Synapse and primary cilia dysfunctions in Autism Spectrum Disorders. Avenues to normalize these functions.

AIM: An update on the plasticity of the brain networks involved in autism (autism spectrum disorders [ASD]), and the increasing role of their synapses and primary non-motile cilia. METHODS: Data from PubMed and Google on this subject, published until February 2024, were analyzed. RESULTS: Structural and functional brain characteristics and genetic particularities involving synapses and cilia that modify neuronal circuits are observed in ASD, such as reduced pruning of dendrites, minicolumnar pathology, or persistence of connections usually doomed to disappear. Proteins involved in synapse functions (such as neuroligins and neurexins), in the postsynaptic architectural scaffolding (such as Shank proteins) or in cilia functions (such as IFT-independent kinesins) are often abnormal. There is an increase in glutaminergic transmission and a decrease in GABA inhibition. ASD may occur in genetic ciliopathies. The means of modulating these specificities, when deemed useful, are described. INTERPRETATION: The wide range of clinical manifestations of ASD is strongly associated with abnormalities in the morphology, functions, and plasticity of brain networks, involving their synapses and non-motile cilia. Their modulation offers important research perspectives on treatments when needed, especially since brain plasticity persists much later than previously thought. Improved early detection of ASD and additional studies on synapses and primary cilia are needed.

[The neuropathology of sleep in human neurodegenerative diseases]. / Neuropathologie du sommeil des maladies neurodégénératives humaines.

The neuropathology of human sleep remains an ill-defined issue. The data concerning the main structures of human brain areas involved, or supposed to be implicated, in sleep organisation are reviewed. Five levels of organisation can be schematically recognized: (i) the ascending arousal system, (ii) the non REM and REM systems (iii) regulated by hypothalamic areas, (iv) and the biological clock, (v) modulated by a number of "allostatic" influences. These are briefly described, with emphasis on the location of structures involved in humans, and on the recently revised concepts. Current knowledge on the topography of lesions associated with the main sleep disorders in degenerative diseases is recalled, including REM sleep behavior disorders, restless legs syndrome and periodic leg movements, sleep apneas, insomnia, excessive daily sleepiness, secondary narcolepsy and disturbed sleep-wake rhythms. The lesions of sleep related structures observed in early and late stages of four degenerative diseases are then reviewed. Two synucleinopathies (Lewy lesions associated disorders, including Parkinson's disease and Dementia with Lewy bodies, and Multiple System Atrophy) and two tauopathies (Progressive Supranuclear Palsy and Alzheimer's disease) are dealt with. The distribution of lesions usually found in affected patients fit with that expected from the prevalence of different sleep disorders in these diseases. This confirms the current opinion that these disorders depend on the distribution of lesions rather than on their biochemical nature. Further studies might throw insight on the mechanism of normal and pathological sleep in humans, counterpart of the increasing knowledge provided by animal models. Specially designed prospective clinicopathological studies including peculiar attention to sleep are urgently needed.

Neurophysiologie du sommeil

Le sommeil est une fonction doublement cyclique puisqu´elle répond au rythme circadien de 24 heures de l´horloge interne située dans l´hypothalamus antérieur et au rythme ultradien de 90 minutes qui assure l´alternance des cycles du sommeil. Ces cycles, qui comportent la succession du sommeil lent léger, du sommeil lent profond puis du sommeil paradoxal, résultent de l´activité concertée de nombreuses régions du cerveau et de nombreux neurotransmetteurs. Le chef d´orchestre est la région préoptique de l´hypothalamus. L´alternance jour-nuit et la mélatonine jouent les rôles de synchroniseurs.(AU)

[Neuropathology of tauopathies and synucleinopathies, and neuroanatomy of sleep disorders: meeting the challenge]. / Neuropathologie des taupathies et synucléinopathies et neuroanatomie des troubles du sommeil: un challenge à relever.

