Brain magnetic resonance imaging of siblings from families with two or more children with learning or intellectual disabilities and need for full-time special education.

BACKGROUND: Several factors are involved in determining a child's need for special education (SE). Thus, the value of brain magnetic resonance imaging (MRI) for subjects with learning and intellectual disabilities is uncertain. PURPOSE: To evaluate the usefulness of MRI in the diagnostic process of siblings with learning and intellectual disabilities and need for full-time SE. MATERIAL AND METHODS: Altogether, 119 siblings (mean age 11.9 years) from families in which two or more children attended/had previously attended full-time SE underwent prospective brain MRI. SE grouping included three levels, from specific learning disabilities (level 1) to global intellectual disabilities (level 3). Forty-three controls (level 0, mean age 12.0 years) attended mainstream education groups. Signal intensity and structural abnormalities were analyzed, and areas of the cerebrum, posterior fossa, corpus callosum, vermis and brain stem, and diameters of the corpus callosum were measured. In analyses, all area measurements were calculated in proportion to the total inner skull area. RESULTS: Abnormal finding in MRI was more common for siblings (n=62; 52%) in SE (58% for level 3; 49% for level 2; 35% for level 1) than for controls (n=13; 16%). The siblings showed enlarged supra- (P<0.001) and infratentorial (P=0.015) cerebrospinal fluid (CSF) spaces and mild corpus callosum abnormalities (P=0.003) compared to controls. Siblings in SE had smaller inner skull area than controls (P<0.001). Further, the relative area of the mesencephalon (P=0.027) and the diameter of the body of the corpus callosum (P=0.015) were significantly smaller than in controls. In binary logistic regression analysis, enlarged supratentorial CSF spaces increased the probability of SE (odds ratio 4.2; P=0.023). CONCLUSION: Subjects with learning and intellectual disabilities commonly have more MRI findings than controls. Enlarged supratentorial CSF spaces were a frequent finding in siblings in full-time SE.

Two brothers with macrocephaly, progressive cerebral atrophy and abnormal white matter, severe mental retardation, and Lennox-Gastaut spectrum type epilepsy: an inherited encephalopathy of childhood?

Two brothers with severe mental retardation of unknown origin were found to share several physical anomalies, including large round head, small concave nose, downslanted palpebral fissures, and gingival hyperplasia. In addition to relative macrocephaly, magnetic resonance imaging (MRI) showed severe cerebral atrophy, especially fronto-temporally. The brothers also had a thin corpus callosum and atrophic caudate nuclei. The reduced white matter showed patchy periventricular signal intensity changes. The lateral and third ventricles were large, but the fourth ventricle was of normal size. The boys had large cisterna magna, communicating widely with the fourth ventricle, but no vermian hypoplasia. Both boys had Lennox-Gastaut spectrum type epilepsy. No chromosomal anomalies were found, despite the suggestive clinical picture. Some of the clinical findings resembled fetal alcohol effects/fetal alcohol syndrome (FAE/FAS), which was also suggested by history. Current diagnostic criteria for FAE/FAS, however, excluded full-blown FAS in these cases and failed to explain the entire clinical picture in the boys. We argue that these boys had an unidentified inherited syndrome, possibly modified by fetal alcohol exposure.

Transdermal fentanyl therapy for pains in children with infantile neuronal ceroid lipofuscinosis.

We used infantile neuronal ceroid lipofuscinosis (INCL), in which deterioration of the central nervous system is extremely rapid, to study constant release of an opioid for pains of central origin in a metabolic disease. The effect of a transdermal fentanyl patch was studied in five children with INCL. In two of them, measurements of 17 fentanyl serum concentrations and also visual analogue pain scale were obtained during a 15-day study period. Low doses of transdermal fentanyl usually provided good pain relief for the first two days, but not for the third day, of the three-day patch change interval. Pain relief of this type seems mandatory for pains mostly of central origin.

Neurological impairments and sleep-wake behaviour among the mentally retarded.

