Neuropathology of Insomnia in the Adult: Still an Enigma! Part 2

REM Sleep

REM sleep system remains hypothetical. It is also due to thalamocortical activity, like slow wave sleep, but in a desynchronised pattern, as it occurs during waking state (McCormick DA and Bal T, 1997; Wehrle R et al, 2007), under the influences of several upper brain stem nuclei. Mechanisms for tonic REM sleep and phasic REM sleep are probably somewhat different : during phasic REM periods, thalamocortical network includes basal forebrain, limbic and parahippocampal areas activity (Nofzinger EA et al, 1997; Wehrle R et al, 2007).

The mechanisms that set on and set off REM sleep have been recently debated, their dysfunction being responsible for several disorders. Reciprocal inhibitory interactions between cholinergic brain stem neurons promoting REM (« REM-on ») and monoaminergic inhibitors « REM-off ») were up to now largely accepted (Siegel J, 2004). Selective lesions of these systems, however, do not seem to affect significantly REM sleep. Cholinergic system may, in fact, modulate rather than initiate this stage. Actually, recent studies in rats showed the existence of mutually inhibitor neurons, « REM-on » in the tegmentum pontis sublaterodorsal nucleus and precoereuleus area, and « REM-off » in ventrolateral periaqueductal grey matter and tegmentum latero-pontis. Each of these two neuronal populations contains interconnected GABAergic neurons. This system of reciprocal inhibition has been called " flip-flop switch ", from electronic binar switch used to proceed quickly from a state to the other (Lu J et al, 2006). The existence, in human, of similar structures as "REM-on" and "REM-off’ found in rats is highly probable. Their precise topography remains hypothetical. However, it has been possible to suggest a human equivalent of the rat sublaterodorsal nucleus and precoeruleus area « REM-on » which needs to be confirmed. The ventrolateral regions of the periaqueductal grey matter and tegmentum lateroponti may correspond to « REM-on » regions (Boeve B et al, 2007). Two "REM-on" glutamatergic neuronal groups may be activated, one projecting toward the basal telencephalon, setting EEG pattern ; the other one projecting to the ventromedial medulla and spinal cord, setting muscle atonia.

Ponto-geniculo-occipital sharp waves (PGO) which precede and accompany rapid eye movements are related to neurons of the mesencephalon tegmentum (rostral part of the alpha locus coeruleus and of the mesopontine nuclei). They project on the lateral geniculate nucleus of the thalamus which is a cortical relay. In human, they are assumed to be located at the pedunculopontine nucleus (Lim AS et al, 2007).

Two motor systems appear implicated. One is responsible for muscular atonia, the other for suppression of motor activity (the last relay being the bulbar gigantocellularis nucleus). The former is characterised by the activation of two neuronal groups, some bearing cholinergic receptors in the locus coeruleus/subcoeruleus areas, the other glycinergic receptors in the magnocellular reticular nucleus (Fuller P et al, 2007; Luppi H et al, 2007).

Sublaterodorsal nucleus could be at the origin of the common final pathway towards spinal interneurons which inhibit muscular tonus. This hypothesis remains to be confirmed (Boeve et al, 2007).

The latter system responsible for suppression of nocturnal movements appears to be influenced by indirect pathways linking midbrain dopamine neurons with pre-motor structures in the mesopontine tegmentum and ventromedial medulla (Rye DB, 2004). Descending dopaminergic neurons from the telencephalon (A11) to the spinal cord may contribute to abnormal movements during sleep.

Schematically, during REM sleep, cholinergic system is active, as it is during waking state, whereas monoaminergic systems are silent, as they are during slow stages of sleep.

In summary: Lesions, in the brain stem, of sublaterodorsal nucleus, rostral part of the alpha locus coeruleus and of the mesopontine nuclei, could affect REM sleep organisation. (Dysfunction of thalamocortical loops or limbic system may also play a role in reducing the amount of REM sleep). Lesions of the noradrenergic locus coeruleus/subcoeruleus, cholinergic pedunculo-pontine nucleus and tegmentum laterodorsal, impair atonia during REM sleep. Lesions are mainly neurodegenerative in nature: progressive supra-nuclear palsy (PSP), Parkinson disease (PD) and Alzheimer disease (AD):

a) In Progressive supra-nuclear palsy (PSP), apart from insomnia, the other sleep disorders include REM sleep behaviour disorder (RBD), and, less frequently, hypersomnia and pseudo-narcolepsia. On sleep records there is a lower percentage of REM sleep (Montplaisir J et al, 1997).

