Neurometabolic functioning and neuropsychological correlates in children with ADHD-H: preliminary findings

Proton magnetic resonance spectroscopy (MRS) and neuropsychological testing were conducted on 8 children with attention-deficit/hyperactivity disorder (ADHD-H), with no learning disabilities or comorbidities and 8 controls. Magnetic resonance spectroscopy revealed increased Glutamate/Glutamine in both frontal areas, and increased N-acetyl aspartate and Choline in the right frontal area of the ADHD-H subjects. Neuropsychological testing revealed few within- and between-group differences. Findings related to frontal lobe dysfunction in ADHD-H subjects were noted. N-acetylasparte/creatine (NAA/Creatine) in the right frontal region, and myoinositol/creatine (Myo inositol/Creatine) in the right and left frontal regions appear to be highly associated with the regulation of sensorimotor, language, and memory and learning functioning in children with ADHD-H.     

Restricted unilateral Sydenham's chorea: reversible contralateral striatal hypermetabolism demonstrated on single photon emission computed tomographic scanning.

Sydenham's chorea results from group A streptococcus infection and subsequent generation of antineuronal antibodies directed at the caudate nucleus and putamen. Predominantly bilateral, in up to 30% of cases the chorea can be unilaterally restricted. Imaging studies, both structural (magnetic resonance imaging) and functional (positron emission tomography), in patients with bilateral Sydenham's chorea have suggested reversible striatal abnormalities. Two patients with unilateral Sydenham's chorea are presented. Computed tomographic and magnetic resonance imaging were normal in both. However, hexamethylpropylenamine oxime single photon emission tomographic (HMPAO SPECT) studies demonstrated hypermetabolism in the contralateral basal ganglia. Resolution of symptoms in one of the patients coincided with normalization of the SPECT scan. Thus, unilateral striatal hypermetabolism appears to underlie the contralateral chorea observed. A SPECT scan probably should be included in the work-up of new-onset chorea.     

Poststreptococcal acute disseminated encephalomyelitis with basal ganglia involvement and auto-reactive antibasal ganglia antibodies.

Antibasal ganglia antibodies (ABGA) are associated with Sydenham's chorea and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. We present 10 patients with acute disseminated encephalomyelitis (ADEM) associated with Group A beta hemolytic streptococcal infection. The clinical phenotype was novel, with 50% having a dystonic extrapyramidal movement disorder, and 70% a behavioral syndrome. None of the patients had rheumatic fever or Sydenham's chorea. Enzyme-linked immunosorbent assay, Western immunoblotting, and immunohistochemistry were used to detect ABGA. Neurological (n = 40) and streptococcal (n = 40) controls were used for comparison. Enzyme-linked immunosorbent assay results showed significantly elevated ABGA in the patients with poststreptococcal ADEM. Western immunoblotting demonstrated ABGA reactivity to three dominant protein bands of 60, 67, or 80 kDa; a finding not reproduced in controls. Fluorescent immunohistochemistry demonstrated specific binding to large striatal neurones, which was not seen in controls. Streptococcal serology was also significantly elevated in the poststreptococcal ADEM group compared with neurological controls. Magnetic resonance imaging studies showed hyperintense basal ganglia in 80% of patients with poststreptococcal ADEM, compared to 18% of patients with nonstreptococcal ADEM. These findings support a new subgroup of postinfectious autoimmune inflammatory disorders associated with Group A beta hemolytic streptococcus, abnormal basal ganglia imaging, and elevated ABGA.     

Glutaric aciduria type 1: proton magnetic resonance spectroscopy findings

Glutaric aciduria type 1 is an inborn error of lysine, hydroxylysine, and tryptophan metabolism caused by deficiency of glutaryl-coenzyme A dehydrogenase. The disease often appears in infancy with an encephalopathic episode that results in acute basal ganglia and white matter degeneration. The neuroimaging findings in glutaric aciduria type 1 have been well defined. However, the changes in magnetic resonance spectroscopy, a noninvasive tool for identifying the biochemical state of the brain, are scarce in glutaric aciduria type 1. This report presents the magnetic resonance spectroscopy findings in a 19-month-old male with glutaric aciduria type 1. Magnetic resonance spectroscopy of right frontal white matter and right lentiform nuclei revealed decreased N-acetylaspartate/creatine ratio, slightly increased choline/creatine ratio, and increased myoinositol/creatine ratio, compared with the age-matched control patients. We thought that these changes were in accordance with neuroaxonal damage, demyelination, and astrocytosis in these areas. In conclusion, proton magnetic resonance spectroscopy provides a tool for assessing metabolic disturbances and the extent of brain damage noninvasively in glutaric aciduria type 1.     