Abnormalities of tau and alpha-synuclein have been described in a variety of neurodegenerative diseases often associated with sleep disorders. Neuropathological descriptions concerning these diseases are rapidly expanding, and they become difficult to summarise. On the other hand, the human neuroanatomy of sleep remains an ill defined issue. Main tauopathies are Alzheimer's disease, progressive supranuclear palsy, cortico-basal degeneration, argyrophilic grain disease, Pick disease and fronto-temporal degeneration with Parkinsonism associated with chromosome 17. In contrast to Alzheimer's disease, where abnormal tau containing cells are mainly neurones, in the other disorders, both neurones and glial cells are affected. The presynaptic protein alpha-synuclein is a major constituent of Lewy-type lesions in Parkinson disease and in dementia with Lewy bodies. Alpha-synuclein is also found in neurones and glia of Multi System Atrophy. This led to group these disorders into the still ill defined group of synucleinopathies. The lesions of tauopathies and synucleinopathies are presented, and their distribution in the most common disorders is described, distinguishing when possible neuronal loss and neuropathological markers. Recent data show that their extension is far larger than previously assumed and that they involve a variety of areas possibly involved in sleep regulation. Sleep disorders have been described in various tauopathies and synucleinopathies. However, no detailed clinico-pathological reports concerning the distribution of affected and spared areas in patients studied by polysomnography are available. Furthermore, the similarities of sleep disorders associated with different diseases, the interindividual variability, the frequently associated disorders, and the difficulties in quantifying neuronal loss make any clinicopathological correlation uncertain. The knowledge of sleep neuroanatomy is mainly based on animal studies. The few data concerning the structures of human brain areas involved in sleep organisation are recalled. Several systems known to be acting in sleep physiology are usually affected by tauopathies and synucleinopathies, but the pattern of their involvement in sleep pathology remains highly conjectural. The neuropathology of sleep disorders in tauopathies and synucleinopathies is a still uncultivated field.

[Obstructive sleep apnea syndrome and the upper airway muscles]. / Syndrome d'apnées obstructives du sommeil et muscles des voies aériennes supérieures.

Pharyngeal muscles are prone to distorsion during inspiratory negative pressure. Some pharyngeal muscles, called pharyngeal dilatators, exhibit tonic and/or phasic inspiratory activity. At the velar level, tensor palatini, glossopharyngeus, palatopharyngeus and musculus uvula drive the airflow towards nasal or buccal breathing. Genioglossus and geniohyoid muscles exert a forward propulsion to the tongue. The contraction of the dilatators muscles precedes the diaphram contraction. These muscles show a poor endurance. In obstructive sleep apnea syndrome, they contract during unfavorable metabolic (hypoxia and hypercapnia) as well as mechanical (excentrical contraction) conditions. Histological changes occur in upper airway dilator muscles: muscle volume and proportion of type Ila fibers are increased. These changes, considered as compensatory mechanisms, are variable within the different studied pharyngeal muscles. The initial pharyngeal obstructive site, and its further extension, could be determined by the different strength and endurance properties of these muscles.

[Obstructive-sleep apnea syndrome: brain oxygenation measured with near-infrared spectroscopy. Preliminary results]. / Syndrome d'apnées obstructives du sommeil: oxygénation cérébrale mesurée par la spectrométrie dans le proche infrarouge. Résultats préliminaires.

This study assessed cerebral oxygenation in four obstructive sleep apnea syndrome (SAOS) patients (age = 51.8 +/- 15 years, apnea-hypopnea index = 68-125 per hour), during sleep and waking time, using near infrared spectoscopy (NIRS), during a standard polysomnography. Oxyhemoglobin (HbO2, reflecting cerebral oxygenation), total hemoglobin (Hbt, reflecting cerebral blood volumes) and cerebral oxygen saturation (SaO2c = HbO2/Hbt), were compared to the data obtained in four snorers not presenting apneas (age = 51.8 +/- 6.6, apnea-hypopnea index = 2.6-6.2 per hour) examined in the same way. The main result was that HbO2 values were reduced in SAOS patients, both during sleep (at stage 2: 52.54 +/- 9.60 mumol/L versus 73.80 +/- 11.70 mumol/L) and during waking state (53.67 +/- 7.20 mumol/L versus 63.05 +/- 5.55 mumol/L). Hbt was also reduced in apneic patients as compared to snorers during waking state (72.73 +/- 13.90 mumol/L versus 96.05 +/- 6.30 mumol/L). During sleep, Hbt increased in a similar way for snorers and apneics (12.4% versus 13%), whereas HbO2 values were constant for apneics. SaO2c paralleled SaO2p in snorers and apneics, values for SaO2c being 20-30% lower than values for SaO2p. The difference in the values was probably due to the use of different monitoring techniques. Cerebral oxygenation and cerebral blood volumes were continuously low in apneic patients, and peripheral hypoxia was associated with same-range cerebral hypoxia. Cerebral hemodynamic mechanisms related to sleep, although in part efficient in apneic patients, were not able to increase cerebral oxygenation up to normal values.

Objective patient compliance in long-term use of nCPAP.