Neuropathological gross findings include severe atrophy in midbrain where it predominates on the tectum, extending to a lesser degree to the pons. Other lesions include loss of pigment in the substantia nigra, and atrophy of the subthalamic nucleus and the superior cerebellar peduncle. Microscopic lesions, which are tauopathies, affect as well some neurons (neurofibrillary tangles in the cell body, neuropil threads in the dendrites) as some glial cells (tufted astrocytes and oligodendrocytic coiled bodies). They widely spread in brain stem and basal telencephalon where they involve several systems implicated in sleep organisation. were unchanged compared with controls. Regions severely involved include substantia nigra (more than 80% of the reported cases), then periaqueductal grey matter, locus coeruleus, and central pontine nuclei (more than 50% of reported cases). Pedunculo-pontine nuclei involvement is variable (Verny M et al, 1996 ; Hauw JJ et Agid Y, 2003). Other injured nuclei are superior colliculi, oculomotor nuclei, locus ceruleus, pontine nuclei, vestibular nuclei, medullary tegmentum, inferior olives and cerebellar dentate nucleus. Nuclei responsible for autonomic regulation, intermediate zone of bulbar reticular formation and gigantocellularis nucleus are the most lesionned area. Other very markedly affected regions include the pontine reticular formation, medial parabrachial nucleus, and nuclei raphe magnus and obscurus. Lateral parabrachial nucleus is less injured (Rub U et al, 2002a). Meso-cortico-limbic dopaminergic projections are relatively spared, which contrasts with the extreme severity of nigro-striatal system lesions, especially for its ventral part (Oyanagi K, 2001).

The lesions of REM "on" and "off’ systems in the brain stem, could explain the reduction of REM percentage on sleep records and REM sleep behaviour disorders and episodes of pseudo-narcolepsy, occurring in the late stages of the disease (Boeve B et al, 2001; Arnulf I et al, 2005).

b) In Parkinson’s disease (PD), REM sleep is often reduced. Other sleep disorders include REM sleep behaviour disorders (RBD), restless legs and periodic limb movement syndrome, hypersomnia and pseudo-narcolepsy (Arnulf I et al, 2005 ; Park M et al, 2006 ; Hausser-Hauw C, 2007).

PD is a synucleinopathy (Duyckaerts C et Hauw JJ, 2003), the spectrum of which comprises Parkinson disease and dementia with Lewy bodies, according to the predominance of signs and topography of the lesions. The lesions (Lewy bodies and fibers immunolabelled by synuclein directed antibodies) involve preferentially the brain stem in Parkinson disease, and the cortex in Lewy body dementia.

Immunohistochemistry of alpha-synuclein allowed Heiko Braak et al (2003) to suggest that the synucleinopathy occurs according to a stereotyped hierarchic temporo-spatial fashion, similar to that described for neurofibrillary degeneration and other tau-associated lesions in Alzheimer disease. They first studied the topography of lesions labelled by anti-synuclein antibody in two series of autopsied cases: i.: clinically characterized Parkinson disease, and ii. brains from people free from neurological symptoms and signs. The synucleinopathy could be restricted either to the olfactory bulb and peduncle or to the medulla. In the former case, the lesions remained confined to the olfactory bulb and had no tendency to spread to adjacent regions. At the opposite, brain stem synucleinopathies always involved the medulla, from which they seemed to spread progressively toward the pons, then ventral mesencephalon, diencephalon, and antero-medial mesocortex of the temporal lobe.

The brain stem is affected very early: At stage I, besides dorsal nucleus of IXth and Xth nucleus, dorsal spinal cord intermediolateral horn, gastro-intestinal nervous system are involved; at stage II, inferior raphe nuclei, magnocellularis reticular formation, among which bulbar gigantocellularis nucleus, and coeruleus-precoeruleus complex are involved. Substantia nigra and ventral tegmental area are involved at stage III (Braak H et al, 2008).

In summary: in PD, Pedunculo-pontine nuclei, Meynert basal nucleus, tubero-mamillary nucleus and oral raphe nuclei involvement could explain REM sleep disorders.

c) In Alzheimer’s disease (AD), REM sleep alterations may not be present early in the disease, and a relationship between the severity of sleep disturbance and the severity of dementia is found (Montplaisir J et al, 1995). Superior and dorsal brain stem regions involvement could explain REM sleep disorders (Parvizi J et al, 2001).