The objective of the present study was to evaluate the relationship between the sleep-wake behaviour and neurological impairments among mentally retarded people. The sleep-wake behaviour of 293 mentally retarded subjects living in a rehabilitation center was studied by a standardized observation protocol carried out by trained staff members. The protocol consisted of brief check-ups of the subjects' sleep-wake status at 20-min intervals for five randomly chosen 24-h periods during 4 months. From the raw data five sleep-wake behaviour variables were formed. The data concerning the subject characteristics (age, body mass index (BMI), gender, degree of mental retardation, presence of locomotor disability, that of epilepsy, blindness or deafness and the usage of psychotropic medications) were collected from the medical records. Two main findings emerged: (1) severe locomotor disability, blindness and active epilepsy were found to be independent predictors of increased daytime sleep and increased number of wake-sleep transitions and (2) the subjects with a combination of two or all three of these impairments had a significantly more fragmented and abnormally distributed sleep than those with none or milder forms of these impairments. Age, BMI, degree of mental retardation and the studied medications played a minor role in the sleep disturbances of the study population. Finally, deafness was not found to be associated with any of the measured sleep-wake variables.

A patient with 2 different repeat expansion mutations.

BACKGROUND: Many inherited progressive encephalopathies have a poor outcome, and some are caused by repeat expansion mutations. How would the presence of 2 different expansion mutations affect the phenotype? OBJECTIVE: To describe a patient who has 2 distinct, rare genetic disorders: myotonic dystrophy (DM, OMIM 160900) and progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1, OMIM 254800). Both conditions are caused by repeat expansion mutations. They affect the central nervous system causing mental retardation, but also produce a wide spectrum of disabilities in daily living. SETTING: Referral center. METHODS: Clinical description with accompanying photographs, electroencephalography and magnetic resonance imaging; DNA analysis of both of the mutations and chromosomal analysis with prometaphase spreads. RESULTS: The patient had clinical characteristics and findings of both myotonic dystrophy and progressive myoclonus epilepsy of the Unverricht-Lundborg type. Electroencephalographic recordings over a 3-year period showed typical findings for myoclonus epilepsy. The patient had no gross anomalies in brain magnetic resonance imaging. She had a normal karyotype, and both of the diagnoses were confirmed at the molecular level with the direct detection of the mutations. CONCLUSIONS: Despite having 2 different progressive inherited disorders affecting the central nervous system, the patient, at age 28 years, showed only mild mental retardation with very slow progression. However, clear deterioration in activities of daily living has taken place during last 3 years. Arch Neurol. 2000;57:1199-1203

No evidence for extraocular light induced phase shifting of human melatonin, cortisol and thyrotropin rhythms.

The view that light affects the mammalian circadian clock only through the eyes was recently challenged by a study in which the phases of human circadian rhythms were shifted by extraocular light exposure. This finding has not been confirmed, however. We studied the effects of light exposure (3 h, broad spectrum fluorescent white light, 13000 lux) on abdomen and chest on the circadian rhythms of serum melatonin, cortisol and thyrotropin in six subjects. The protocol consisted of two 3-day sessions in a dimly lit (< 10 lux) experimental unit. In both sessions hourly serum samples were collected for hormone analysis on days 1 and 3. The skin light exposure was delivered on day 2 from 22.00 to 01.00h in one of the two sessions in a randomized order. In both sessions all three rhythms tended to delay, presumably due to the endogenous circadian cycle length being slightly longer than 24 h. However, the phase shifts did not differ significantly between the sessions. Thus, the present study does not support the existence of extraocular photic regulation of the circadian rhythms in humans.

Extensive cerebral white matter abnormality without clinical symptoms: a new hereditary condition?

A 30-year-old father and his 2 sons with slight hyperkinesia and mildly dysmorphic features and their close relatives were examined clinically and with computed tomography (CT) and magnetic resonance imaging (MRI). Neurophysiological and biochemical examinations were normal; however, brain MRI of the father and sons revealed extensive cerebral white matter changes. No radiological progression could be detected at a 13-year follow-up examination of the father, and proton magnetic resonance spectroscopy (MRS) of the father at the age of 30 years was normal. MRI findings in the relatives were normal, suggesting an autosomal dominant syndrome due to a new mutation in the father.