Concerns remain regarding patient compliance with nasal continuous positive airway pressure (nCPAP). Poor objective compliance during the first months of treatment has been reported, but no data are available among chronically treated patients. Use of nCPAP, in 17 chronically treated obstructive sleep apnoea patients (820+/-262 days) was evaluated objectively using a pressure monitor (MC+; Sefam, France). Two consecutive recording periods of 30 sessions of treatment were scheduled at the patient's home. To minimize the potential bias caused by the introduction of the monitor, only the pressure data obtained at the end of the second period of recording (T2) were analysed. During the 28.1+/-2.6 monitored days, the mean effective daily rate of use was 7.1+/-1.1 h, 97% of the rate indicated by the standard in-built time counter. The prescribed pressure was observed during 95% of the machine run time. The nCPAP system was used for 94% of the monitored days. Sixty percent of the patients used their device every day. These preliminary results suggest that, contrary to reported compliance during the early period of the treatment, objective use of nasal continuous positive airway pressure therapy in chronically treated patients is satisfactory.

A laboratory validation study of the diagnostic mode of the Autoset system for sleep-related respiratory disorders.

We performed a validation study of the diagnostic mode of the Autoset system (ResMed, Australia) on a group of 44 snorers (10 women). We compared the result of the Autoset's automatic analysis of nasal airflow (using nasal prongs) to those of an in-laboratory polysomnographic study with a Fleisch facemask pneumotachograph. For the first 29 patients, the Autoset software was set to recognize only apneas; for the remaining 15, the software was modified to recognize both apneas and hypopneas. Relative to polysomnography, the Autoset overestimated the number of apneas. Oral breathing or displacement of the nasal prongs partially explained these differences. A significant correlation was found between the apnea indices (AI) assessed by the two methods (r = 0.98). For an AI of 20/hour the Autoset was 100% sensitive and 88% specific. The Autoset significantly underestimated the number of hypopneas compared to the polysomnograph with pneumotachograph (62.9 +/- 4.7 vs. 85.5 +/- 73.1, P = 0.04), although for an apnea-hypopnea index of 20, Autoset was 100% sensitive and 88% specific. The lack of linearity of Autoset's volume evaluation at low volumes could explain most of the differences. Our results indicate that the Autoset system, in its diagnostic mode, is a useful tool for identifying patients with significant obstructive sleep apnea syndrome. The system is less useful in patients with mild to moderate sleep disordered breathing, where it may give erroneous results.

Long-term compliance to continuous positive airway pressure therapy (nCPAP) set up during a split-night polysomnography.

We studied prospectively the acute and long-term compliance with nasal continuous positive airway pressure (nCPAP) therapy set up during a split-night polysomnography in 31 patients suffering from severe obstructive sleep apnea syndrome (OSAS). The mean apnea-hypopnea index (AHI) was 66 +/- 23/hour. An effective nCPAP (AHI < 10/hour in all sleep stages in the dorsal decubitus) was titrated in 27/31 patients. The mean effective nCPAP was 11 +/- 2 cm H2O. In three patients, a subsequent night was necessary to determine the effective nCPAP during rapid eye movement sleep, and one patient did not support the treatment. Of the 27 patients with successful titration, 21 accepted home treatment, three chose a surgical procedure and three refused to be treated. Of the 21 accepting home treatment, one patient did not receive his insurance agreement and could not participate in follow-up. Among the 20 other patients, four interrupted their treatment during the 1st month because of discomfort, and 16 were followed for 285 +/- 84 days. The daily rate of nCPAP use for the compliant patients was 6.7 +/- 1.5 hours. These preliminary results indicate that a split-night technique is reliable and cost saving in a majority of patients suffering from severe OSAS.

[The value of motor evoked potentials in the localization of radicular lesions. 2 cases of herniated cervical disc]. / Intérêt des potentiels évoqués moteurs pour la localisation des lésions radiculaires. Deux cas de hernie discale cervicale.

Cervical electrical stimulation evokes a potential in the muscle innervated by the cervical and brachial plexuses. We present 2 cases of herniated cervical intervertebral disc which illustrate the usefulness of motor stimulation to localize a motor radicular lesion. The simultaneous recording of several muscles innervated by different radicular levels has enabled us to demonstrate the exact level and side of the lesion. Cervical motor tract stimulation is a good means of diagnosing a radicular lesion when peripheral nerve conduction velocities are normal.

The clinical spectrum of alcoholic pellagra encephalopathy. A retrospective analysis of 22 cases studied pathologically.

A retrospective clinical study of 22 heavy alcohol drinkers is reported in which postmortem study showed diffuse chromatolysis of neurons identical to that found in neurological pellagra, associated in 13 cases with Marchiafava-Bignami disease and/or Wernicke-Korsakoff disease. The clinical features included confusion and/or clouding of consciousness, marked oppositional hypertonus ('gegenhalten') and myoclonus. Because of the frequent coexistence of other alcoholic encephalopathies in the same patient, alcoholic pellagra was often unrecognized. Fifteen patients received thiamine and pyridoxine therapy without niacin. It appeared to aggravate the neurological state or to trigger the development of alcoholic pellagra encephalopathy in 9 cases. The relationship between pellagra occurring during thiamine and pyridoxine therapy and 'nicotinic acid deficiency' is discussed. Multiple vitamin therapy should be given in the treatment of undiagnosed encephalopathies in alcoholic patients.

