oralis nucleus (RPO). Homologous high frequency oscillations appeared in the simultaneously recorded hippocampal EEG, synchronized with the neuronal activity, during fornix stimulation. RPO stimulation evoked increments (57%) or decrements (43%) in the firing rate of lateral septum neurons. Thus, they could participate in different septal networks to modulate the theta rhythm. The marked functional relationship between lateral septum neurons and hippocampal theta rhythm supports the proposal that lateral septum represents a feedback system for the improvement of medial septum theta rhythm. The hypothalamic projections could be a way to introduce theta and higher rhythms into this structure that control many biological rhythms.

Hippocampal theta waves as an electrocardiogram rhythm timer in paradoxical sleep.

Episodes of heart arrhythmia are present during paradoxical sleep, a known non-homeostatic--'open loop'--physiological state, while wakefulness and slow wave sleep exhibit 'closed-loop' control. A brain-stem autonomic oscillator, a hypothalamic and a corticofrontal center, entrained by baroreceptor input, has been proposed as the main heart rhythm control system. We are postulating another neural timer, i.e. the hippocampal theta rhythm. Cross-correlation between the R-wave of the electrocardiogram and the hippocampal theta revealed phase-locking during behavioral periods under 'open-loop' operations as paradoxical sleep indicative of a participation of such a rhythm in autonomic heart rate timing, in coordination with hypothalamic neuronal activities.

Auditory deprivation modifies sleep in the guinea-pig.

After destruction of both cochleae, a significant enhancement of both paradoxical sleep and slow wave sleep together with decreased wakefulness, were observed for up to 45 days. The sleep augmentation consisted of an increment in the number of episodes of both slow wave and paradoxical sleep rather than in the duration of single episodes. The partial isolation provoked by deafness is postulated as explanation. We suggest that the suppression of one input to a complex set of networks related to the sleep-waking cycle, introduce an imbalance that leads to sleep enhancement.

Auditory cortical efferent actions upon inferior colliculus unitary activity in the guinea pig.

Differential actions on inferior colliculus central nucleus (ICc) single cells spontaneous activity were observed with both ipsilateral and contralateral auditory cortical electrical stimulation (ACx stimulation). Following ACx stimulation, a firing depression of the spontaneous activity was obtained using contralateral or ipsilateral cortical stimulation, although a greater effect was elicited by the contralateral cortex. In contrast, ipsilateral ACx stimulation elicited more excitation with a shorter latency than contralateral stimulation. In units that failed to show spontaneous firing, the sound-evoked responses and ACx stimulation were studied; approximately 50% of them demonstrated firing depression to ACx stimulation on either side with either clicks or tone-bursts. Thirty percent of the units failed to show changes in response to any cortical stimulation. A temporary disruption of ICc-evoked neuronal discharge was elicited during contralateral cortex stimulation, as previously reported to occur during sleep. The demonstration that auditory cortices may differentially affect the same ICc unit activity, i.e. spontaneous and evoked, suggests that auditory processing may depend on the ongoing spontaneous activity plus the effects exerted from each auditory cortex activation.

Periaqueductal gray influence on anteroventral cochlear nucleus unitary activity and naloxone effects.

The effect of periaqueductal gray (PAG) electrical stimulation on the response properties of auditory and 'spontaneously' firing units (abolished when the cochlea is destroyed) in the anteroventral cochlear nucleus (AVCN) was explored using extracellular recordings in acute guinea-pigs. Significant increases and decreases in firing rate were detected in both neuronal groups: only 4% of the sound-responding units were insensitive to PAG stimulation while the 'spontaneous' units showed significantly smaller changes in firing rate in response to PAG stimulation. The auditory AVCN neurons were categorized both by their sound post stimulus time (PST) histograms at their characteristic frequency (CF) and the changes in the probability of discharge after PAG stimulation while the tone burst was maintained constant. PAG was implicated in pain input modulation through enkephalin actions. Because enkephalins have been also observed at the CN level, a pharmacological approach administering naloxone was carried out. We observed that 1) naloxone abolished the unit discharge shifts observed after PAG stimulation and 2) when the drug was injected without PAG stimulation, it produced changes in the firing, increasing or decreasing, and shifts in the probability of discharge versus time, even in cases in which the firing rate was not altered. An involvement of the auditory efferent pathways to CN is postulated and a possible enkephalinergic factor is suggested as a modulator of the auditory input at this level. The probability of discharge observed in the PSTH at the AVCN is dependent on the auditory input plus the central efferent action to its neurons.