Functional brain imaging in Sydenham's chorea and streptococcal tic disorders

Group A streptococcal infections cause a wide range of neuropsychiatric disorders, such as Sydenham's chorea, tics, obsessive-compulsive disorders, and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Structural (computed tomography and magnetic resonance imaging) and functional (positron emission tomography, single-photon emission computed tomography) imaging studies in patients with Sydenham's chorea have suggested reversible striatal abnormalities. The objective of this study was to investigate the cerebral perfusion patterns of the subcortical structures by using hexamethylpropylenamine oxime single-photon emission computed tomography (HMPAO-SPECT) in seven cases of Sydenham's chorea and two cases of streptococcal tic disorder. HMPAO-SPECT studies revealed a hyperperfusion pattern in two and a hypoperfusion pattern in five of the chorea patients and in two patients with tic disorder. The results are discussed in relation to the duration and severity of the symptoms and the response to therapy. Functional imaging findings can be variable in Sydenham's chorea, and hyperperfusion of the striatum and thalamus could be an indicator of the response to therapy and the severity of symptoms. However, the number of cases so far investigated by either SPECT or positron emission tomography is still too limited to draw any firm conclusions.     

Cerebral vasculitis in a case of Sydenham's chorea

A 10-year-old girl with acute-onset hemichorea had multiple areas of abnormal signal seen on magnetic resonance imaging of the brain, associated with middle and anterior cerebral artery vasculitis seen on cerebral angiography. Her serology and clinical course were supportive of the diagnosis of Sydenham's chorea. Other causes of cerebral vasculitis were excluded. Follow-up studies revealed resolution of changes seen on magnetic resonance imaging and partial resolution of angiographic abnormalities. This is the first report of abnormal cerebral angiography in Sydenham's chorea.     

High prevalence of obsessive-compulsive symptoms in patients with Sydenham's chorea

The 20-item Leyton Obsessional Inventory--Child Version was completed by children and adolescents who had had Sydenham's chorea (N = 23) or rheumatic fever without chorea (N = 14). The Sydenham's chorea subjects had significantly more obsessive thoughts and compulsive behaviors and significantly greater interference from these behaviors. Three Sydenham's chorea patients but no rheumatic fever patients had substantial obsessional interference and met criteria for obsessive-compulsive disorder when interviewed by telephone. This suggests that obsessive-compulsive disorder, at least in some patients, may be due to basal ganglia dysfunction.     

Magnetic resonance spectroscopy study in basal ganglia of patients with myoclonic epilepsy with ragged-red fibers

Abnormal magnetic resonance spectroscopic (MRS) signals in the basal ganglia may be one of the characteristics in mitochondrial disease. We report MRS study in a family with myoclonic epilepsy with ragged-red fibers (MERRF). Their MRS studies over the basal ganglia revealed decreased N-acetylaspartate/creatine ratio and increased choline/creatine ratio in the four symptomatic members, but normal in the two asymptomatic members. However, negative MRI study was found in all members of this family. Our report suggests that the increased choline/creatine ratio in basal ganglia MRS may be one of the early information to suspect MERRF disease.     

Is Sydenham's chorea an antiphospholipid syndrome?

In 1686, Thomas Sydenham described a syndrome of chorea occurring in youth which was subsequently shown to be a complication of rheumatic fever. An association between chorea and antiphospholipid antibodies has been reported since 1985. We report two females presenting with chorea, aged 17 and 22, who fulfilled the Jones' criteria for rheumatic fever and concurrently had antiphospholipid antibodies detected in serum. A third patient presented at the age of 16 with two bouts of Sydenham's chorea; no assays for antiphospholipid antibodies were performed at the time but 13 years later she was found to have high titres of anticardiolipin antibodies. No patient had abnormalities in the basal ganglia detected on magnetic resonance imaging. Sydenham's chorea may be part of the spectrum of antiphospholipid-associated neurological disease.     

