Estimated frequency of genetic and nongenetic causes of congenital idiopathic cerebral palsy in west Sweden.

Mathematical analysis of prenatal and perinatal risk factors was performed on the first 681 published cases of idiopathic congenital cerebral palsy (born 1959-1970) in the west Swedish population-based cerebral palsy (CP) study. Analysis indicates that an estimated 40% of etiologically undiagnosed cases of CP in the community (48% of those born at term and 24% of those born prematurely) are genetically caused. These proportions of genetic causation are no less in CP than in idiopathic mental retardation. Genetic causes account for 60% of maturely born hemiplegics, 45% of maturely born spastic diplegics, 32% of premature spastic diplegics and virtually all cases of pure ataxia. About 23% of CP cases in the community have suffered nongenetic brain damage in accordance with the two-stage model. The residue of 37% is characterized by a single risk factor, usually perinatal.

Ineffectiveness of oral coenzyme Q10 supplementation in 3-methylglutaconic aciduria, type 3.

Coenzyme Q10 was administered under placebo controlled blinded crossover conditions to six subjects suffering from type 3 3-methylglutaconic aciduria ('optic atrophy plus'), following a report of benefit. Despite attainment of high plasma levels of coenzyme Q10, no clinical benefit was observed and there was no diminution of urinary excretion of 3-methylglutaconic acid.

CT findings in persistent vegetative state following blunt traumatic brain injury.

The use of linear measurements in the analysis of CT scans of TBI patients was found to contribute to the understanding of brain damage and were correlated with outcome in severe traumatic close brain injured patients. The purpose of the present study was to analyse the data obtained by the linear measurements on CT studies of TBI patients who remained in persistent vegetative state following blunt head trauma. All 27 patients included in the study were reported to be neurologically normal prior to injury. Thirteen patients, 11 remaining in persistent vegetative state (responsive but unaware) and two who died, constituted the worst outcome group. Fourteen patients who regained consciousness, underwent multidisciplinary evaluation when their recovery reached a plateau and were ranked according to severity of residual symptoms and outcome. The degree of correlation with the overall vocational outcome parameter with the various radiological indices was calculated as the Spearman rank correlation coefficient, with correction for tied scores. Fisher's z transformation was used to combine results with those of our previous analysis. Three radiological parameters showed a statistically significant correlation with clinical outcome. These were the right and left septum-caudate distance and the cerebroventricular index 2; these showed Spearman rank coefficients of 0.52, 0.45 and 0.48; with two-tailed p-values under 0.01, 0.02 and 0.01 respectively. The width of the third ventricle suggested correlation with the clinical scoring. The findings of the present study point to the importance of loss of deep gray matter of the caudate nuclei and widening of the adjacent part of the lateral ventricles in catastrophic brain injury. This finding may highlight the role of localized ischemic changes, in addition to diffuse axonal injury. Values of over 8 mm for the width of the third ventricle and over 11 mm for septum caudate distance are suggestive of catastrophic and poor prognosis for recovery.

Iraqi-Jewish kindreds with optic atrophy plus (3-methylglutaconic aciduria type 3) demonstrate linkage disequilibrium with the CTG repeat in the 3' untranslated region of the myotonic dystrophy protein kinase gene.

Iraqi-Jewish optic atrophy plus is an autosomal recessive condition characterized by infantile optic atrophy, an early onset movement disorder, and 3-methylglutaconic aciduria. Other features include spastic paraplegia, mild ataxia, mild cognitive deficiency and dysarthria. This disorder was identified in inbred Iraqi-Jewish kindreds in which relationships between most of the affected individuals were unknown. In this study we identify linkage to chromosome 19q13.2-q13.3 by using a DNA pooling strategy to perform a genome wide screen followed by a high density search for shared segments among affected individuals in candidate regions identified in the initial genome wide screen. A significantly high positive lod score of 6.14 at zero recombination was obtained for the CTG repeat in the 3' untranslated region of the myotonic dystrophy protein kinase gene. The existence of multiple recombinant individuals indicates the disease interval can be further narrowed with additional markers. Linkage disequilibrium was seen in six polymorphic markers across a 1 Mb interval. This region is well characterized and contains several candidate genes.

3-Methylglutaconic aciduria in the Iraqi-Jewish 'optic atrophy plus' (Costeff) syndrome.

Eleven new patients of Iraqi-Jewish origin with bilateral optic atrophy, neurological abnormalities ('optic atrophy plus' syndrome) and 3-methylglutaconic aciduria (type III) are described. Clinical abnormalities in decreasing order of frequency were bilateral optic atrophy, extrapyramidal signs, spasticity, ataxia, dysarthria and cognitive deficit. An association with age was found only for spasticity. Spasticity, extrapyramidal signs and optic atrophy frequently led to major disability, in contrast to ataxia, dysarthria and cognitive deficit. The combined excretion of 3-methylglutaconic and 3-methylglutaric acid ranged between 9 and 187 mmol/mol creatinine. The primary enzymatic defect possibly may reside in the mitochondrial respiratory chain.