Melatonin ineffective in neuronal ceroid lipofuscinosis patients with fragmented or normal motor activity rhythms recorded by wrist actigraphy.

Melatonin was tested as a sleeping pill in five patients with neuronal ceroid lipofuscinoses. The single-blind, placebo-controlled study consisted of motor activity recordings, sleep logs, and administration of placebo or melatonin (2.5 or 5 mg). Daily motor activity rhythms were measured by wrist actigraphy during four 7-day periods (baseline, placebo, melatonin 2.5 mg, and melatonin 5 mg). The placebo or melatonin was administered in the evenings for 3 weeks, and the recordings were made during the last week of the 3-week treatment. Sleep logs were kept by the caregivers during the recordings. Based on period analyses, the activity recordings were evaluated to display a normal (24-h) or fragmented rhythm. Three patients had normal motor activity patterns during the baseline recordings, and administration of placebo or melatonin did not affect their rest/activity rhythms. Two patients had abnormally fragmented activity rhythms during the baseline periods, and administration of placebo or melatonin did not induce synchronization. According to the actigraphic data, there were no changes in activity rhythms resulting from administration of melatonin. However, based on the observations, three families reported that melatonin slightly improved the sleep quality of the patients. These controversial findings show the difficulties involved in specifying the role of melatonin in modulating sleep. Thus, we conclude that more evidence is required before the significance of melatonin as a sleeping pill is defined.

Bright light suppresses melatonin in blind patients with neuronal ceroid-lipofuscinoses.

We studied whether light information can reach the pineal glands of clinically blind patients with neuronal ceroid-lipofuscinoses. The suppression of melatonin by light was used as an indicator. Seven patients and seven control subjects were exposed to 3,000-lux light for 60 minutes at the rising phase of the melatonin synthesis. Most patients were not cooperative, and their eyelids were opened by a researcher every 2 minutes for 2 seconds. The control subjects opened and closed their eyes similarly by themselves. Light suppressed melatonin in three of seven control subjects and in all patients. The average postlight levels were 80% (control subjects) and 51% (patients) of the corresponding levels during the dim-light session. Despite degenerated retinas of the blind patients, light can penetrate their visual system to the hypothalamic and pineal levels and regulate neuroendocrine function.

CSF ACTH and beta-endorphin in infants with West syndrome and ACTH therapy.

Corticotrophin (adrenocorticotropic hormone, ACTH) and beta-endorphin levels of the cerebrospinal fluid (CSF) were determined in 16 infants with the West syndrome during individualized ACTH treatment. Prior to treatment, the levels of CSF ACTH were significantly higher in infants with cryptogenic spasms, normal perinatal events, or normal development than in infants with symptomatic spasms or delayed development. The CSF beta-endorphin levels did not differ among the groups. At response, the infants could be divided into three groups: (1) short-course, low-dose responders with a substantial CSF ACTH decline, (2) long-course, high-dose responders with no such effect (but with a tendency towards an upward incline), and (3) non-responders with no significant CSF ACTH changes. The changes in CSF beta-endorphin were somewhat similar to the changes in CSF ACTH, but the greater variability did not allow statistical significance.

Community-based study of Lennox-Gastaut syndrome.

