Differences in globus pallidus neuronal firing rates and patterns relate to different disease biology in children with dystonia.

BACKGROUND: The pathophysiology underlying different types of dystonia is not yet understood. We report microelectrode data from the globus pallidus interna (GPi) and globus pallidus externa (GPe) in children undergoing deep brain stimulation (DBS) for dystonia and investigate whether GPi and GPe firing rates differ between dystonia types. METHODS: Single pass microelectrode data were obtained to guide electrode position in 44 children (3.3-18.1 years, median 10.7) with the following dystonia types: 14 primary, 22 secondary Static and 8 progressive secondary to neuronal brain iron accumulation (NBIA). Preoperative stereotactic MRI determined coordinates for the GPi target. Digitised spike trains were analysed offline, blind to clinical data. Electrode placement was confirmed by a postoperative stereotactic CT scan. FINDINGS: We identified 263 GPi and 87 GPe cells. Both GPi and GPe firing frequencies differed significantly with dystonia aetiology. The median GPi firing frequency was higher in the primary group than in the secondary static group (13.5 Hz vs 9.6 Hz; p=0.002) and higher in the NBIA group than in either the primary (25 Hz vs 13.5 Hz; p=0.006) or the secondary static group (25 Hz vs 9.6 Hz; p=0.00004). The median GPe firing frequency was higher in the NBIA group than in the secondary static group (15.9 Hz vs 7 Hz; p=0.013). The NBIA group also showed a higher proportion of regularly firing GPi cells compared with the other groups (p<0.001). A higher proportion of regular GPi cells was also seen in patients with fixed/tonic dystonia compared with a phasic/dynamic dystonia phenotype (p<0.001). The GPi firing frequency showed a positive correlation with 1-year outcome from DBS measured by improvement in the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS-m) score (p=0.030). This association was stronger for the non-progressive patients (p=0.006). INTERPRETATION: Pallidal firing rates and patterns differ significantly with dystonia aetiology and phenotype. Identification of specific firing patterns may help determine targets and patient-specific protocols for neuromodulation therapy. FUNDING: National Institute of Health Research, Guy's and St. Thomas' Charity, Dystonia Society UK, Action Medical Research, German National Academic Foundation.

Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) as a cause of liver disease in infants in the UK.

Citrin deficiency is a disorder with two phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), and adult-onset type II citrullinaemia (CTLN2). NICCD presents in the first few weeks of life with prolonged cholestasis and metabolic abnormalities including aminoacidaemia (notably citrulline, tyrosine, threonine, arginine and methionine) and galactosuria. Symptoms resolve within the first year of life, thus making a diagnosis difficult after this time. Although patients subsequently remain generally healthy, some may develop more severe symptoms of CTLN2, characterized by neurological changes, one or more decades later. To date more than 400 cases have been reported, almost all from East Asia (mainly Japan). Here we describe the first two cases of NICCD in infants from the UK, one of caucasian origin and one of Pakistani origin. Both showed typical clinical and biochemical changes with a diagnosis confirmed by the presence of previously unreported mutations in the SLC25A13 gene. The presence of citrin deficiency in other ethnic groups means that NICCD needs to be considered in the diagnosis of any neonate with an unexplained cholestasis. We discuss both the difficulties in diagnosing these patients in populations where very few DNA mutations have been identified and the problems faced in the management of these patients. These findings also raise the possibility of adults with CTLN2 in whom a diagnosis has yet to be made.

Dislocation of the hips in children with bilateral spastic cerebral palsy, 1985-2000.