The Structures Responsible for Waking State

Sleep-wake organisation depends on oscillatory connections between sleep and arousal structures through feedback and reentry mechanisms. Thus lesions of structures related to arousal may impair sleep.

The waking state is the result of a depolarisation of thalamocortical and thalamic reticular neurons and enhanced excitability in many pyramidal cells under the release of several different neurotransmitters from limbic system and brain stem nuclei (Steriade M and Timofeev I, 2003).

The cholinergic systems are issued from two main pathways: the basal forebrain (magnocellular formations of the base, among which the basal nucleus of Meynert is the best known), and from the brain stem, originating from the tegmentum laterodorsal and pedunculo-pontine nuclei (also called "meso-pontine" or "peri-brachial") and from the bulbar gigantocellularis nucleus. It stimulates the cortex directly or through the mesencephalon reticular formation or the thalamocortical diffusely projecting nuclei, i.e. intralaminar formations (aspartate/glutamate). It could also stimulate the hypothalamic tubero-mamillary nucleus.

Monoaminergic systems include: histaminergic pathways from the hypothalamic tubero-mamillary nucleus, noradrenergic projections from the locus coeruleus, and serotoninergic pathways from the pontine raphe nuclei. They project directly to the cortex.

The role of dopamine is uncertain. However pharmacological, biochemical and physiological studies suggest that mesocorticolimbic dopamine may help maintain wakefulness (Rye DB, 2004). Pharmacological evidence suggests the involvement of dopamine neurons, especially in the ventral tegmental area (A10), for the control of alertness (Lu J et al, 2002). On the other hand, L-DOPA and dopamine agonists induce sleepiness!

Orexin/hypocretin system: Orexin (or hypocretin) is secreted in neurons of the lateral and posterior hypothalamus, and this system gives projections to the locus coeruleus, tuberomamillary nucleus and raphe nuclei, among others. They are highly excitatory neuropeptide hormones. They strongly stimulate the various brain nuclei including dopamine, norepinephrine, histamine and acetylcholine systems and appear to play an important role in stabilising wakefulness and sleep (Mignot E et al, 2002).

All these systems also give descending projections for control in variations of breathing and muscle tonus associated with the different stages of sleep and wakefulness.

During wakefulness, cholinergic afferent system to the thalamus, monoaminergic afferent systems to the cortex, orexin/hypocretin system widespread afferences, are active ; during slow stages of sleep, they are supposed to be inactive, or strongly inhibited.

Lesions of the waking structures may produce hypersomnia, insomnia or both disorders. Some strokes, brain trauma, limbic encephalitides and Morvan’s fibrillary chorea, several neurodegenerative disorders and prion diseases are examples of sleep and wake disorders occurring after arousal system lesions.

a) Insomnia has been reported, though rarely, with ventral pons and mesencephalon strokes (Garrel S, 1966; Baldy-Moulinier M et al, 1977).Insomnia and hallucinations were also present in 7 patients in association with small vascular lesions of the pontine tegmentum. Insomnia affected both non-REM and REM sleep, appeared in the acute phase and tended to improve with time. Autopsy of one case revealed lesions of the pontis centralis caudalis and pontis centralis oralis nuclei (Forcadas MI and Zarraz JJ, 1994). In another case, sleep and dream suppression followed a lateral medullary infarct (Hobson A J 2002). As a matter of fact, medullary infarcts are exceptionally responsible for insomnia. To our knowledge, it is the only reported case.

b) In severe brain injury responsible for lesions located caudally to the mesencephalon, there is no longer any EEG activity corresponding to sleep (Mangin P et al, 1979). If patients recover from coma, they may suffer from insomnia. A case of insomnia related to post-traumatic pontine lesions was reversed by 5HTP(Guilleminault C et al,1973).

c) Limbic encephalitis is a clinico-pathologic complex of symptoms which merged half a century ago, and the aetiology of which progressively diversified. Initially characterized by symptoms and signs indicating lesions predominant in the limbic system (memory and behaviour troubles, temporal seizures) and by neuropathological lesions suggesting an immunopathologic mechanism in the same territory, it went through many, diversely intricated, periods: viral, paraneoplasic and dysmetabolic.