PURPOSE: Before 1986, the spectrum of childhood epilepsies, including Lennox-Gastaut syndrome (LGS) and Doose syndrome (DS), known collectively as "epilepsia myoclonica astatica," was believed to represent a single disease. More recently, some investigators have considered these syndromes to be parts of a continuum. To clarify these theories, neurobiologic factors of the syndromes were studied to determine which qualities were shared and which were unique. METHODS: A retrospective (1975-1985), community-based (Helsinki metropolitan area and the province of Uusimaa) study was designed to seek children with features of LGS and DS. It was assumed that recall bias and the selection of documented history would be similar throughout the group. Ranks of increasing pathology were assigned to different seizure types, EEG results, and drug treatments. A similar procedure was applied to epidemiologic data. Spearman rank-order correlations were calculated to determine which features correlated with LGS and which correlated with less severe epilepsy. RESULTS: The survey comprised 75 patients with broadly defined LGS. The annual incidence was 2 in 100,000 children aged 0 to 14 years. Prenatal or perinatal abnormalities did not correlate with severity of epilepsy. As compared with the relatively favorable ranks, the severe epilepsy ranks were more often associated with an early onset of epilepsy, an infectious disease at the onset, delayed development before epilepsy, abnormalities in neurologic or neuroradiologic examinations, and a deteriorating course of the condition. CONCLUSIONS: Patients with LGS are more likely than patients with less severe epilepsy to have a younger age at onset of epilepsy, an infection or both, and a deteriorating course of the condition.

Brain perfusion SPECT abnormalities in neuronal ceroid lipofuscinoses.

Brain perfusion was studied with the Tc-99m-HMPAO SPECT method in 19 INCL patients, 21 JNCL patients and 5 patients with Jansky-Bielschowsky variant disease (JBVD). The typical SPECT findings at an early stage of INCL were bilateral anterior frontal, posterior temporoparietal and occipital hypoperfusion, whereas reduction in cerebellar perfusion appeared later. However, perfusion of basal ganglia and thalami, although atrophic on MRI, was usually well preserved up to the terminal stage. All JNCL patients except one had at least one hypoperfused area. Mild hypoperfusion was usually located in the parietal and occipital lobes and cerebellum, whereas more severe hypoperfusion was observed in the temporal lobes. In JNCL, SPECT revealed lesions not detected on CT. All JBVD patients had supra- and infratentorial hypoperfusion, which was usually bilateral. This study shows that although in NCLs brain hypoperfusion can appear prior to structural abnormalities seen on MRI or CT, such abnormalities are not always associated with significant hypoperfusion.

Lamotrigine therapy in infantile neuronal ceroid lipofuscinosis (INCL).

Since 1990, altogether 16 INCL patients received lamotrigine (LTG) because of intractable epilepsy. The response to LTG was favorable in 15/16 children. The severity of seizures decreased significantly in 15/16 patients, the frequency of seizures decreased in 14/16, and the effects were maintained. In addition, LTG had a beneficial effect on the well-being of 14/16 children. LTG failed to maintain it's efficacy in monotherapy. No severe side effects were found.

West syndrome: individualized ACTH therapy.

Individualized ACTH treatment of the West syndrome (WS) was assessed in a prospective multicenter study, in which each patient's dosage was increased stepwise according to response. Our series included six patients with cryptogenic and 24 with symptomatic infantile spasms. During the treatment period the total ACTH dose ranged from 58 to 373 i.u./kg. In the cryptogenic group one patient responded to pre-ACTH pyridoxine and four to the lowest dosage of ACTH (3 i.u./kg daily) with cessation of spasms and good outcome; one patient needed the highest dosage (12 i.u./kg daily) for cessation of seizures and became developmentally retarded. In the symptomatic group, 21 of the 24 patients needed 6-12 i.u./kg daily; 12 became seizure-free or having infrequent non-IS fits. Complications such as arterial hypertension, cerebral ventricle dilatation, cardiac hypertrophy, and prolonged adrenocortical hyporesponsiveness were related to the dose. The individualization provides all the benefits of ACTH treatment with minimal side effects and cost.

Brain perfusion SPECT in juvenile neuronal ceroid lipofuscinosis.

The juvenile neuronal ceroid-lipofuscinosis (JNCL) is a recessively inherited progressive encephalopathy. We studied 21 JNCL patients with a duration of illness of 1 to 17 years by 99mTc-HM-PAO single photon emission computed tomography (SPECT) and correlated the findings with clinical parameters. All patients had at least one hypoperfused brain area, the median number of such areas was 5 per patient. Parietally, occipitally, and in the cerebellar lobes hypoperfusion was usually mild whereas it was temporally more severe. Right parietal hypoperfusion correlated to neurological dysfunction.

