Ruthmary K. Deuel

Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders.

OBJECTIVE Etiologically unexplained disorders of language and social development have often been reported to improve in patients treated with immune-modulating regimens. Here we determined the frequency of autoantibodies to brain among such children. DESIGN We collected sera from a cohort of children with (1) pure Landau-Kleffner syndrome (n = 2), (2) Landau-Kleffner syndrome variant (LKSV, n = 11), and (3) autistic spectrum disorder (ASD, n = 11). None had received immune-modulating treatment before the serum sample was obtained. Control sera (n = 71) were from 29 healthy children, 22 with non-neurologic illnesses (NNIs), and 20 children with other neurologic disorders (ONDs). We identified brain autoantibodies by immunostaining of human temporal cortex and antinuclear autoantibodies using commercially available kits. RESULTS IgG anti-brain autoantibodies were present in 45% of sera from children with LKSV, 27% with ASD, and 10% with ONDs compared with 2% from healthy children and control children with NNIs. IgM autoantibodies were present in 36% of sera from children with ASD, 9% with LKSV, and 15% with ONDs compared with 0% of control sera. Labeling studies identified one antigenic target to be endothelial cells. Antinuclear antibodies with titers >/=1:80 were more common in children with ASD and control children with ONDs. CONCLUSION Children with LKSV and ASD have a greater frequency of serum antibodies to brain endothelial cells and to nuclei than children with NNIs or healthy children. The presence of these antibodies raises the possibility that autoimmunity plays a role in the pathogenesis of language and social developmental abnormalities in a subset of children with these disorders.

Language regression in childhood

Language regression is observed both in autistic regression and as part of acquired epileptic aphasia (Landau-Kleffner Syndrome). We prospectively identified 177 children with language regression at four major medical centers, and their clinical characteristics were recorded. Their mean age at regression was 22.8 months. The mean time-to-specialist referral was 38 months of age. Most children (88%) met criteria for autism or manifested autistic features. Males (P = 0.02) and children less than 3 years of age who regressed (P = 0.016) had a higher probability of developing autistic behaviors. Seizures were more common in children who regressed after they reached 3 years of age (P < 0.001), and children with seizures were less likely to have associated autistic regression (P < 0.001). Electroencephalogram abnormalities were reported in 37% of patients and were more common in children with seizures (P < 0.001). At last follow-up, language function was impaired in 88% of the children, although some improvement was noted in 57%. We conclude that the loss of previously acquired language at any age, even if that language only includes a few words or communicative gestures, is often associated with a more global regression in cognition and/or behavior and has serious implications for future function. Early identification and referral of these children is necessary to allow for diagnosis and intervention.Language regression is observed both in autistic regression and as part of acquired epileptic aphasia (Landau-Kleffner Syndrome). We prospectively identified 177 children with language regression at four major medical centers, and their clinical characteristics were recorded. Their mean age at regression was 22.8 months. The mean time-to-specialist referral was 38 months of age. Most children (88%) met criteria for autism or manifested autistic features. Males (P = 0.02) and children less than 3 years of age who regressed (P = 0.016) had a higher probability of developing autistic behaviors. Seizures were more common in children who regressed after they reached 3 years of age (P < 0.001), and children with seizures were less likely to have associated autistic regression (P < 0.001). Electroencephalogram abnormalities were reported in 37% of patients and were more common in children with seizures (P < 0.001). At last follow-up, language function was impaired in 88% of the children, although some improvement was noted in 57%. We conclude that the loss of previously acquired language at any age, even if that language only includes a few words or communicative gestures, is often associated with a more global regression in cognition and/or behavior and has serious implications for future function. Early identification and referral of these children is necessary to allow for diagnosis and intervention.

