Electrophysiological brainstem testing in the diagnosis of reversible brainstem ischemia

The aim of this study was to evaluate the sensitivity of multimodal electrophysiological brainstem testing in the diagnosis of clinically suspected reversible ischemic deficits of the brainstem compared with diffusion weighted MR imaging. We investigated 158 consecutive patients presenting with signs of acute brainstem dysfunction. Serial electrophysiological brainstem tests including masseter reflex, blink reflex, masseter inhibitory reflex, AEP, MEP, EOG and the oculoauricular phenomenon were applied. In 14 of the 158 patients neurological deficits resolved in less than 24 hours, which was suggestive of a transitory ischemic attack (TIA), 19 patients had brainstem signs for more than 24 hours but less than 1 week, suggestive of a reversible ischemic neurological deficit (RIND). Electrophysiological data indicated acute functional brainstem lesions in 54,5 % of patients with transient clinical brainstem impairment. Lesion detection rate was significantly higher when combining electrophysiological data and MRI (60,4 %) than using acute brainstem abnormalities in diffusion weighted MRI alone (39,4 %). We conclude that diffusion weighted MRI and electrophysiological brainstem testing are complimentary sensitive indicators of acute brainstem lesions in patients with reversible neurological deficits. Correct identification of brainstem ischemia influences the therapeutic regimen and may improve patient outcome. Received: 5 November 2001 Received in revised form: 28 January 2002 Accepted: 1 February 2002     

Hypersomnia in bipolar depression: a comparison with narcolepsy using the multiple sleep latency test

OBJECTIVE: This study characterized objectively the hypersomnia frequently seen in the depressed phase of bipolar affective disorder. On the basis of previous work in sleep and affective disorders, it has been hypothesized that the hypersomnia is related to greater REM sleep. This hypothesis was tested by using a multiple sleep latency test to compare bipolar affective disorder with narcolepsy, a well-defined primary sleep disorder associated with known REM sleep dysfunction. METHOD: Twenty-five bipolar depressed patients were selected on the basis of complaints of hypersomnia. They underwent 2 nights of polysomnography followed by a multiple sleep latency test. Data on their nocturnal sleep and daytime naps were compared with similar data on 23 nondepressed narcoleptic patients referred for sleep evaluation. RESULTS: Despite their complaints of hypersomnia, no abnormalities were noted for the bipolar group in the results from the multiple sleep latency test. Contrary to the working hypothesis, REM sleep was notably absent during daytime naps in the depressed patients, in marked contrast to the findings for the narcoleptic group. CONCLUSIONS: The complaint of sleepiness in the hypersomnic bipolar depressed patient appears to be related to the lack of interest, withdrawal, decreased energy, or psychomotor retardation inherent in the anergic depressed condition, rather than an increase in true sleep propensity or REM sleep propensity.     

Motor dyscontrol in narcolepsy: rapid-eye-movement (REM) sleep without atonia and REM sleep behavior disorder.

Narcolepsy involves abnormalities of rapid-eye-movement (REM) sleep, including a short latency to the onset of REM sleep, hypnagogic hallucinations, and sleep paralysis. In addition, persistence of muscle tone by electromyographic criteria or excessive muscle twitching during REM sleep or both have been reported in treated and untreated narcoleptic patients. We report that another previously described abnormality of REM sleep, REM sleep behavior disorder, may also be a symptom of narcolepsy. This disorder was found in 10 narcoleptic patients during routine clinical evaluations involving polysomnography and multiple sleep latency tests. During REM sleep, 7 additional narcoleptic patients displayed persistent muscle tone and/or excessive twitching, which we believe to be subclinical components of REM sleep behavior disorder. These 17 patients, diagnosed by established criteria for narcolepsy and for REM sleep behavior disorder, ranged in age from 8 to 74 years. Seventy-one percent were male. Narcolepsy and REM sleep behavior disorder most commonly emerged in tandem. In 3 patients, treatment of narcolepsy-cataplexy with stimulants and tricyclics either induced or exacerbated REM sleep behavior disorder.     