Corsellis JAN et al (1968) described a paraneoplastic encephalitis of the limbic system developing in patients with systemic cancers, among encephalitides affecting mainly the temporo-cingular areas, the large majority of which were necrotic and of herpetic aetiology. Soon, however, the lesions revealed to be more diffuse than initially thought (extending to other brain areas, and mostly to the diencephalon, cerebellum, brain stem and spinal cord), which allowed to unify a number of clinico-pathologic descriptions («paraneoplastic polioencephalomyelitides ») (Goldbert GJ and Norton AR, 1968 ; Dubas F et al, 1982 ; Rosenfeld MR et al, 2001 ; Dalmau J et al, 2004). Lymphoid cells were found in the cerebral tissue where necrotic lesions were rare or absent. Multiple antibodies against onco-neural antigens (neuromuscular junction proteins, nerve terminal/vesicle-associated proteins, neuronal RNA binding proteins, or neuronal signal-transduction proteins) were found in the blood and the CSF, and were called for example anti HU, anti Yo … (Seeger RC et al, 1979 ; Darnell RB, 1996). On neuropathologic criteria, these encephalitides were grouped together with similar disorders arising in the absence of cancer (Dubas F et al, 1982). In 2004, indeed, Vincent A et al. showed that analogous encephalitides, often unrelated to systemic cancers, were associated with antibodies against either voltage-gated potassium channel or other neuronal membrane antigens. In most cases, MRI abnormalities were seen in the temporal lobe only. In a few cases, however, more diffuse lesions (frontal lobes, insula, cerebellum) were seen. These affections could be improved by reduction of the antibody levels. More recently, it was shown that encephalitides related to ovarian cancer were associated with antibodies to some membrane receptors of N-methyl-D-aspartate, NR1 and 2, and had a favourable outcome under plasma exchange and corticosteroids (Seki M et al, 2008). Limbic encephalitis, which could be linked also to the as yet not understood Rasmussen’s encephalitis and maybe Morvan’s fibrillary chorea, is an expanding concept (Graus F et al, 2008).

Among 130 000 suspected paraneoplastic autoimmunity patients, 80 cases were positive for voltage-gated potassium channel (VGKC) autoantibodies (Tan KM et al, 2008). The pathogenic role of anti VGKC IgG is well known and intravenous immunoglobulins or plasmapheresis are most of the times efficient treatments. For these patients, clinical signs and symptoms included: cognitive alteration, with or without hallucinations, agitation and depression (71%); temporal lobe seizures or extra-temporal seizures, partial or generalized (38%); hypothalamic involvement: hyponatremia and hyperphagia (38%); dysautonomia (33%); myoclonus (29%); peripheral nervous system involvement (neuromyotonia, myokimia, cramps, sensitive or motor neuropathy, Morvan’s syndrome (25%) ; extrapyramidal signs, tremor, rigidity, akinesia, chorea (21%); cranial nerves involvement, diplopia, dysarthria, dysphagia, facial palsy, facial hemispasm (19%). A cancer occurred in 33% of the cases, another autoimmune disorder in 33% (thyroiditis and diabetes).

Sleep disorders occurred in 26% of the cases, including hypersomnia (13%) and insomnia (14%).Brain MRI showed T2/FLAIR hyperintensity in mesial temporal regions, unilateral in 8 cases or bilateral (12 cases), hyperintensity of the corpus callosum (1 case) and multifocal cortical hyperintensity (1 case) or generalised cortical atrophy (4 cases).

The lesions of limbic encephalitis, whatever the mechanism (paraneoplastic or not) may be quite inconspicuous at gross examination, but, when severe, they can induce brain atrophy. They are often most pronounced in the limbic system, being bilaterally located in the hippocampus, medial temporal lobes, amygdaloid nuclei, mamillary bodies and orbital cortex. Histologic study reveals an interstitial infiltration of T-cells which can be grouped into clusters, cuffing the small vessels or dispersed in the grey mater. The T cells may be immunolabelled with antibodies against various antigens. The white matter is characteristically spared, and demyelination is not conspicuous. The remainder of the hemispheres is usually spared. (for review, see Dalmau J, 2008 ; Graus F et al, 2008)

Other causes of limbic encephalitis, such as viral encephalitis (herpesvirus 6) in stem cell transplant recipients have been observed also. In five cases, clinical signs were short-term memory loss, insomnia and seizure activity in the temporo-basal areas. MRI showed increased hippocampal T2 and FDG-PET showed increased hippocampal glucose uptake (Wainwright MS et al, 2001).