Definition and Classification of Negative Motor Signs in Childhood

In this report we describe the outcome of a consensus meeting that occurred at the National Institutes of Health in Bethesda, Maryland, March 12 through 14, 2005. The meeting brought together 39 specialists from multiple clinical and research disciplines including developmental pediatrics, neurology, neurosurgery, orthopedic surgery, physical therapy, occupational therapy, physical medicine and rehabilitation, neurophysiology, muscle physiology, motor control, and biomechanics. The purpose of the meeting was to establish terminology and definitions for 4 aspects of motor disorders that occur in children: weakness, reduced selective motor control, ataxia, and deficits of praxis. The purpose of the definitions is to assist communication between clinicians, select homogeneous groups of children for clinical research trials, facilitate the development of rating scales to assess improvement or deterioration with time, and eventually to better match individual children with specific therapies. “Weakness” is defined as the inability to generate normal voluntary force in a muscle or normal voluntary torque about a joint. “Reduced selective motor control” is defined as the impaired ability to isolate the activation of muscles in a selected pattern in response to demands of a voluntary posture or movement. “Ataxia” is defined as an inability to generate a normal or expected voluntary movement trajectory that cannot be attributed to weakness or involuntary muscle activity about the affected joints. “Apraxia” is defined as an impairment in the ability to accomplish previously learned and performed complex motor actions that is not explained by ataxia, reduced selective motor control, weakness, or involuntary motor activity. “Developmental dyspraxia” is defined as a failure to have ever acquired the ability to perform age-appropriate complex motor actions that is not explained by the presence of inadequate demonstration or practice, ataxia, reduced selective motor control, weakness, or involuntary motor activity.

Primary motor cortex reorganization in a long-term monkey amputee

The primary motor cortex (M1) was mapped with intracortical microstimulation (ICMS) in a 15 year-old macaque whose right upper extremity was amputated at the shoulder joint prior to 2 years of age. Movements of the right shoulder girdle and stump were evoked by ICMS throughout the left M1 upper extremity region. The size of the left M1 upper extremity region contralateral to the amputated arm was not appreciably different from the size of the right upper extremity region contralateral to the intact arm. Long stimulus trains and/or higher stimulus currents were needed to evoke detectable movements at significantly more loci in the left than in the right M1 upper extremity region. These observations would be consistent with unmasking of a high threshold representation of shoulder musculature that normally exists throughout the central core of the upper extremity region, where it underlies a lower threshold representation of the distal forelimb. Alternatively, invasion of the de-efferented distal forelimb core by surrounding shoulder representation may have occurred. Differences between the limited M1 reorganization observed in the present study and the more extensive reorganization of S1 observed in other studies may reflect fundamental differences between M1 and S1, and/or differences in the extent of de-efferentation versus deafferentation.

Recovery from unilateral neglect

Spontaneous recovery of function occurs in the syndrome of hemisensory neglect in monkeys. We produced this syndrome in 13 macaques by unilateral operative resection of the frontal polysensory association cortex. Using standardized behavioral measures, we documented severe acute neglect and followed the course of its improvement. Using the 2-deoxy[14C]glucose autoradiographic method, we studied animals in the acute phase of neglect and found decrements in local glucose utilization in subcortical structures, but not in cortical regions with known frontal connections. After spontaneous behavioral recovery, mild local glucose utilization decrements remained, but only in nucleus medialis dorsalis of the thalamus. The findings suggest that acute behavioral symptoms are based on widespread depression of neuronal activity in uninjured structures with synaptic relations to damaged cortex, and that return of neuronal activity in those structures is accompanied by restitution of behavioral function.

A Quantitative Analysis of Apraxia in Senile Dementia of the Alzheimer Type: Stage-Related Differences in Prevalence and Type

Apraxia is clinically separable from other cognitive dysfunctions and has the potential to interfere with motor performance in everyday living. To determine its prevalence and severity at each stage o

Parietal hemineglect and motor deficits in the monkey

To study the parietal hemineglect syndrome, we trained and operated nine Macaca fasicularis monkeys. Contralateral to the lesion they showed response abnormalities to visual and somatic sensory stimuli, and misreaching toward targets in visual space, abberant finger and wrist postures and lack of pincer grasp. The latter did not appear during performance of a preoperatively practised task, nor depend for severity upon lesion size, whereas sensory response abnormalities did. We conclude that abnormal motor patterns are separable from hemineglect in parietal animals, and are worst when the movement is directed to a visual target in extrapersonal space.