Voxel-based magnetic resonance imaging study of structural brain changes in patients with idiopathic REM sleep behavior disorder

PurposeRapid eye movement (REM) sleep behavior disorder (RBD) is considered to result from dysfunction of the brain stem structures that regulate REM sleep. In this study, we investigated structural brain changes using magnetic resonance imaging (MRI) in patients with idiopathic RBD (iRBD) to determine structural brain alterations associated with the disorder.MethodsVoxel-based MRI morphometry was applied to 20 patients with iRBD and findings were compared with those from 18 age-matched controls.ResultsCompared with the controls, the patients with iRBD had significant gray matter volume reduction in the anterior lobes of the right and left cerebellum, tegmental portion of the pons, and left parahippocampal gyrus.ConclusionThe present study provides in vivo evidence suggesting that structural lesions of the brain stem are responsible for the occurrence of iRBD. In addition, the pattern of gray matter loss is consistent with morphological changes commonly observed in patients with Lewy body disease and multiple system atrophy, indicating that iRBD can share a common morphological abnormality with alpha-synucleinopathies.     

Electrophysiological brainstem investigations in obstructive sleep apnoea syndrome

Phasic inspiratory genioglossus activity prevents pharyngeal airway collapse in healthy subjects during sleep and is diminished or absent in obstructive sleep apnoea syndrome (OSAS), thus leading to pharyngeal obstruction. Case reports of OSAS after pontomedullary lesions indicate that impaired inspiratory genioglossal activity may result from brainstem lesions. We therefore investigated brainstem functions in 18 awake patients with OSAS using brainstem auditory evoked potentials, blink reflex, masseter reflex, masseter inhibitory reflex (in 11 of 18 patients), magnetic evoked potentials of the tongue and electrooculography with vestibular testing. Fifteen of 18 patients showed no electrophysiological abnormalities. One patient had a left pontine and two patients a bilateral pontomesencephalic lesion, although a causal connection with OSAS was not conclusively confirmed. Our results do not support the assumption of a relevant structural brainstem lesion in OSAS patients with normal neurological findings.     

Seventh nerve palsies may be the only clinical sign of small pontine infarctions in diabetic and hypertensive patients

Backgroud: Small brainstem infarctions are increasingly recognized as a cause of isolated ocular motor and vestibular nerve palsies in diabetic and/or hypertensive patients. This raises the question whether there are also isolated 7^th nerve palsies due to pontine infarctions in patients with such risk factors for the development of cerebrovascular diseases. Methods: Over an 11-year-period, we retrospectively identified 10 diabetic and/or hypertensive patients with isolated 7^th nerve palsies and electrophysiological abnormalities indicating pontine dysfunction. All patients had examinations of masseter and blink reflexes, brainstem auditory evoked potentials, direct current electro-oculography including bithermal caloric testing, and T1- and T2-weighted MRI (slice thickness: 4–7 mm). Results: Electrophysiological abnormalities on the side of the 7^th nerve palsy included delayed masseter reflex latencies (4 patients), slowed abduction saccades (4 patients), vestibular paresis (2 patients), and abnormal following eye movements (2 patients). Electrophysiological abnormalities were always improved or normalized at re-examination, which was always associated with clinical improvement. MRI revealed an ipsilateral pontine infarction in 2 patients. Another 2 had bilateral hyperintense intrapontine lesions, and one an ipsilateral cerebellar infarction. Conclusions: Simultaneous improvement or recovery of abnormal clinical and electrophysiological findings strongly indicated that both were caused by the same actual pontine lesions. A 7^th nerve palsy may be the only clinical sign of a pontine infarction in diabetic and/or hypertensive patients. Such mechanism may be underestimated if based on MRI only. Received: 24 January 2002, Received in revised form: 22 May 2002, Accepted: 4 June 2002 Correspondence to Frank Th?mke, MD     

Long-term changes in sleep and electroencephalographic activity by chronic vagus nerve stimulation in cats