Late recurrences of Sydenham's chorea are not associated with anti-basal ganglia antibodies

Anti-basal ganglia antibodies (ABGA) have been associated with 100% of acute cases and 69% of persistent cases of Sydenham's chorea. We describe two cases of late recurrences of Sydenham's chorea with absence of ABGA. Both patients had several childhood episodes of Sydenham's chorea. MRI imaging of the basal ganglia and exhaustive investigations for other causes of chorea were normal or negative. The absence of ABGA may be evidence against an autoimmune pathology in late and some persistent recurrences. We suggest the likely pathophysiology to be dopamine hypersensitivity of chronically damaged basal ganglia neurones possibly following induction of an autoimmune antibody response in childhood.     

Sydenham's chorea: not gone and not forgotten

Sydenham's chorea is an ancient disease that continues to afflict large numbers of children throughout the world. A major manifestation of rheumatic fever, Sydenham's chorea is commonly manifested by movement disorder and psychiatric problems, and also may be a marker for a life-threatening carditis. Because Sydenham's chorea is triggered by streptococcal pharyngitis, the most important component of its therapy is antibiotic prophylaxis against further streptococcal infections. Because the pathogenesis of Sydenham's chorea includes the production of anti-basal ganglia antibodies, therapies that modulate immune function or that restore neurotransmitter balance within the basal ganglia may be effective for Sydenham's chorea. Recent reports have suggested that Sydenham's chorea may be part of a spectrum of neuropsychiatric syndromes induced by streptococcal infection.     

Sydenham's chorea, and its complications affecting the nervous system

The well-known symptoms of rheumatic fever and Sydenham's chorea are briefly discussed. Then the associated psychiatric and neurological disorders are considered, especially the obsessive-compulsive and the attention deficit hyperactivity disorders; all linked to previous haemolytic streptococcal infections. Dystonic syndromes, and acute disseminated encephalopathies, also show such links; and may be part of the clinical spectrum of the post-infectious streptococcal illnesses. The causes of Sydenham's chorea are considered, especially an immune reactivity against the basal ganglia, supported by the finding of antibodies reactive against the neurons of the caudate nucleus. The resulting imbalance between dopaminergic and cholinergic systems may cause the involuntary choreiform movements, and account for the beneficial effects of certain drugs. The differential diagnosis of Sydenham's chorea is discussed, and the role of tests such as special imaging techniques. The possible treatments include prophylaxis with penicillin and the use of drugs like sodium valproate, carbamazapine and haloperidol. Immune therapy occupies a special role in selected patients, There is still a need for research into the links between these conditions.     

PANDAS with catatonia: a case report. Therapeutic response to lorazepam and plasmapheresis

This is a report of an 11-year-old, prepubertal boy with acute-onset urinary urgency and frequency, obsessions and compulsions related to urination, severe mood lability, inattention, impulsivity, hyperactivity, and intermittent periods of immobilization. Fever, cough, otitis, and sinusitis preceded neuropsychiatric symptoms. Antistreptolysin O and DNAse B antibody titers were elevated, and magnetic resonance imaging revealed bilateral diffuse caudate nuclei swelling. Plasmapheresis resulted in significant and rapid clinical improvement of obsessive-compulsive disorder symptoms and a simultaneous decrease in basal ganglia swelling, consistent with an immune-mediated pathophysiological process involving group A beta-hemolytic streptococci. Hyperactivity, impulsivity, and inattention improved with lorazepam, suggesting that the attention-deficit/hyperactivity disorder symptoms could be manifestations of catatonia.     

Tourette syndrome associated with unilateral cystic changes in the gyrus rectus.

Brain magnetic resonance imaging of an 11-year-old male with Tourette syndrome demonstrated multicystic changes predominately in the gyrus rectus of the left frontal lobe. Other brain regions, including the basal ganglia, were normal. He did not have any symptoms of the comorbid conditions associated with Tourette syndrome, such as attention-deficit disorder or obsessive-compulsive disorder. The possible neurobiologic connection between Tourette syndrome and the gyrus rectus and its interconnecting pathways is discussed.     