Correlative changes of auditory nerve and microphonic potentials throughout sleep.

Gross cochlear potentials in response to alternating clicks and pure tone bursts were recorded in guinea-pigs with chronically implanted electrodes in the round window during sleep and the awake state. A significant increase in both averaged potentials, the compound auditory nerve action potential (cAP) and cochlear microphonics (CM) occurred in slow wave sleep (SWS) with a subsequent diminution in paradoxical sleep (PS) periods. The cAP, CM, amplitude and area averages were similar during quiet wakefulness and in PS. Moreover, as an episode of PS progressed, the recorded potentials continued to decrease. On the other hand, increased averaged values were again observed during a subsequent episode of SWS. An involvement of the efferent olivo-cochlear bundle is postulated, first, because it is the only known pathway connecting the CNS and the auditory periphery and, second, because several key pre-receptor variables (middle ear muscles and ossicles and sound-source ear relation) were either abolished or altered dramatically.

Internally-generated sound stimulates cochlear nucleus units.

The body generates many physiological sounds. One of the most prominent is that produced by the blood flowing inside the vessels with each heart beat. On the other hand, the cochlea is a very sensitive receptor with a low threshold. Given the anatomical close proximity of the carotid artery and other vessels to the inner ear, the possibility of its being stimulated is very high. Cochlear nucleus spontaneous as well sound-responding auditory units were studied. A close relationship between the heart beat, that is the blood flow, and the cochlear nucleus firing was demonstrated, in anesthetized and awake guinea-pigs. Temporary mechanical interruption of the blood flow through the ipsilateral carotid artery abolished firing increments at the cochlear nucleus time-locked to the heart beat. We conclude that one component of the so called 'spontaneous' firing in the auditory system is actually evoked activity due to normal body-generated sounds or noises.

Changes in the cerebral blood flow in postlingual cochlear implant users.

Five postlingually deaf patients (age range 28-58 years) with multichannel cochlear implants were examined with single photon emission tomography (SPECT) (triple-head rotating gamma camera). Changes in the regional cerebral blood flow (rCBF) after intravenous administration of technetium-99m ethyl cysteinate dimer (Tc-99m ECD) were assessed through a stimulation paradigm, consisting of: i) click stimuli (75 dB SPL) in the ear that was to be implanted, 2 weeks before surgery; ii) stimulation with the same click, one month after initial fitting; iii) stimulation with hearing sequential Spanish sentences one month after initial fitting. The results showed a significant increase in the rCBF in the primary left auditory area and in the right auditory cortex, in conditions ii) and iii). The rCBF also showed a significant asymmetrical increase in the frontal lobes when the patient was hearing sequential sentences (condition iii)) with asymmetrical distribution among patients. These results are discussed, principally the correlation between speech discrimination scores and the rCBF distribution in the frontal and temporal lobes.

Intracellular in vivo recording of inferior colliculus auditory neurons from awake guinea-pigs.

Intracellular recordings of identified inferior colliculus (ICc) auditory neurons, were analyzed in in vivo awake, chronically implanted guinea-pigs. The passive membrane characteristics as well as the spontaneous and click evoked synaptic potentials and spike activity, were studied. The injection of current pulses revealed little, if any, adaptation and membrane voltage shifts that outlasted the electrical stimuli. The spontaneous action potentials, observed in all the units studied, were of the short-duration type. During wakefulness, spontaneous synaptic potentials of higher amplitude were observed in comparison to the anesthetized preparation as well as an enhanced firing rate. The click evoked synaptic potentials far outlasted the sound (click, 0.1 ms) duration. The binaural, contralateral and ipsilateral sound stimulation evoked different sequences of synaptic potentials and firing. This was mostly in agreement with studies of extracellular recordings from the ICc, in anesthetized and behaving animals.