In summary: In limbic encephalitis, insomnia seems to be related to involvement of the limbic system, but the exact mechanism remains unexplained.

d) Morvans’s fibrillary chorea is a rare autoimmune disorder clinically characterized by acute and severe insomnia associated with anxiety, tachycardia, profuse perspiration and neuromyotonia (Serratrice G and Azulay JP, 1994 ; Hudson LA et al., 2008). The clinical course is benign in about 90% of the cases. In the remainder, the disease evolves into death in several weeks or months. Sleep is absent in the four months preceding death in malignant cases (Fisher-Perroudon et al, 1974) or is severely impaired if the evolution is more benign (Silber et al, 1995). A case of Morvan’s syndrome occurred in a 76-year-old patient suffering from pulmonary adenocarcinoma and antibodies to VGKC. He was confused, restless and disoriented in time and space. When left alone, he would slowly lapse into a stuporous state with dreamlike episodes (enacted dreams) but was never asleep. Marked hyperhidrosis and excessive salivation and lacrimation were present as well as diffuse muscle twitching and spontaneous myoclonus. A 24-hour-video polysomnography showed that spindles, K complexes and delta waves were absent. EEG was dominated by "wakefulness" and "subwakefulness" alternating or intermingled with short atypical REM sleep phases, characterized by loss of muscle atonia (Liguori R et al, 2001). Actually, sleep records show similarities between Morvan’s chorea and fatal familial insomnia (Provini F et al, 2008). Fundamentally, the neuropathology of Morvan’s chorea is not understood. It could be related to an humoral immunopathologic disorder. In the case of Liguori R (2001) the brain was grossly unremarkable. Histological examination was also unremarkable. Direct immunohistochemistry on frozen sections of the post-mortem brain tissue showed areas of substantial leakage of IgG in the thalamus and striatum and diffusion into the parenchyma of antibodies bound to neuronal cells. In sections of cortex, there was evidence of antibodies in the blood vessels with only mild leakage into the surrounding tissue. However, these findings are non specific, and no control case was studied (Liguori R et al, 2001).

e) In Fatal Insomnia, involvement of the cortex, when seen, is remarkably mild. When present, it includes slight spongiform change and gliosis often confined to the limbic cortex: orbitofrontal cortex, anterior gyrus cingulus and the entorhinal cortex, in short duration cases. In long duration cases, isocortical spongiform change and gliosis may be widespread, and even seen in the cerebellum, but they are always most prominent in the corticolimbic regions, including hippocampus and entorhinal cortex. According to Lugaresi E (1998), the degeneration of the thalamic nuclei, involved in the circuit of gyrus cinguli and orbitofrontal cortex to hypothalamus and reticular brainstem formation, releases hypothalamus and brainstem from corticolimbic control, and may result in loss of sleep.

f) In neurodegenerative disorders, waking structures as well as sleeping structures are involved so that hypersomnia as well as insomnia are frequent. The part played by lesions of the waking structures is difficult to assess.

• In PSP lesions of waking network, either cholinergic (Javoy-Agid F, 1994) or adrenergic, are precocious. Cholinergic nuclei of the brain stem are severely affected (Warren NM et al, 2005).

• In PD there is massive neuronal loss in intra-laminar thalamic nuclei, which are important relays of the cholinergic network for waking state (Henderson J et al., 2000) and in the thalamo-limbic nuclei (Rub U et al, 2002b). The limbic system is affected earlier, at Braak’ stage III, where the amygdala, the limbic cortex (entorhinal cortex and ammonian fields) are involved. In contrast, the cingular cortex is spared until stages V and VI. Lateral hypothalamic areas are involved at a precocious stage with orexin/hypocretin neuronal loss, as seen by immunohistochemistry, starting at stage I (23%) and being at its zenith at stage V (62%) (Thannickal TC et al, 2007).

• In AD, various structures in the brain stem implicated in waking network and "allostatic" influences are precociously injured : initial tauopathy occurs in the peri-rhinal and entorhinal areas, locus coeruleus (German DC et al, 1992), raphe pontine nuclei (Rub U et al, 2000), medial part of the substantia nigra (Uchihara T et al, 1992), and tegmento-pontine reticular nuclei.