We previously reported the effect of vagus nerve electrical stimulation (VNS) on sleep and behavior in cats. The aim of the present study is to analyze the long-term effects of VNS on the electroencephalographic (EEG) power spectrum and on the different stages of the sleep-wakefulness cycle in the freely moving cat. To achieve this, six male cats were implanted with electrodes on the left vagal nerve and submitted to 15 rounds of 23 h continuous sleep recordings in three categories: baseline (BL), VNS and post-stimulus recording (PSR). The following parameters were analyzed: EEG power spectrum, total time and number of sleep phases, ponto-geniculo-occipital (PGO) wave density of the rapid eye movement (REM) sleep, and the number of times the narcoleptic reflex was present (sudden transition from wakefulness to REM sleep). Significant changes were detected, such as an enhancement of slow-wave sleep (SWS) stage II; a power increase in the bands corresponding to sleep spindles (8-14 Hz) and delta waves (1-4 Hz) with VNS and PSR; an increase in the total time, number of stages, and density of PGO wave in REM sleep with VNS; a decrease of wakefulness in PSR, and the eventual appearance of the narcoleptic reflex with VNS. The results show that the effect of the VNS changes during different stages of the sleep-wakefulness cycle. In REM sleep, the effect was present only during VNS, while the SWS II was affected beyond VNS periods. This suggests that ponto-medullar and thalamic mechanisms of slow EEG activity may be due to plastic changes elicited by vagal stimulation.     

Role of wake inducing brain stem area on rapid eye movement sleep regulation in freely moving cats

Some of the characteristic symptoms associated with rapid eye movement (REM) sleep are opposite to, while some apparently resemble, those of wakefulness. Therefore, it was hypothesised that the neurons present in the wakefulness inducing area(s) in the brain are likely to communicate with the REM sleep related neurons. Brain stem neurons were classified based on their firing rates in relation to electrophysiological correlates associated with spontaneous sleep and wakefulness recorded from freely moving, normally behaving cats. Thereafter, the responses of those classified neurons to stimulation of brain stem reticular wakefulness inducing area were studied. Results from 63 neurons showed that the wake inducing area affected 62% of the neurons. Fifty-eight percent of the neurons which increased firing during wakefulness, including the REM-OFF neurons, were excited, while 70% of the neurons which decreased firing during wakefulness, including the REM-ON neurons, were inhibited. These observations support our hypothesis and, along with their physiological significance, are discussed.     

Autonomic function in narcolepsy: power spectrum analysis of heart rate variability

Ten narcoleptic patients that had never been treated previously and ten healthy volunteers of comparable age underwent 48-h polygraphic recording to assess the effects of wakefulness and sleep on beat-to-beat heart rate variability by means of power spectrum analysis. The study revealed decreased power in the low frequencies (LF) during sleep (whereby an increase of the power in this band is associated with sympathetic activation) compared with wakefulness, with minimal values during stage 3–4 non-REM sleep and higher levels during REM sleep, both in patients and controls. Significantly reduced power in high frequencies (HF; mainly expression of parasympathetic control) and a significantly increased LF/HF ratio during wakefulness before sleep in narcoleptics compared with controls were found. Our study excludes a primary disturbance of cardiac autonomic nervous system in narcoleptics but suggests an altered circadian autonomic function in these patients. Received: 23 May 1996 Received in revised form: 3 December 1996 Accepted: 17 January 1997     

瞬目反射及脑干听觉诱发电位对脑干梗死疗效的评价

目的探讨瞬目反射和脑干听觉诱发电位对脑干梗死患者疗效的评价作用。方法40例经临床症状、体征定位于脑干髓内并经头部MRI检查明确诊断的脑干梗死患者(脑桥梗死31例、中脑梗死4例和延髓梗死5例),分别计算治疗前后瞬目反射各成分的平均潜伏期;观察脑干听觉诱发电位波形及各波潜伏期、峰间期的变化。结果经治疗后40例患者临床症状及体征均有不同程度改善,治疗前后瞬目反射各成分平均潜伏期之间差异无统计学意义(P>0.05);3例脑桥梗死患者R1波恢复正常,临床基本痊愈。治疗前后脑干听觉诱发电位各波潜伏期及峰间期比较,差异亦无统计学意义(P>0.05);治疗后中脑梗死及脑桥梗死患者各有2例恢复正常,临床症状明显好转。结论瞬目反射与脑干听觉诱发电位均能敏感地反映脑干功能的变化,与临床表现具有一致性,但在发病15d内大部分病例的电生理活动不能恢复正常。     

Disturbances of rapid-eye-movement sleep in 3 brothers with Pelizaeus-Merzbacher disease.