Course and outcome of patients in vegetative state of nontraumatic aetiology.

A follow up study is reported of 100 consecutive unconscious patients admitted to an intensive care coma facility with a history of 30 days or more of unconsciousness of nontraumatic cause. Twenty recovered consciousness, all within 5 months of injury. 31 of the remaining patients died within 6 months following injury, while 49 continued unconscious until death. The mean life expectancy of these 49 was 26-34 months from that time. All 20 patients who recovered awareness continued to suffer from major disability. The prognosis for life or death and for recovery or not of consciousness was not significantly correlated with age or aetiology of the vegetative state. Among those who recovered consciousness, the younger patients showed somewhat better results in three parameters of function: locomotion, ADL and day-placement, but not in cognition, behaviour or speech accuracy and fluency. The overall results for these nontraumatic patients with postcomatose unawareness are clearly worse than those for patients with a similar period of unconsciousness following craniocerebral trauma.

Multiple syndromes of 3-methylglutaconic aciduria.

The most common clinical syndromes associated with 3-methylglutaconic aciduria are presented. In some patients these syndromes are multisystemic, progressive disorders of unknown etiology. Tissues deriving significant energy through oxidative metabolism (notably brain and cardiac muscle) are most often affected and in some the primary defect may reside within the mitochondrial respiratory chain. Although increasing biochemical evidence suggests that 3-methylglutaconic aciduria may correlate with deranged mitochondrial energy metabolism, the biochemical origin of 3-methylglutaconic acid and the significance of its increased excretion remain unknown. This review describes these syndromes and illustrates the necessity of urinary organic acid analysis to assist in the differential diagnosis.

3-Methylglutaconic aciduria in "optic atrophy plus".

Behr's syndrome consists of recessively inherited infantile optic atrophy, together with chronic neurological disturbances such as ataxia, extrapyramidal dysfunction, and juvenile spastic paresis. This syndrome was found to be relatively common among Iraqi Jews. For our study, 18 such patients underwent metabolic study. All 18 showed abnormally elevated excretion of 3-methylglutaconic acid in their urine. The basic enzymatic defect is as yet unknown. We recommend that patients with early optic atrophy, and especially those with motor dysfunction, be examined for this organic aciduria.

Late CT findings in brain trauma: relationship to cognitive and behavioral sequelae and to vocational outcome.

OBJECTIVE: The purpose of this study was to determine the degree of correlation between cerebral atrophy observed on CT scans after severe blunt brain trauma and later neuropsychological status, as well as to evaluate the relative prognostic values of a number of indexes of cerebral atrophy. MATERIALS AND METHODS: The study group comprised 32 previously healthy men 18-65 years old who had severe blunt trauma of the brain (initial scores on Glasgow coma scale of 7 or less). Their cognitive and behavioral statuses were evaluated when the patients were discharged from the hospital, which occurred when the recovery process showed a plateau. Overall vocational status was evaluated 1 year after discharge. The clinical evaluation was performed by a multidisciplinary team. Multiple linear indexes derived from brain CT scans obtained about 3 months after injury in patients with blunt brain trauma were correlated with cognitive and behavioral sequelae of brain damage and with vocational placement, as evaluated by a rehabilitation team about 1 year after trauma. RESULTS: A high correlation was found between the width of the third ventricle and outcome. The prognostic value of the width of the third ventricle was superior to that of any other index studied, and it correlated best with late cognitive status (Spearman r = .57, p < .01). CONCLUSION: The width of the third ventricle is a useful prognostic index in cases of diffuse brain trauma. It indicates diencephalic atrophy, caused either by diffuse axonal injury or by hypoxia. It may indicate a role of diencephalic structures in higher cortical functions.

Epidemiological findings in traumatic post-comatose unawareness.

We have examined the epidemiological background of 134 consecutive patients admitted to our centre who suffered from post-traumatic unconsciousness of over 1 month's duration. The incidence of such unconsciousness in Israel is estimated as 4 per 1,000,000, or one case in 410 hospitalizations for head trauma. The cause of trauma was a road accident in 69% of cases. Among victims, pedestrians and cyclists were more likely than four-wheeled vehicle drivers and their passengers to suffer from prolonged unconsciousness, from which they were less likely to recover.

Covariance analysis of laboratory variance in steady-state serum phenytoin concentrations.

Inpatients (n = 57) on long term prophylaxis with 2 oral phenytoin preparations were followed up via monthly checks of serum drug concentrations. Duplicate serum aliquots were submitted to 2 laboratories, and covariance analysis was used to estimate laboratory error. The laboratory-associated variance of examinations using the 'EMIT' or 'TDX' systems was 7.1 to 10 (mg/L)2, while that of chromatographic assays was 37.1 (mg/L)2. Laboratory errors were distributed in a non-normal fashion. The ratio of the maximum rate of metabolism (Vmax) and the Michaelis-Menten constant (Km) tended to remain constant between individuals. A linear analytical model showed little more residual variance than one based on Michaelis-Menten pharmacokinetics.

Prognosis for recovery from prolonged posttraumatic unawareness: logistic analysis.