• In HD, in the limbic system, the neuronal density in the granule cells of the CA1 area of the hippocampus is significantly reduced (Braak H and Braak E, 1982 ; Spargo E et al, 1993). The cellular expression of dopamine D1 and D2 receptor mRNAs was investigated in the post-mortem human caudate nucleus of control cases and pathologically confirmed cases of HD. For D2 receptor m-RNA, the number of detectable D2-positive medium-sized cells decreased with increasing pathology. By contrast, for D1 receptor mRNA, despite a decrease in the number of D1 mRNA-positive cells detected, the average cellular expression of D1 mRNA was markedly reduced only in grade 1 HD and then increased with increasing pathology, presumably reflecting the relative survival of D1-expressing striatal interneurons (Augood SJ et al, 1997). In the brain stem, in situ hybridation revealed extensive loss of tyrosine hydroxylase (TH) mRNA, the rate-limiting enzyme for dopamine biosynthesis, and decreased dopaminergic cell size in the substantia nigra. TH-immunoreactive protein was reduced in human grade 4 HHD substantia nigra by 32% compared to age-matched controls (Yohrling GJ et al, 2003). In summary, in HD limbic system involvement and reduced striatal and nigral dopamine may play a role in insomnia.

The Structures Responsible for "Need for Sleep"

There is a representation of motivational drives, especially for sleep and food intake, in mesial cortex, medial thalamus, hypothalamus and midbrain (Sewards RV and Sewards MA, 2003). Motivational drives could be impaired by numerous allostatic factors and by organic lesions. Actually we don’t know why we need to sleep but there is an homeostatic system that fix sleep-wake cycles. The homeostatic facet of sleep-wake regulation correspond to regulation of "sleep need" which increases during wakefulness and decreases during sleep. The neurochemical mechanisms underlying sleep homeostasis are poorly understood, but there is compelling and convergent evidence that adenosinergic neurotransmission plays a role in nonREM homeostasis in human (Landolt HP, 2008). Adenosine release in the brain may occur when energy-storing molecules containing adenosine triphosphate (ATP) are broken down to provide energy for cell activity. When brain cells burn ATP, adenosine builds up. During long sleep deprivation periods, the over regulation of A1 adenosine receptors takes place not only at the basal telencephalon level but also over the whole cortex (McCarley R, 2007).

Some other regions react to sleep deprivation. These structures, the lesions of which causes insomnia in rats (Lu J et al, 2000), include ventrolateral preoptic area, as shown in rats and cats using the c-fos protein immunohistochemical method (Semba K et al, 2001). It has to be recalled that when a gene called c-fos, present in people and mice, is knocked out by genetic engineering, the mice act like human insomniacs, they have difficulty getting to sleep and staying asleep. Ventrolateral periacqueductal grey matter (Landis CA et al, 1993) and an area within anterior cingulated/medial prefrontal cortex are also activated after prolonged sleep deprivation (Cirelli C et al, 1995). In human, sleep deprivation causes the activation of a site within area 32 of medial prefrontal cortex (Clark CP et al, 2001). The thalamic representation of the need for sleep is probably located in the posterior part of the paraventricular thalamic nucleus, since neurons in this part of the nucleus are activated by sleep deprivation (Cirelli C et al, 1995; Semba K et al, 2001). In rats, this nucleus receives afferent projections from the suprachiasmatic nucleus, ventrolateral preoptic area, and ventrolateral periacqueductal grey matter (Krout KE et al, 2000).

The regions responsible for need for sleep in human are not totally established. Some of them correspond to structures involved in sleep onset and maintenance, other to structures more related to waking state (limbic system and frontal cortex). They may thus give explanation for the occurrence of insomnia related to waking state related structures lesions. Some frontal tumors, maybe restless legs syndrome and basal ganglia disorders responsible for a reduction in adenosine could be cited as examples of insomnia related to loss of need for sleep.

