Slow progression of juvenile metachromatic leukodystrophy 6 years after bone marrow transplantation.

Metachromatic leukodystrophy refers to a group of genetic neurologic diseases caused by deficiencies of the enzyme arylsulfatase A and the resulting accumulation of sulfatides in white matter. Bone marrow transplantation has been advocated as a treatment in an attempt to correct the enzyme deficiency. Such a transplant was performed in 1991 in a 16-year-old girl with a form of late juvenile metachromatic leukodystrophy caused by a homozygous P426L mutation in the arylsulfatase A gene. Engraftment was prompt and resulted in constant enzymatic normalization of circulating lymphocytes. The elevated urinary excretion of sulfatides remained unaffected. Clinical findings up until transplantation consisted of gait disturbances, impairment of cognitive functioning, and deterioration in school performance over several years. During a 6-year follow-up period, the patient's condition was subject to major fluctuations but, on the whole, findings showed slow neurologic and neurophysiologic deterioration. The clinical course observed after bone marrow transplantation probably more or less reflects the natural course expected in this form of late-onset metachromatic leukodystrophy.

Habituation of the infant arousal response.

STUDY OBJECTIVES: Arousal is considered to be an important protective response in a sleeping infant and its depression could leave an infant vulnerable to a life threatening stimulus. We found previously that arousal to a non-respiratory (tactile) stimulus occurs in a sequence of events that begins with spinal, followed by brainstem responses, and then a cortical electroencephalographic (EEG) arousal response. We hypothesized that repeated stimuli would depress the arousal responses by habituation and that spinal and brainstem responses would be more resistant to habituation than cortical responses. PARTICIPANTS: We studied 22 normal infants. INTERVENTIONS: The infants underwent polysomnographic monitoring during a daytime nap. Tactile stimuli was applied to the infants foot at 5-second intervals. MEASUREMENTS AND RESULTS: We found that spinal, brainstem, and cortical responses occurred on the first trial of each test. Repeated trials during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep resulted in a decrease in the incidence of each individual response and eventually elimination of the arousal responses. Cortical responses were eliminated first, followed by brainstem responses and finally spinal responses. The elimination of each of the responses occurred more rapidly during REM sleep that during NREM sleep. CONCLUSIONS: Habituation of the infant arousal sequence occurs with repeated tactile stimulation. There is a serial habituation of responses from the cortical to the spinal level, which occurs more rapidly during REM sleep. Rapid habituation to innocuous stimuli is probably beneficial in avoiding detrimental sleep disruptions. However, in situations requiring the protective functions of arousal, such habituation could be detrimental to an infant.

Characteristics of the infant arousal response.

Arousal is considered to be an important response to a life-threatening stimulus. Recently, it has been shown that the infant arousal response to an elevated inspired CO2 level occurs as a sequence of events involving presumptive brain stem responses before awakening (A. Lijowska, N. Reed, B. Chiodini, and B. T. Thach. Am. J. Respir. Crit. Care Med. 151: A151, 1995; A. S. Lijowska, N. W. Reed, B. A. Mertins Chiodini, and B. T. Thach. J. Appl. Physiol. 83: 219-228, 1997). We wanted to further evaluate the relationship of subcortical reflexes to cortical arousal in infants. We used a nonrespiratory (tactile) stimulus to elicit arousal in infants during non-rapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep. We found that a tactile stimulus elicited an arousal sequence that commenced with a spinal withdrawal reflex, was followed by brain stem responses (respiratory and startle responses), and ended in a cortical arousal. The entire pathway or part of it in the order of spinal to cortical responses could be elicited. REM and NREM responses were similar except for significant differences in the latencies of spinal and subcortical reflexes. These observations suggest that the infant arousal response to a tactile stimulus involves a progression of central nervous system activation from the spinal to cortical levels. The different components of the arousal pathway may be important for an infant to respond appropriately to stimuli during sleep without necessarily disturbing sleep.

Suppression of sigma spindle electroencephalographic activity as a measure of transient arousal after spontaneous and occlusion-evoked sighs and startles.