The aim of this study was to assess the rate of hip dislocation at different ages in children with bilateral spastic cerebral palsy attending special schools in southern Derbyshire, UK, between 1985 and 2000. The medical notes of 110 individuals (68 males, 42 females) were obtained. They were divided into four groups according to the Gross Motor Function Classification System (GMFCS). We determined whether or not their hips were dislocated at the ages of 5, 10, and 15 years, and the kind of surgery performed in each case. The percentage of individuals with one or both hips dislocated increased with age and with severity of disease. Of those in GMFCS Level II (n=18), none had dislocations; Level III (n=16), none had dislocations at ages 5 and 10, but 11% had by the age of 15; Level IV (n=35), 8% had dislocations by age 5, 19% by age 10, and 30% by age 15; Level V (n=41), 22% had dislocations by age 5, 48% by age 10, and 50% by age 15. Forty-two per cent of individuals with hip dislocation had not had previous preventive surgery. Twenty-one per cent of hips operated on still proceeded to dislocation. We conclude that there was a high rate of hip dislocation, especially in GMFCS groups Levels IV and V, and that this often occurred very early. Preventive surgery avoided dislocation in many children. However, orthopaedic referral was often not made before dislocation was discovered, or the referral was made too late for surgery on soft tissue to be successful. These results may be compared with those from current programmes of hip management, involving radiological surveillance and early use of conservative and surgical interventions.

Comparison of spinal myotatic reflexes in human adults investigated with cross-correlation and signal averaging methods.

A cross-correlation method for recording spinal myotatic reflexes has been developed to meet the need for brief test periods in babies and children and subjects with central neurological pathology. In normal adult subjects the method has been validated by comparing excitatory and inhibitory reflexes obtained with cross-correlation with those obtained with conventional signal averaging. In the cross-correlation method a pseudo-random binary sequence of 64 brief tendon taps was delivered in <1.5 s, and in the averaging method 20-150 taps at one per second. The reflexes were expressed as unit impulse responses to enable direct, quantitative comparisons to be made. With cross-correlation the responses were slightly expanded in time, had lower peak amplitudes, and onset latencies advanced by 10 ms, the clock period of the pseudo-random binary sequence. The amplitude of biceps phasic stretch reflex increased with muscle contraction in a similar manner with both methods. In tests for stationarity the amplitude of biceps phasic stretch reflex varied <10% in the first six repeats of the pseudo-random binary sequence. The tap force required at threshold for cross-correlation was approximately half that for averaging, but with both methods the magnitude of biceps phasic stretch reflex varied linearly with tap force over the range of one to two times threshold. The validity of responses obtained with cross-correlation was assessed by a statistical procedure. In conclusion, the cross-correlation method is robust and gives similar results to those obtained with averaging.

Short latency heteronymous excitatory and inhibitory reflexes between antagonist and heteronymous muscles of the human shoulder and upper limb.

The aims were (i) to investigate heteronymous excitatory and inhibitory Group Ia reflexes linking agonist/antagonist muscle pairs acting at the shoulder and elbow; clavicular pectoralis major (Pmajor) and posterior deltoid (Pdeltoid); biceps brachii (Bi) and Tri brachii (Tri), and linking muscles acting at the elbow (Bi and Tri) with muscles acting at the shoulder (Pmajor and Pdeltoid). (ii) To test the hypothesis that the excitability of the reflexes would vary between different tasks in a functionally relevant manner. The study was performed on 45 adults. Reflexes were recorded in the surface EMG when the target muscle was contracting at 10% maximum voluntary contraction. Reflexes were recorded in Bi and Tri with the elbow joint in one of three positions: 105 degrees, 80 degrees, or 55 degrees from full extension. Group Ia reflexes were evoked using a small, brief tap to the tendon of the muscle being stimulated. Reflexes were recorded by cross-correlation of the surface EMG and pseudo-random series of taps. All subjects demonstrated short latency inhibition and excitation between agonist/antagonist muscle pairs; inhibition was significantly more frequent than excitation. Excitation and inhibition occurred with equal frequency between muscle pairs acting between elbow and shoulder. Minimum central delays for excitatory reflexes were 1 ms, consistent with monosynaptic projections and for inhibitory responses were 2 ms consistent with disynaptic linkage. Later excitatory and inhibitory reflexes with central delays of up to 15 ms also occurred. The probability of evoking excitation or inhibition in Tri or Bi changed with the different elbow positions.