a) Rare cases of insomnia related to frontal tumors have been described. A 53-year-old man presented with insomnia for the previous 3 months. Psychological tests showed regression and schizophreniform and moderate organic deterioration signs. Neuropsychological testing revealed no deficit. MRI disclosed a presumed low-grade glioma or a dysgenetic tumor in the posterior part of the left gyrus rectus extending to the subcallosal area and the septal region, displacing the anterior cerebral artery. Polysomnography showed fragmented sleep with short deep slow wave sleep and no or little REM sleep. K-complexes and sleep spindles were present. Majority of sleep was unstable with high rate of cyclic alternating pattern (Szucs A et al, 2001). In another case, a right frontal lobe gliosarcoma induced sleep disturbance for 4 months and some headache and memory changes in a 79 year-old woman. The precise localisation of the tumor is unknown (Paueksakon P et al, 2003). In a case of nasal-subfrontal giant schwannoma, the patient presented with a year-long history of increasingly severe headache associated with insomnia. No neurological deficit was recorded except for anosmia (Bezircioglu H et al, 2008).

b) Restless legs syndrome (RLS) is a sensorimotor disorder with a profound impact on sleep, inducing refractory insomnia, fatigue and sleepiness during the day. It affects both men and women, with a prevalence in the general population of 5% to10% (Berger K et al, 2004). RLS is characterized by an urge to move the legs or other parts of the body, accompanied by uncomfortable sensations. Symptoms occur during periods of rest and have a circadian peak of expression in the evening and at night. RLS is at times genetic autosomal dominant.The pathophysiology of RLS remains unclear, but there is evidence that impairment of brain iron availability and hypofunctioning of the brain dopaminergic system, play an important role. MRI metrics are suggestive of subnormal iron content in the substantia nigra (SN). T2 relaxation time values are higher in SNr than in SNc suggesting a higher iron content in SNc. The whole brain fMRI study evaluating patients with RLS during active dorsiflexion-plantar flexion of the foot show that only patients, and not controls, activate the thalamus, putamen, middle frontal gyrus and cingulated gyrus. Patients have higher activation of the dorso-lateral prefrontal cortex (Astrakas LG et al, 2008).TEMP and SPECT brain imagery did not show difference in presynaptic dopamine fixation in basal ganglions in RLS patients as compared to control group (Mrowkra M et al, 2005). TEP scan showed only slight reduction of presynaptic dopamine in the caudate nucleus and putamen (Ruottinen HM et al, 2000) or no difference at all (Trenkwalder C et al, 1999). The diencephalo-spinal dopaminergic pathway A11 is probably more important than the striatal dopamine in RLS physiology (Trenkwalder C et al, 2005).The genetic studies showed the association of several variants of the NOS1 (located at the level of the locus RLS1) with RLS. This result implicates that the system NO/arginine plays a role in RLS physiopathology. NOS1 gene is involved in the control of sleep-wake cycles and in the modulation of dopaminergic transmission (Winkelmann J et al, 2008).Autopsy studies in patients with early-onset RLS have demonstrated decreased H-ferritin and normal L-ferritin (usually stocked in oligodendrocytes) in the SN. Moreover transferrine fixation is increased in neuromelanine cells at the same times as transferrine receptors are reduces in theses cells, which suggests redistribution of iron toward cells that do not feed neurons (Connor JR and al, 2003). No autopsy in patients with late-onset RLS are available.In summary, insomnia occurring in RLS syndrome may be due to the activation of the dorso-lateral prefrontal cortex. It also could be related to an hypofunction of brain dopamine which is probably involved in sleep-wake cycles.

c) A case of bilateral globus pallidus lesion due to hypoxia induced severe chronic insomnia. Acute mountain sickness occurs when someone move quickly to high altitude. Low oxygen partial pressure induces cerebral oedema responsible for loss of consciousness and coma. In one case, a 56-year-old female patient suffered severe chronic insomnia as the unique symptom following acute mountain sickness. MRI showed bilateral pallidus lesions (Shiota J et al, 1990). Globus pallidus is a part of the basal ganglia mainly involved in motor control, it is not traditionally associated with sleep organisation. Bilateral globus pallidus lesion usually change emotional and motivation but not sleep (Vijayaraghavan L et al, 2008). However, it may play a role in motor control of non-REM sleep through its connection with the fronto-central cortex during sleep (Salih F et al, 2009). The distribution of adenosine A2A, involved in sleep homeostasis is restricted in the basal ganglia (Kase H, 2001) so that a lesion to globus pallidus may theoretically reduce need for sleep.

General Influences (« Allostatic »)

Various factors could overwhelm these regulatory systems. They include multiple stimuli, the best known being stress. Depression, systemic diseases and illness-related discomfort, drugs, alcohol, lack of light, are other very frequent factors inducing insomnia.

