The neuroanatomy of sleep. Considerations on the role of the thalamus in sleep and a proposal for a caudorostral organization

This review synthetizes the most important historical contributions in sleep anatomy and the pioneer discoveries in sleep medicine in the light of our clinical observations in Fatal Familial Insomnia FFI, a genetic prion disease. Together with Morvan's chorea and Delirium Tremens, FFI is characterized by inability to sleep with severe loss of sleep spindles and delta sleep, with preserved presleep behaviour and abnormal REM sleep, associated with motor and autonomic overactivation. We labelled this pattern as Agrypnia Excitata AE. AE is due to dysfunction in thalamolimbic circuits, which emphasizes the key role of the thalamus in sleep physiology and indicates that the anatomo-functional substrate of stage 1 non-REM sleep differs from that generating slow-wave-sleep SWS, spindle and delta activity. Accordingly, the sleep-wake cycle in man should be conceptualized as consisting of 5 different behavioural and electrophysiological distinct states: active wakefulness, quiet wakefulness, drowsiness or stage 1 non-REM, SWS which incorporates spindle and delta sleep and REM sleep. An intricate neuronal network extending from the caudal brainstem to the forebrain controls these different wake and sleep behaviours with several, at least three distinct generators (AU)

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Insomnia associated with thalamic involvement in E200K Creutzfeldt-Jakob disease.

BACKGROUND: Insomnia with predominant thalamic involvement and minor cortical and cerebellar pathologic changes is not characteristic of familial Creutzfeldt-Jakob disease (CJD) but is a hallmark of fatal familial insomnia. OBJECTIVE: To report a 53-year-old woman with intractable insomnia as her initial symptom of disease. METHODS: The authors characterized clinical, pathologic, and molecular features of the disease using EEG, polysomnography, neurohistology, Western blotting, protein sequencing, and prion protein (PrP) gene (PRNP) analysis. RESULTS: The patient developed dysgraphia, dysarthria, bulimia, myoclonus, memory loss, visual hallucinations, and opisthotonos, as well as pyramidal, extrapyramidal, and cerebellar signs. Polysomnographic studies showed an absence of stages 3 and 4, and REM. She died 8 months after onset. On neuropathologic examination, there was major thalamic involvement characterized by neuronal loss, spongiform changes, and prominent gliosis. The inferior olivary nuclei exhibited chromatolysis, neuronal loss, and gliosis. Spongiform changes were mild in the neocortex and not evident in the cerebellum. PrP immunopositivity was present in these areas as well as in the thalamus. PRNP analysis showed the haplotype E200K-129M. Western blot analysis showed the presence of proteinase K (PK)-resistant PrP (PrP(sc)) with the nonglycosylated isoform of approximately 21 kd, corresponding in size to that of type 1 PrP(sc). N-terminal protein sequencing demonstrated PK cleavage sites at glycine (G) 82 and G78, as previously reported in CJD with the E200K-129 M haplotype. CONCLUSIONS: Insomnia may be a prominent early symptom in cases of CJD linked to the E200K-129M haplotype in which the thalamus is severely affected.

Fatal familial insomnia: clinical features and molecular genetics.

Fatal familial insomnia (FFI) is an autosomal dominant prion disease clinically characterized by inattention, sleep loss, dysautonomia, and motor signs and pathologically characterized by a preferential thalamic degeneration. FFI is linked to a missense mutation at codon 178 of the prion protein gene, PRNP, coupled with the presence of the codon methionine at position 129, the locus of a methionine-valine polymorphism. Homozygotes at codon 129, expressing methionine also in the nonmutated allele, have a shorter disease course (often less than 1 year), prominent sleep and autonomic disturbances at disease onset, and pathology restricted to the thalamus. Heterozygotes at codon 129, expressing valine in the nonmutated allele, have a longer disease course (often longer than 1 year), ataxia and dysarthria at disease onset, and lesions widespread to cerebral cortex. Both in the thalamus and in the cortex, the limbic structures are those most consistently and severely involved: the anterior ventral and mediodorsal thalamic nuclei, the cingulate gyrus, and the orbitofrontal cortex. FFI is thus a prion disease selectively damaging the thalamocortical limbic structures. Loss of sleep, sympathetic hyperactivity, and flattening of vegetative and hormonal circadian oscillations characterize FFI and result from a homeostatic imbalance caused by the interruption of the thalamocortical limbic circuits, the phylogenetically most advanced structures involved in the control of the sleep-wake cycle and the body's homeostasis. The selective atrophy of the limbic thalamus that characterizes FFI might be due to the binding of FFI toxic PrP or PrPres to specific receptors on thalamolimbic neurons.