The electrophysiological features of 3 brothers with the classic form of Pelizaeus-Merzbacher disease (PMD) were studied. Two consecutive overnight polygraphic sleep recordings indicated a gross distortion of rapid-eye-movement (REM) sleep for all patients. A lower than normal percentage of REM sleep in these patients was consistent with their retarded intellectual development, which supports current thinking that REM sleep may be a sensitive index of brain function integrity. Non-rapid-eye-movement (NREM) sleep, in contrast to reported findings in 1 patient with PMD, was uniformly characterized by distinct stages in which the electroencephalograms contained frequent vertex waves and spindles. Tests of peripheral nerve conduction velocity, acoustic brainstem reflexes, and visual and auditory evoked potentials did not indicate any abnormalities, nor did electroencephalograms obtained during wakefulness. One patient did have epileptiform spikes and spike waves recorded during an all-night EEG, an unusual finding in a child with cerebral white matter disease.     

REM Sleep Behavior Disorder and Epileptic Phenomena: Clinical Aspects of the Comorbidity

Summary:  Purpose: To document the occurrence of REM sleep behavior disorder (RBD) episodes in patients with epilepsy, and of interictal EEG epileptiform abnormalities (IEA) in patients with idiopathic RBD.
Methods: Consecutive observations in a tertiary epilepsy center and a tertiary sleep center. RBD diagnosis was based on standard clinical and video-polysomnographic findings.
Results: Co-occurrence of epileptic seizures and RBD episodes was found in six cases (all men; mean age 70.5 ± 11.1 years). Focal, isolated, sporadic sharp waves during wakefulness and/or during sleep were documented in 9 out of 34 (26.4%) patients with idiopathic RBD; no significant differences in age at onset and duration of RBD emerged between RBD patients with and without IEA.
Conclusions: RBD episodes can occur in epilepsy patients and focal IEA in patients with idiopathic RBD. This, apart from being a possible cause for misdiagnosis, may indicate a possible link between the two disorders. Further systematic investigations of the occurrence of RBD episodes in epilepsy will help to establish the real extent of this comorbidity and its ultimate neurobiological significance.     

Hypersomnolence and increased REM sleep with low cerebrospinal fluid hypocretin level in a patient after removal of craniopharyngioma

Here we report a hypersomnolent girl with extensive hypothalamic damage after removal of a craniopharyngioma. The presence of a short sleep latency, sleep onset REM periods during a multiple sleep latency test (MSLT) and negative HLA DQB1*0602 typing suggested a diagnosis of symptomatic narcolepsy. Low cerebrospinal fluid hypocretin-1 level indicated destruction of hypocretin-producing neurons in the hypothalamus. An increased amount of REM sleep and a lack of REM sleep cyclicity documented by all-night polysomnography were different findings from previous reports of hypocretin-deficient idiopathic symptomatic narcolepsy. A more global hypothalamic lesion demonstrated by brain magnetic resonance imaging (MRI) after surgery seemed to cause marked disinhibition of REM sleep as well as hypersomnolence in this patient.     

Diffuse brain stem tumor in an adolescent with multiple enchondromatosis (Ollier's disease)

Among patients with enchondromatosis, those with Ollier's disease are usually considered to be at a lower risk for extra-osseous malignancy than those with Maffucci's disease. However, several reports suggest that Ollier's disease may also be associated with gliomas. We report here the youngest patient in the literature (16 years) to be detected with a brain tumor and Ollier's disease. This is also the first case with diffuse brain stem involvement. Thus, counselling of patients with Ollier's disease may become more difficult than initially thought. Received: 13 November 1998     

Sleep electroencephalograms and sleep stages in hypoparathyroidism.