Visceral sensory systems and autonomic regulatory neurons are clearly implicated, but a lot remains to be clarified in this field. Projections toward supra-chiasmatic nucleus, ventro-lateral preoptic nucleus and orexin neurons of the cortical limbic system, for instance, have been advocated (Saper C et al, 2005). The role of the thalamic limbic system (anterior and dorso-medial areas), part of the "central autonomic network" is also obvious. It is especially important in FFI (Provini F et al, 2005). Hormonal influences, the network of hypnogenic substances (VIP, somatostatine, CLIP or ACTH 18-39) and other molecules (prostaglandine D2, adenosine) (Huang Z et al, 2007; Bennaroch E, 2008) are implicated in these regulatory systems.

These influences are not easy to illustrate but may play an important role in the occurrence of insomnia in normal persons and in those suffering from brain lesions, making clinicopathological correlations difficult.

Discussion and Conclusion

Insomnia is theoretically induced by lesions of the structures implicated in sleep. However, structures involved in sleep and wake are so intimately interconnected that insomnia related to a brain lesion is rare and almost never an isolated symptom (Autret A et al, 2001).

One methodological problem related to insomnia is the lack of sleep records. Sleep records are more often prescribed for hypersomnia or parasomnias than for insomnia. The symptom of insomnia is even not mentioned in many patients charts. Insomnia is considered as a "soft sign", related to so many allostatic factors that its description doesn’t bring much interest. At the opposite, hypersomnia, REM-sleep behaviour disorders, periodic limb movements are much more taken into consideration.

Clinicopathological correlations are done according to the current knowledge about sleep and wake mechanisms. This knowledge is far from being accurate and is in constant evolution. For instance, the discovery of orexin/hypocretin system, few years ago, modified the known pathways of waking network and threw light on narcolepsy mechanisms. In the present paper, several levels or sleep organisation were considered in a classical hierachic manner : hypothalamus that sets schedule for sleep, thalamocortical bundles that set slow waves sleep, limbic system and frontal areas more involved in waking state and need for sleep, and brain stem nuclei responsible for REM-sleep organisation.

With hypothalamic lesions, insomnia and delayed sleep syndrome occur when anterior hypothalamus is lesionned.

Thalamo-cortical activity is modulated by limbic system and by several nuclei of the hypothalamus and brain stem, involved in sleep or in wakefulness. Thalamo-cortical activity is thus involved in alertness, waking state, slow sleep, and REM sleep, so that lesions involving thalamus, cortex, or thalamocortical bundles could induce altered states of consciousness, as well as insomnia and/or hypersomnia. Thalamic lesions, whether infectious, degenerative, ischemic, tumourous or others, never keep within the boundaries of selective thalamic nuclei, so that sleep related clinicopathological correlations are variable from patients to patients.

The hypothesis of Lugaresi is that limbic cortex exerts an inhibitory control on the entire neuronal network regulating sleep and wakefulness (Lugaresi et al, 2004). According to the literature, the role of the limbic system is not so clear. It seems more involved in arousal and in phasic REM sleep than in sleep organisation. However fMRI shows significant BOLD signal changes in relation to slow wave sleep in specific brain areas including inferior and medial frontal gyrus, parahippocampal gyrus, precuneus, posterior cingulated cortex, pontomesencephalic tegmentum and cerebellum (Dang-Vu TT et al, 2008). Limbic system, inferior and medial frontal gyrus, and cerebellum may thus be implicated in sleep organisation, or at least, be strongly inhibited during slow wave sleep. Actually fMRI changes are dependant upon an hypermetabolism which could be inhibitory or excitatory in nature.

The lesions of the limbic system could disorganise the sleep-wake circuit and induce insomnia (or hypersomnia).

In the brain stem, the density of nuclei or tracts involved in sleeping or waking is so high that the risk that a lesion could impair only one group of nuclei is low. In Steele-Richardson’s and Parkinson’s diseases, insomnia is frequent but patients may also suffer from daytime hypersomnia and from several other sleep disorders. Strokes of the ventral pons and mesencephalon could lead to insomnia, probably by a dysfunction of the raphe nuclei (involved in arousal). With regard to traumatic lesion, clinicopathological correlations are poor for lesions are widespread and seldom localised.

This schematic division is probably a caricature of genuine sleep organisation. A lot remains to discover. For instance, the role in sleep organisation of the striatum, and of several other structures, is still unknown.

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