The pathophysiology of fatal familial insomnia.

The key clinical aspects of FFI, i.e. hypovigilance and attention deficit, inability to generate EEG sleep patterns, sympathetic hyperactivity and attenuation of vegetative and hormonal circadian oscillations, are related to selective atrophy of the anteroventral and mediodorsal thalamic nuclei. These nuclei constitute the limbic part of the thalamus interconnecting limbic and paralimbic regions of the cortex and other subcortical structures in the limbic system including the hypothalamus. The hypothalamus released from cortico-limbic control is shifted to a prevalence of activating, as opposed to deactivating, functions including loss of sleep, sympathetic hyperactivity and the attendant attenuation of autonomic circadian and endocrine oscillations. These findings document that the limbic thalamus has a strategic position in the central autonomic network running from the limbic cortical regions to the lower brain stem which regulates the body's homeostasis in an integrated fashion.

Molecular pathology of fatal familial insomnia.

Fatal familial insomnia (FFI) is linked to a mutation at codon 178 of the prion protein gene, coupled with the methionine codon at position 129, the site of a methionine/valine polymorphism. The D178N mutation coupled with the 129 valine codon is linked to a subtype of Creutzfeldt-Jakob disease (CJD178) with a different phenotype. Two protease resistant fragments of the pathogenic PrP (PrPres), which differ in molecular mass, are associated with FFI and CJD178, respectively, suggesting that the two PrPres have different conformations and hence they produce different disease phenotypes. FFI transmission experiments, which show that the endogenous PrPres recovered in affected syngenic mice specifically replicates the molecular mass of the FFI PrPres inoculated and is associated with a phenotype distinct from that of the CJD178 inoculated mice, support this idea. The second distinctive feature of the FFI PrPres is the underrepresentation of the unglycosylated PrPres form. Cell models indicate that the underrepresentation of this PrPres form results from the PrP dysmetabolism caused by the D178N mutation and not from the preferential conversion of the glycosylated forms. Codon 129 on the normal allele further modifies the FFI phenotype determining patient subpopulations of 129 homozygotes and heterozygotes: disease duration is generally shorter, insomnia more severe and histopathology more restricted to the thalamus in the homozygotes than in the heterozygotes. The allelic origin of PrPres fails to explain this finding since in both cases FFI PrPres is expressed only by the mutant allele. Despite remarkable advances, many issues remain unsolved precluding full understanding of the FFI pathogenesis.

Clinical and brain bioenergetics improvement with idebenone in a patient with Leber's hereditary optic neuropathy: a clinical and 31P-MRS study.

We used phosphorus magnetic resonance spectroscopy (31P-MRS) to study in vivo brain and muscle bioenergetics in a male patient with Leber's hereditary optic neuropathy (LHON) and mtDNA mutation at 11,778 bp who developed spastic paraparesis with white matter lesions on brain MR imaging. The study was performed before and during treatment with idebenone (135 mg t.i.d.) and after withdrawal. Clinical amelioration and worsening were associated with parallel changes in brain and skeletal muscle bioenergetics following the administration or withdrawal of idebenone. Reversal of paraparesis by idebenone was paralleled by normalization of 31P-MRS, serum lactate and central motor conduction. Extra-ocular neurological dysfunction in LHON may be amenable to treatment by appropriate quinones.

Sleep-wake cycle abnormalities in fatal familial insomnia. Evidence of the role of the thalamus in sleep regulation.

Alterations in sleep organization were longitudinally studied in 6 new cases of fatal familial insomnia (FFI) by 24 h polygraphic recording. All patients showed an early reduction in sleep spindles and K complexes, and a drastic reduction in total sleep time and disruption of the cyclic sleep organization. Complete abolition of NREM sleep and persistence of only brief residual periods of REM sleep without atonia were features characteristic of the 3 patients with a short (less than 1 year) clinical course, and lacking in the 3 cases with a longer (more than 2 years) disease course. In the latter, sudden transitions from waking to NREM or REM sleep occurred, sometimes recurring periodically. Our findings confirm that impairment of sleep-wake regulation is a consistent distinctive feature of FFI.