2 patients with hypoparathyroidism, one idiopathic and the other pseudoform, were studied by overnight polygraphic recording of the sleep EEG and related activities before and after start of treatment to investigate their sleep EEG patterns and states, with the results as follows. (1) Conspicuous abnormalities were noted in the sleep record, namely, disappearance of humps, spindles and hill waves, emergence of the mitten pattern and rather monotonous delta rhythm bursts. The EEGs, both awake and asleep, showed findings suggestive of a possible disorder of the desynchronizing mechanism of the brain stem. Normal sleep EEG patterns were restored after the serum calcium level had returned to the normal range. (2) In the course of overnight sleep, disturbance in the cyclic changes of sleep EEG pattern and absence of REM sleep were observed. Restoration to the normal course of sleep was achieved following the normalization of serum calcium level. Divalent calcium ion is considered to have intimate bearing upon the mechanism whereby synaptic chemical transmitters are activated. When viewed with reference to the monoamine hypothesis of Jouvet, the disturbance in the course of sleep observed in the present cases, especially the absence of or disturbed REM sleep, is inferred to be related to the hypocalcemia.     

Pontine lesions mimicking acute peripheral vestibulopathy

OBJECTIVES: Clinical signs of acute peripheral vestibulopathy (APV) were repeatedly reported with pontine lesions. The clinical relevance of such a mechanism is not known, as most studies were biased by patients with additional clinical signs ofbrainstem dysfunction. METHODS: Masseter reflex (MassR), blink reflex (BlinkR), brainstem auditory evoked potentials (BAEPs), and DC electro-oculography (EOG) were tested in 232 consecutive patients with clinical signs of unilateral APV. RESULTS: Forty five of the 232 patients (19.4%) had at least one electrophysiological abnormality suggesting pontine dysfunction mainly due to possible vertebrobasilar ischaemia (22 patients) and multiple sclerosis (eight patients). MassR abnormalities were seen in 24 patients, and EOG abnormalities of saccades and following eye movements occurred in 22 patients. Three patients had BlinkR-R1 abnormalities, and one had delayed BAEP waves IV and V. Clinical improvement was almost always (32 of 34 re-examined patients) associated with improvement or normalisation of at least one electrophysiological abnormality. Brain MRI was done in 25 of the 44 patients and confirmed pontine lesions in six (two infarcts, three inflammations, one tumour). CONCLUSIONS: Pontine dysfunction was suggested in 45 of 232 consecutive patients with clinical signs of APV on the basis of abnormal electrophysiological findings, and was mainly attributed to brainstem ischaemia and multiple sclerosis. The frequency of pontine lesions mimicking APV is underestimated if based on MRI established lesions only.     

Clinical significance of cataplexy and HLADR1501 in narcolepsy

Clinical symptoms and multiple sleep latency test (MSLT) measures among narcoleptic patients with both cataplexy and HLADR1501 were compared with cataplexy-free narcoleptic patients with a positive finding of HLADR1501 and cataplexy-free patients without HLADR1501. Both mean sleep onset latencies and rapid eye movement (REM) latencies on MSLT were shorter in the patients with cataplexy compared with the cataplexy-free patients. In four cataplexy-free patients without HLADR1501, nocturnal sleep was remarkably long and their excessive daytime sleepiness did not respond to treatment. The findings suggest that the severity and disease mechanism of narcolepsy might become heterogenous when cataplexy and HLADR1501 are considered.     

Polysomnographic and quantitative EEG analysis of subjects with long-term insomnia complaints associated with mild traumatic brain injury.

OBJECTIVE: The aims of this study were (1) to characterise the extent and nature of disrupted sleep in individuals with long-term sleep complaints subsequent to mild traumatic brain injury (MTBI), and (2) to determine whether sleep disturbances in MTBI subjects were more characteristic of psychophysiological, psychiatric, or idiopathic insomnia. METHODS: Nine MTBI patients (27.8 months post-injury; SD=15.5 months) and nine control subjects underwent polysomnographic testing and completed self-report questionnaires on sleep quality. Power spectral (FFT) analysis of the sleep onset period was conducted, with both the power and variability in power being quantified. RESULTS: Individuals with MTBI exhibited long-term sleep difficulties, along with various cognitive and affective abnormalities. The MTBI group had 4% less efficient sleep (p=0.019), shorter REM onset latencies (p=0.011), and longer sleep onset latencies, although the latter were highly variable in the MTBI group (F-test: p=0.012). FFT analysis revealed greater intra-subject variability in the MTBI group in sigma, theta, and delta power during the sleep onset period. CONCLUSIONS: MTBI patients with persistent sleep complaints differ significantly from controls on a number of electrophysiological outcomes, but could not be easily classified into existing insomnia subtypes. SIGNIFICANCE: Sleep disturbances can persist well after the injury in a subset of patients with MTBI.     