Defective arousal mechanisms are viewed as contributory to sleep hypopnea disorders and sudden infant death syndrome. Sighs (i.e. augmented breaths) as well as startles have not traditionally been viewed as arousal-related phenomena in infants. We hypothesized that, if sighs and startles are the initial event in a sequential arousal process, then they might be associated with specific EEG activity changes, because activation of the arousal-related ascending reticular activating system can suppress thalamus-generated sigma spindle oscillations. We studied spontaneous sighs and startles and those elicited by briefly occluding the infants face mask airway in 12 normal infants (age 10-19 wk) during non-rapid eye movement sleep. We recorded EEG (C3-P3), ECG, O2 saturation, diaphragmatic electromyography, limb electromyography, and video of the infant. The startle intensity was scored on a scale of 0 to 3 based on video recorded movements. Sleep spindle periodicity was analyzed by using a threshold over a compressed spectral band array. Spontaneous sighs and sleep startles were immediately followed by an interspindle interval prolongation from (mean +/- SEM) 8.0 +/- 0.16 s (control period) to 17.9 +/- 1.45 s after spontaneous sighs, to 23.8 +/- 1.26 s after spontaneous sighs accompanied by startles and to 26.5 +/- 1.45 s after occlusion-related sighs and startles. Furthermore, the intensity of occlusion-evoked startles was positively correlated with the interspindle interval prolongation (p < 0.01). We conclude that spontaneous as well as evoked sighs and startles are immediately followed by a transient sleep spindle suppression. This phenomenon indicates a close linkage between sighs, startles, and reticular formation-related arousal mechanisms.

Submental and diaphragmatic muscle activity during and at resolution of mixed and obstructive apneas and cardiorespiratory arousal in preterm infants.

Pathomechanisms involved in obstructive apneas remain obscure. Apnea arousal failure has been proposed as a cause for sudden death during sleep. The present study hypothesizes an interdependency between upper airway dilating submental muscle electromyogram (EMG) activity (EMGsub), diaphragmatic muscle activity (EMGdia), incidence of bradycardia, and transcutaneous measured PO2 (tcpO2) upon termination of apnea. Polygraphic recordings, including surface EMG (EMGsub, EMGdia), EEG, ECG, and transcutaneous PO2/PCO2 (tcpO2/tcpCO2) were performed on 10 preterm infants at 36, 40, 44, and 52 wk of conceptional age. EMGsub increased initially, then decreased in 28 of 33 non-rapid eye movement (N-REM) sleep apneas (REM: 35 of 69 events). This correlated with a decrease of tcpO2 during N-REM sleep (p < 0.05). A parallel decrease of EMGsub and EMGdia was correlated with the occurrence of bradycardia (REM and N-REM: p < 0.01). Concomitant termination of apnea and bradycardia (n = 22), occurred in the presence of a phasic, simultaneous activation of EMGsub and EMGdia in 64% of REM sleep and in 79% of N-REM sleep-related event, was characterized by a deep inspiration preceded by a short expiration, and correlated with the extent of tcpO2-decline during REM sleep apneas (p < 0.05). In one apnea with bradycardia that progressed to asystolia, this mechanism was missing, but was evoked by a slight tactile stimulation, where-upon cardiorespiratory functions were immediately reestablished whereas N-REM sleep continued uninterrupted. Our data demonstrate an interdependency between changes of EMGsub and EMGdia activity, tcpO2 decline, and occurrence of bradycardia. A "cardiorespiratory arousal" terminated apneas and bradycardia without a change in sleep phase.

The ontogeny of sensory perception in preterm infants.

The extra- vs intrauterine development of both visual and auditory cortical evoked response patterns was compared at 33, 37 and 40 weeks conceptional age. The maturation of visual cortical evoked responses is retarded in infants at 37 and 40 weeks conceptional age when born with a gestational age of less than 32 weeks, which thus implies a long extrauterine life span. The maturation of the auditory cortical evoked responses is not influenced by premature exposure to the extrauterine environment. The results are explained on the basis of the particular central nervous system growth spurt periods and a thus defined vulnerable period of different brain structures.