Fatal familial insomnia and familial Creutzfeldt-Jakob disease: clinical, pathological and molecular features.

Fatal familial insomnia (FFI) and a subtype of familial Creutzfeldt-Jakob disease (CJD178) are two prion diseases that have different clinical and pathological features, the same aspartic acid to asparagine mutation (D178N) at codon 178 of the prion protein (PrP) gene, but distinct genotypes generated by the methionine-valine polymorphism at codon 129 (129M or 129V) in the mutant allele of the PrP gene. The D178N, 129M allele segregates with FFI while the D178N, 129V allele segregates with CJD178. The proteinase K resistant PrP (PrPres) isoforms present in FFI and CJD178 differ in degree of glycosylation and size. Thus, the amino acid, methionine or valine, at position 129 of the mutant allele, in conjunction with D178N mutation results in significant alterations of PrPres in FFI and CJD178. The 129 polymorphic site also exerts influence through the normal allele: the course of the disease is shorter in the patients homozygous at codon 129 and other minor but consistent phenotypic differences occur between homozygous and heterozygous FFI patients. The comparative study of PrPres distribution in FFI homozygotes and heterozygotes at codon 129 has lead to the conclusion that the phenotypic differences observed between these two FFI patient populations may be the result of different rates of conversion of normal PrP into PrPres, at least in some brain regions.

31P-magnetic resonance spectroscopy in migraine without aura.

We investigated 22 patients with migraine without aura, all drug-free and in headache-free periods, by means of 31P-magnetic resonance spectroscopy (MRS) of brain and muscle. Brain 31P-MRS showed significantly low phosphocreatine, increased adenosine diphosphate, and decreased phosphorylation potential. There was a slow rate of phosphocreatine recovery after exercise in the muscle of 12 of 22 patients. Energy metabolism is abnormal in migraine without aura, as previously demonstrated in patients with migraine stroke and migraine with aura.

[18F]FDG PET in fatal familial insomnia: the functional effects of thalamic lesions.

We used [18F]2-fluoro-2-deoxy-D-glucose ([18F]FDG) and positron emission tomography (PET) to study regional cerebral glucose utilization (rCMRglc) in four patients with fatal familial insomnia (FFI), a prion disease with a mutation at codon 178 of the prion protein gene. Two patients, presenting only with insomnia and dysautonomia, had a prominent and, in one case, selective thalamic hypometabolism. The remaining two cases presented a more complex clinical picture with multiple neurologic deficits, with both thalamic and widespread brain hypometabolism involving the majority of cortical structures, basal ganglia, and the cerebellum. This widespread pattern was present in the early stage of the disease and showed significant worsening as the disease progressed in one patient examined twice. The thalamic hypometabolism, consistently found with PET in FFI patients, is in agreement with the neuropathologic findings and is a hallmark of the disease.

The thalamus and insomnia.

The thalamus has been shown to play a primary role in the organization of the wake-sleep rhythm. This was confirmed by experimental findings in which athalamic cats displayed severe and persistent insomnia, and by clinical observations that thalamic degeneration, with selective or prevalent involvement of the anterior or dorsomedial nuclei, virtually abolishes the ability to generate electroencephalographic sleep patterns. Loss of sleep has been associated with autonomic (tachycardia, hyperthermia, tachypnea) and endocrine (increased plasma cortisol and catecholamine levels) activation. The clinical and experimental evidence suggests that degeneration of the anterior and dorsomedial thalamic nuclei (so-called "visceral thalamus") leads to permanent loss of autonomic and endocrine homeostasis and restorative body processes by relieving the hypothalamus of cortical inhibitory control.

"Fatal familial insomnia": neuropsychological study of a disease with thalamic degeneration.

Fatal Familial Insomnia (FFI) is an inherited disease characterized clinically by sleep, autonomic and motor disturbances and pathologically by marked atrophy of the anterior and dorsomedial nuclei of the thalamus. The neuropsychological study of three cases of FFI showed: (1) a progressive disturbance of attention and vigilance, (2) a memory deficit with lability of mnesic traces and difficulty in manipulation and ordering of events, suggesting an alteration of working memory and (3) a deficit of frontal abilities with impairment in planning and prevision of events but preservation of general intelligence.