A Discrete Glycinergic Neuronal Population in the Ventromedial Medulla That Induces Muscle Atonia during REM Sleep and Cataplexy in Mice

During rapid eye movement (REM) sleep, anti-gravity muscle tone and bodily movements are mostly absent, because somatic motoneurons are inhibited by descending inhibitory pathways. Recent studies showed that glycine/GABA neurons in the ventromedial medulla (VMM; Gly^VMM neurons) play an important role in generating muscle atonia during REM sleep (REM-atonia). However, how these REM-atonia-inducing neurons interconnect with other neuronal populations has been unknown. In the present study, we first identified a specific subpopulation of Gly^VMM neurons that play an important role in induction of REM-atonia by virus vector-mediated tracing in male mice in which glycinergic neurons expressed Cre recombinase. We found these neurons receive direct synaptic input from neurons in several brain stem regions, including glutamatergic neurons in the sublaterodorsal tegmental nucleus (SLD; Glu^SLD neurons). Silencing this circuit by specifically expressing tetanus toxin light chain (TeTNLC) resulted in REM sleep without atonia. This manipulation also caused a marked decrease in time spent in cataplexy-like episodes (CLEs) when applied to narcoleptic orexin-ataxin-3 mice. We also showed that Gly^VMM neurons play an important role in maintenance of sleep. This present study identified a population of glycinergic neurons in the VMM that are commonly involved in REM-atonia and cataplexy.SIGNIFICANCE STATEMENT We identified a population of glycinergic neurons in the ventral medulla that plays an important role in inducing muscle atonia during rapid eye movement (REM) sleep. It sends axonal projections almost exclusively to motoneurons in the spinal cord and brain stem except to those that innervate extraocular muscles, while other glycinergic neurons in the same region also send projections to other regions including monoaminergic nuclei. Furthermore, these neurons receive direct inputs from several brainstem regions including glutamatergic neurons in the sublaterodorsal tegmental nucleus (SLD). Genetic silencing of this pathway resulted in REM sleep without atonia and a decrease of cataplexy when applied to narcoleptic mice. This work identified a neural population involved in generating muscle atonia during REM sleep and cataplexy.     

Multiple sleep latency test and polysomnography in patients with central disorders of hypersomnolence

A multiple sleep latency test (MSLT) with occurrence of sleep onset REM periods (SOREMP) is considered one of the central diagnostic criteria for narcolepsy according to the International Classification of Sleep Disorders, but its sensitivity and specificity have been questioned. This study aims to describe MSLT and polysomnography (PSG) findings, including frequency and distribution of SOREMP during the day, in a large cohort of patients with central disorders of hypersomnolence (CDH).We retrospectively analyzed electrophysiological data from MSLT and PSG in 370 consecutive patients with narcolepsy type 1 (NT1, n = 97), type 2 (NT2, n = 31), idiopathic hypersomnia (IH, n = 48), nonorganic hypersomnia (NOH, n = 116) and insufficient sleep syndrome (ISS, n = 78).NT1 and NT2 patients had a significantly shorter mean Sleep Latency (mSL) and REM-Latency (REML) in MSLT and PSG. SOREMP occurred more frequently in narcoleptic vs. non-narcoleptic patients in MSLT and PSG. Occurrence of 3 or more SOREMP in MSLT and a SOREMP in PSG had a very high specificity and positive predictive value (98%/96% and 100% respectively), however relatively low sensitivity (65% and 45% respectively).NT1 more than NT2 patients have shorter mSL and more frequent SOREMP in MSLT and shorter SL as well as REML during nocturnal PSG. Increasing numbers of SOREMP in MSLT and especially SOREMP during PSG increase specificity on the expense of sensitivity in diagnosing narcolepsy. Therefore, frequency of SOREMP in MSLT naps and PSG can help to discriminate but not clearly separate narcoleptic from non-narcoleptic patients.