Interaction between the hemispheres in unimanual somesthetic learning

Abstract The prefrontal and temporal lobes of both hemispheres in monkeys have been found to contribute to unimanual learning of somesthetic discrimination and reversal. To investigate the pathways through which this contribution is made, subjects with bilateral removals of each lobe (B group) were compared with those having corresponding unilateral removals, opposite the hand trained, combined with section of the telencephalic commissures (U+s group). Unoperated monkeys and monkeys with contralateral lesions alone served as controls. Since the deficit was the same for corresponding prefrontal and temporal lesion subgroups, these were combined for further comparisons among the two major types of preparations and the controls. Although monkeys of the B and the U+s groups showed quantitatively similar over-all impairments, further analysis of the course of reversal learning revealed a double dissociation of deficits. The B group subjects were impaired only in extinction of the original habit, whereas those of the U + s group were deficient only in acquisition of the new habit after the acute extinction phase. Differences between these groups were also uncovered by closer examination of their performance on the discrimination tasks. These results were interpreted in terms of the differential roles of “horizontal” and “vertical” connections. It was proposed that the deficit specific to animals of the B group was one of perseverative interference with learning and was due to the loss of vertical connections between nonsensorimotor regions of the endbrain and lower centers; by contrast, the deficit specific to animals of the U+s group was attributed to a sensory and motor “neglect”, resulting from the loss of horizontal connections between nonsensorimotor and sensorimotor regions within the endbrain.

Simultaneous In Vivb Monitoring of Cerebral Deoxyglucose and Deoxyglucos-6-Phosphate by l3C{lH} Nuclear Magnetic Resonance Spectroscopy

Abstract: The capacity of brain to dephosphoirylate glucose‐6‐phosphate has been established, but the magnitude and significance of this capacity in vivo are debated, particularly in regard to dephosphorylation of the glucose analog 2‐de‐oxyglucose. We now report results of external m easurement in the brains of conscious rats with simultaneous resolution and quantification of both 2‐deoxyglucose and its phosphor‐ylated product by nuclear magnetic resonance (NMR) techniques that used 2‐[6‐l3C]deoxyglucose together with proton‐decoupled 13C surface‐coil spectroscopy. As NMR techniques require large doses of 2‐deoxyglucose, a dose comparison was first made using decay curves of total label after tracer doses of 2‐[14C]deoxyglucose without versus with unlabeled deoxyglucose at 500 mg/kg (the NMR dose). Similar cerebral half‐lives for the two doses were found, and no behavioral evidence for toxicity of the NMR dose was seen. In vivo NMR monitoring of conscious rats showed that the analog reached maximal cerebral concentration within 10 min of the intravenous bolus and decayed with a half‐life of 29 ± 7 min (n = 4; mean ± SEM), whereas 2‐deoxyglucose‐6‐phos‐phate reached peak concentration between 30 and 40 min and decayed with a half‐life of 2.1 ± 0.3 h, equivalent to a fractional loss of 0.8%/min. Thirty‐one percent (±5%) of the total analog pool (which showed a half‐life of 1.4 h) consisted of 2‐deoxyglucose at 45 min after the bolus. The results support an active but limited role for dephosphorylation by normal brain in glucose analog (and potentially glucose) metabolism in the unstimulated conscious rat and a wide concentration range for the metabolic operations involved.

Autism: a cognitive developmental riddle.

It has been 60 years since the definitive descriptions of autism, yet it is only in the past decade that related advances in cognitive and basic neuroscience have begun to be incorporated in clinical practice. Some of the resultant clinical advances, which include a trend toward international standardization of diagnosis on the basis of behavioral criteria and which, in turn, seem to allow for earlier, more secure diagnosis and the application of behavioral therapy in early childhood, as well as more thorough genetic studies, are briefly reviewed. The three major defects in thought processing that are postulated by cognitive neuropsychologists to result in aberrant autistic behaviors are also reviewed and linked to recent functional imaging studies in autistic patients and some animal and bench research suggestive of both cortical and subcortical developmental vulnerabilities in autism. Overall it seems at least possible that neuroscientific research may yield results applicable to prevention or remediation of autism, a condition heretofore considered irremediable.