This study reviews the course and outcome of 130 patients who remained in a state of prolonged unawareness 30 days after severe cranio-cerebral trauma. Prognostic indicators and outcome were fitted by a logistic model. The significant prognostic factors observable in the first week after trauma were found to be ventilatory status, motor reactivity and significant extraneural trauma. The significant prognostic factors after the first month of unawareness were early ventilatory status, early motor reactivity, late epilepsy and hydrocephalus. The estimated probability of recovery of awareness (that is, consciousness) ranged from 0.94 in patients with early decorticate posturing in the absence of both extraneural trauma and ventilatory disturbance to 0.06 in patients with flaccidity, extraneural trauma and ventilatory disturbance in the first week after injury.

Growth hormone secretion in Prader-Willi syndrome.

Integrated 12-hour growth hormone secretion studies, peak growth hormone response to clonidine provocation. Somatomedin-C levels, T-4 and TSH levels were studied in six growth-retarded children with the Prader-Willi syndrome, of whom five had a 15 q-karyotype. Only one of the subjects was obese. All showed abnormally low growth hormone secretion. None achieved a nocturnal peak above 10 micrograms/l, none had a mean nocturnal level over 1.8, and none showed a level above 8 micrograms/l after clonidine provocation. These findings contrasted with normal TSH in all and normal T-4 in five. These findings suggest that the poor linear growth in the Prader-Willi syndrome is caused by a true deficiency of growth hormone secretion, and that the low growth hormone levels observed in such cases are not an artifact of obesity.

Long-term follow-up review of 31 children with severe closed head trauma.

Thirty-one children aged 3 to 15 years were followed for 5 to 11 years after suffering severe closed head trauma which caused coma for 1 week or more (median duration of coma 3 weeks). One patient remained in a persistent vegetative state until his death 9 years later. The other 30 recovered consciousness and were discharged. All suffered diminution of their abilities, and 24 of them had major permanent disability. The most common motor disabilities were pure spastic hemiparesis (seven cases), basal ganglia syndromes (four cases), ataxia (three cases), and a combination of hemiparesis and ataxia (five cases). Of the 30 patients, 26 regained independent ambulation, seven were epileptic, and 14 were dysarthric in various degrees. Only 10 had the cognitive ability to profit from the normal educational system, and none had attempted postsecondary education. Social problems were common. The worst outcomes were associated with intracranial bleeding and/or brain contusion seen on computerized tomography (CT) scans at the acute stage; the best were associated with normal CT scans. The degree of residual disability in these children seems no less than that of adults with trauma of similar severity.

Motor abnormalities during sleep in patients with childhood hereditary progressive dystonia, and their unaffected family members.

The structure of sleep and number of body movements (BMS) and periodic leg movements during sleep (PMS), were studied in three unrelated girls suffering from L-DOPA responsive hereditary dystonia with marked diurnal fluctuation and in their 11 healthy, close relatives. All three girls had an increased number of BMS during rapid eye movement (REM) sleep. Five of the six parents and three siblings had abnormal PMS. One pair of parents had BMS similar to those of their affected daughter. The occurrence of BMS and PMS in the families studied may indicate a common mechanism for both. Because familial PMS is quite rare in its pure form, and this type of dystonia is also rarely encountered, the occurrence of BMS and PMS in members of these families may imply a causative relation between these two sleep-related motor phenomena.

A familial syndrome of infantile optic atrophy, movement disorder, and spastic paraplegia.

We describe 19 cases of a familial syndrome consisting of infantile optic atrophy and an early movement disorder in which chorea predominated. About one-half the patients developed spastic paraparesis during the second decade of life. Ataxia and cognitive deficits were common, usually of mild degree. Seventeen of the patients were females. Sixteen had similarly affected siblings, but none had affected parents. All but one belonged to the Iraqi Jewish community in Israel, giving a minimal prevalence rate in this ethnic group of about 1:10,000.

Practice of prophylactic anticonvulsant treatment in head injury.

The policy of patient selection for prophylactic anticonvulsant treatment has been evaluated retrospectively in 124 head-injured patients admitted consecutively for rehabilitation after primary neurosurgical treatment. Prophylaxis had been instituted in about 60% (51/83) of high risk patients and in about 30% (12/41) of the patients who did not belong to the high risk categories. The use of existing risk data as guidelines for decisions about anticonvulsant prophylaxis is discussed.

Rehabilitation outcome after anoxic brain damage.

Outcome was analyzed in a group of 31 patients who were comatose for more than 24 hours after cardiopulmonary arrest and were thereafter referred for inpatient rehabilitation. Seventeen regained functional ambulation, 20 regained oral communication, and 13 regained full independence in activities of daily living. Two regained their approximate previous cognitive level, and one regained his previous level of employment. These outcomes are strikingly inferior to those of patients with prolonged coma after craniocerebral trauma who were hospitalized in the same center during the same period. Both age and coma duration were correlated with outcome. The relatively better outcomes were seen in patients who were 25 years or younger at the time of anoxic injury, and whose coma lasted less than 24 hours.