Circadian rhythm studies in neuronal ceroid-lipofuscinosis (NCL).

Sleep disorders are common in NCL patients. The patients have problems such as frequent awakenings, difficulties with sleep onset, nightmares, and night terrors. The aim of the study was to examine whether the sleep disturbance in NCL can be explained on the basis of desynchronised circadian rhythms. Therefore we studied diurnal patterns of melatonin, cortisol, body temperature, and motor activity of 14 patients. The group consisted of 8 JNCL patients, 5 INCL children, and one boy with Jansky-Bielschowsky disease of the variant type. There were healthy age- and sex-matched control subjects. The blood samples for serum melatonin and cortisol were collected every 2 hours during 24-hour periods. Body temperature was recorded continuously for a 24-hour period by a polygraph. Diurnal motor activity was measured by wrist actigraphy for 5 days. In most of our patients sleep was fragmented and the sleep phase was irregular. Disturbances in the daily hormonal rhythms occurred only in the minority of the patients and only at an advanced stage of the disease. Although disturbances in the body temperature rhythm were found in about half of the patients, a general failure in the circadian regulatory system does not explain the frequent disturbances of the sleep-wake cycle of the NCL patients.

Cortical sensory evoked potentials and communicative forebrain functions.

Cortical evoked potentials were measured to visual, auditory and somatosensory stimuli in 20 subjects with serious neurodevelopmental impairments due to various etiologies. The results were compared with behavioral observations to find out whether the absence/presence of the responses corresponded to the level of social functioning. No cortical evoked potentials were elicited in two subjects, responses to the stimulation of one modality were missing in three subjects (retinal b-waves and brainstem auditory and somatosensory evoked potentials were, however, preserved in them). No communicative behavior was observed in subjects with absent responses. Ten subjects had marked deviations in the evoked potentials, the behavioral observations in them, ranging from no communication to sentenced speech. Five subjects had normal response patterns and they showed a great variety of communicative skills, including speech. The results support the view that bilateral loss of cortical somatosensory, visual, and auditory evoked potentials is a sign of loss of neural substrates of communication.

Melatonin, cortisol and body temperature rhythms in Lennox-Gastaut patients with or without circadian rhythm sleep disorders.

The daily rhythms of melatonin, cortisol and body temperature were studied in 16 institutionalized subjects with the Lennox-Gastaut syndrome. The results of 9 subjects with normal daily rhythms of sleep and wakefulness (group 1) were compared with those of 7 subjects with disordered sleep (group 2). Salivary samples were collected and axillary temperature was measured every 2 h during two or three separate 26-h periods. The hormones were measured by radioimmunoassays. The rhythms were characterized with single cosinor analysis. Two subjects in group 1 and six subjects in group 2 had abnormalities in their rhythms of temperature, cortisol or melatonin. All three rhythms were disrupted in two subjects of group 2. These two subjects were the only ones with disrupted cortisol rhythm. The diversity of rhythm pathologies suggested partly separate regulatory mechanisms for each rhythm. The co-occurrence of circadian rhythm sleep disorders with the deteriorated melatonin rhythm raised the question as to whether the sleep disorders of these subjects, like those of subjects with healthy brains, could be relieved by the induction of normal melatonin rhythm.

Brain perfusion SPECT in children with frequent fits.

We studied 14 children with frequent fits using 99mTc-HM-PAO single photon emission computed tomography (SPECT). There were 11 patients with partial secondary generalized epilepsy (PSGE) and 3 with Lennox-Gastaut syndrome (LGS). The typical regional cerebral blood flow (rCBF) finding in PSGE was a single area of abnormally low perfused cortex, and that in LGS, multiple hypoperfused areas. Clinically, the LGS patients were more severely affected. SPECT was more sensitive in detecting abnormalities than EEG, CT or MRI. Extensive impairment of rCBF may thus indicate unfavourable development of intellectual performance and poor seizure control.