Abnormal brain and muscle energy metabolism shown by 31P magnetic resonance spectroscopy in patients affected by migraine with aura.

We studied brain and muscle energy metabolism by phosphorus 31 magnetic resonance spectroscopy (31P-MRS) in 12 patients affected by migraine with aura (classic migraine) in interictal periods. Brain 31P-MRS disclosed a low phosphocreatine content in all patients, accompanied by high adenosine diphosphate concentration, a high percentage of V/Vmax (adenosine triphosphate), and a low phosphorylation potential--features showing an unstable state of metabolism in classic migraine. Abnormal muscle mitochondrial function, in the absence of clinical signs of muscle impairment, was present in nine of the 12 patients examined.

Muscle mitochondrial DNA deletion and 31P-NMR spectroscopy alterations in a migraine patient.

A 40-year-old female suffering from recurrent migrainous strokes is reported. She did not show any muscle weakness or wasting. Ragged red and cytochrome c oxidase negative fibers were present in the muscle biopsy. Muscle mitochondrial DNA analysis showed a 5 kb deletion, without a point mutation at nucleotide pair 3243 in the mitochondrial tRNALeu(UUR) gene. Phosphorus nuclear magnetic resonance spectroscopy of brain and gastrocnemius muscle showed a defective energy metabolism in both organs. An increased inorganic phosphate to phosphocreatine ratio due to a decreased phosphocreatine content was found in the occipital lobes, while an abnormal work-energy cost transfer function and a low rate of phosphocreatine post-exercise recovery were found in the muscle.

Complicated migraine studied by phosphorus magnetic resonance spectroscopy.

The brain and skeletal muscle of eight adult patients with migraine with prolonged auras or migraine strokes leaving a permanent hemianopic defect were studied by phosphorus magnetic resonance spectroscopy. Biochemical assays performed on muscle biopsy and platelets had revealed abnormal mitochondrial enzyme activities. Brain magnetic resonance spectroscopy showed an abnormally low phosphocreatine to inorganic phosphate ratio in all patients, apparently due to decreased phosphocreatine and increased inorganic phosphate contents. Muscle phosphorus magnetic resonance spectroscopy showed low recovery from exercise in seven patients. Three patients had an increased phosphocreatine/inorganic phosphate ratio at rest, and the exercise transfer characteristics were abnormal in four patients for relatively low levels of exercise. The mitochondrial metabolic defects present in platelets and muscle of complicated migraine patients are therefore also expressed in the brain.

The thalamus participates in the regulation of the sleep-waking cycle. A clinico-pathological study in fatal familial thalamic degeneration.

Loss of slow-wave sleep (SWS) and abnormal REM sleep behaviour were associated with a lack of vegetative and endocrine circadian rhythms in a patient with fatal familial thalamic degeneration. Physiological EEG patterns of SWS (spindles, K complexes, delta activity) were absent. EEG fast rhythms could not be induced by barbiturate or benzodiazepine administration. RO 15-1788, a benzodiazepine antagonist, induced arousal and awakened the patient from coma. Pathological findings were severe neuronal loss restricted to the anterior and dorso-medial thalamic nuclei. The clinical and electrophysiological data, together with the pathological correlates, emphasize the role played by the thalamus in the regulation of the sleep-waking and other circadian cycles.

Inhibitory phenomena during NREM sleep related to auditory stimuli and epileptic spikes.

Auditory stimuli induce facilitation of the H reflex during wakefulness (so-called audio-spinal influence). In 5 subjects we found that, during SWS, the same stimuli may provoke phasic losses of muscle tone and H reflex inhibition. Similar losses of tone and H reflex inhibition were related to epileptic spikes in 3 patients.

Peripheral neuropathy due to gasoline sniffing - A case report.

A case of polyneuropathy in a 14-year-old boy, a chronic gasoline sniffer, is reported. Clinical and electromyographic examination showed a symmetrical motor involvement, mainly distally and in the lower limbs. A sural nerve biopsy showed only slight changes, both of axonal and demyelinating type. The role of gasoline toxic substances in the etiology of this rare polyneuropathy is discussed.