Chromatolysis in alcoholic encephalopathies. Pellagra-like changes in 22 cases.

In 22 patients with alcoholic encephalopathies, chromatolysis similar to that reported in endemic pellagra was found on postmortem examination. No gross macroscopic changes were seen in affected areas and only neurons were involved. The changes consisted of central chromatolysis, seen predominantly in the brainstem, especially in the pontine nuclei, where they were constant, and in the cerebellar dentate nuclei. Nuclei of cranial nerves (mainly the third, sixth, seventh and eighty), the reticular nuclei, arcuate nuclei and posterior horn cells, were also markedly affected. Changes were sometimes seen in the cerebral cortex, the interpeduncular nuclei, the central mesencephalic grey matter, the colliculi, the tenth and twelfth cranial nerve and perihypoglossal nuclei, the gracile and cuneate nuclei and anterior horn cells. This distribution was different from that reported in endemic and 'endogenous' pellagra or in isoniazid-induced pellagra encephalopathy. Central chromatolysis was the only pertinent finding of the CNS examination in 9 cases. In 8 cases, chromatolysis was associated with Marchiafava-Bignami encephalopathy, in 4 cases with Wernicke-Korsakoff encephalopathy, and in 1 other case with both. Mild degeneration of spinal cord tracts was seen in 3 cases. The chromatolysis of alcoholic pellagra did not appear to be a retrograde change related to axonal degeneration. Systemic examination showed liver changes in 15/16 cases. Treatment of these cases had not included niacin. No differences were found between cases given thiamine and pyridoxine and those which had not. Microscopic examination of the pons is essential in alcoholic encephalopathies.

Oculo-facio-skeletal myorhythmia as a cerebral complication of systemic Whipple's disease.

A fifth case of oculomasticatory myorhythmia associated with cerebral Whipple's disease is reported. This peculiar abnormal movement has never been described in association with cerebral dysfunction other than Whipple's disease. The present case exhibited rhythmic convergence of the eyes and synchronous (1-2 Hz) contractions of the masticatory muscles and of the proximal and distal skeletal muscles. These abnormal movements occurred 13 years after the beginning of the disease. They were persistent and unchanged until the death of the patient 3 months later. No treatment was effective to suppress the involuntary movements (clonazepam, baclofen, antibiotics). Associated neurological signs included global supranuclear ophthalmoplegia, facial weakness, bilateral ptosis, absent gag reflex, and intellectual deterioration.

Gustatory hallucinations in epileptic seizures. Electrophysiological, clinical and anatomical correlates.

Of the 718 patients investigated for intractable epilepsy by stereoelectrocencephalographic (SEEG) exploration, 30 (4%) manifested gustatory hallucinations as part of their seizures. In 20 patients, it was possible to make some electrophysiological, clinical and anatomical correlates. Gustatory hallucinations occurred as one manifestation of parietal, temporal or temporoparietal seizures. A brief isolated gustatory hallucination was induced mainly by electrical stimulation of the parietal or rolandic opercula in patients with gustatory seizures, in 1 epileptic patient with parietotemporal epilepsy who had never experienced gustatory hallucinations and in another with temporal lobe epilepsy with no history of gustatory manifestations. The electrically-induced seizures, which included a gustatory hallucination as one of the ictal events, were obtained mainly by stimulation of the hippocampus and amygdala. The associated ictal events of a seizure with gustatory manifestations differed depending upon the origin of the seizure. During parietal seizures, they consisted of staring reactions, clonic contractions of the face, deviation of the eyes and salivation. During temporal lobe seizures, the associated events included mainly oral movements, autonomic disturbances, purposeless movements and epigastric or other abdominal symptoms. Seizures affecting both the infra- and suprasylvian regions were characterized by symptoms of both categories listed above. Emotional disturbances were observed mainly when there was an involvement of the cingulate gyrus. When care was taken to avoid methodological errors in the interpretation of the clinical signs occurring after electrical stimulation, it became clear that gustatory hallucinations in man were related to the disorganization of the parietal and/or rolandic operculum. electrically-induced temporal lobe seizures which included gustatory hallucinations as an ictal event probably spread to the opercular region by a functional reorganization of the connections within these epileptogenic areas.