Antibasal ganglia antibodies and their relevance to movement disorders

PURPOSE OF REVIEW: Recently, autoaggressive immunological responses were included among the causative agents of basal ganglia dysfunction. Autoaggressive immune-mediated illnesses secondary to group A beta-haemolytic streptococcal infections present with motor and psychiatric symptoms, due to basal ganglia involvement. These disorders have been associated with serum antineuronal antibodies, relatively specific to human basal ganglia tissue. This review summarizes the most recent studies concerning antibasal ganglia antibodies, focusing on the associated phenotypes and the hypotheses concerning their pathogenicity. RECENT FINDINGS: The spectrum of post-streptococcal neuropsychiatric disorders associated with antibasal ganglia antibodies seems broader than previously recognized. Other than chorea, tics and obsessive-compulsive disorder, which constituted the bulk of previously described disorders associated with antibasal ganglia antibodies, post-streptococcal neuropsychiatric disturbances include a wider range of motor and behavioural abnormalities, in keeping with the multifunctional role of the basal ganglia. An encephalitis lethargica-like illness following streptococcal infection was reported, and unusual adult-onset movement disorders associated with antibasal ganglia antibodies were documented. Moreover, investigators provided preliminary evidence for a pathogenic role of autoantibodies in Sydenham's chorea, the prototypic post-streptococcal neuropsychiatric disorder. SUMMARY: Antibasal ganglia antibodies are relatively specific in identifying post-streptococcal neuropsychiatric disorders, which constitute a wider spectrum of movement disorders than previously recognized. Although their sensitivity in diagnosing Sydenham's chorea seems excellent, it is not yet possible to extrapolate this sensitivity to all the recently identified post-streptococcal neuropsychiatric disorders. The antigens targeted by these autoantibodies and their pathogenic importance are currently under investigation. Preliminary evidence suggests that antibasal ganglia antibodies may be pathogenic.     

Tourette's syndrome: a cross sectional study to examine the PANDAS hypothesis

BACKGROUND: The classical neurological disorder after group A beta haemolytic streptococcal infection is Sydenham's chorea. Recently a tic disorder occurring after group A streptococcal infection has been described and termed PANDAS (paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection). It is proposed that antibodies induced after group A streptococcal infection react with basal ganglia neurones in Sydenham's chorea and PANDAS. Anti-basal ganglia antibodies (ABGA) are present in most cases of acute Sydenham's chorea, but rarely in controls. OBJECTIVE: To investigate the hypothesis that Tourette's syndrome may be associated with group A streptococcal infection and ABGA. METHODS: 100 patients with Tourette's syndrome (DSM-IV-TR) were enrolled in a cross sectional study. Children with neurological disease (n = 50) and recent uncomplicated streptococcal infection (n = 40), adults with neurological disease (n = 50), and healthy adults (n = 50) were studied as controls. Recent group A streptococcal infection was defined using antistreptolysin O titre (ASOT). ABGA were detected using western immunoblotting and indirect immunofluorescence. RESULTS: ASOT was raised in 64% of children with Tourette's syndrome compared with 15% of paediatric neurological disease controls (p < 0.0001), and in 68% of adults with Tourette's syndrome compared with 12% of adult neurological controls and 8% of adult healthy controls (p < 0.05). Western immunoblotting showed positive binding in 20% of children and 27% of adults with Tourette's syndrome, compared with 2-4% of control groups (p < 0.05). The most common basal ganglia binding was to a 60 kDa antigen, similar to the proposed antigen in Sydenham's chorea. Indirect immunofluorescence revealed autoantibody binding to basal ganglia neurones. Serological evidence of recent group A streptococcal infection, assessed by a raised ASOT, was detected in 91% (21/23) of Tourette's syndrome patients with positive ABGA compared with 57% (44/77) with negative ABGA (p < 0.01). CONCLUSIONS: The results support a role of group A streptococcal infection and basal ganglia autoimmunity in a subgroup of patients with Tourette's syndrome and suggest a pathogenic similarity between Sydenham's chorea and some patients with Tourette's syndrome.     

MRI assessment of children with obsessive-compulsive disorder or tics associated with streptococcal infection

OBJECTIVE: The authors assessed selective basal ganglia involvement in a subgroup of children with obsessive-compulsive disorder (OCD) and/or tics believed to be associated with streptococcal infection. METHOD: Using computer-assisted morphometric techniques, they analyzed the cerebral magnetic resonance images of 34 children with presumed streptococcus-associated OCD and/or tics and 82 healthy comparison children who were matched for age and sex. RESULTS: The average sizes of the caudate, putamen, and globus pallidus, but not of the thalamus or total cerebrum, were significantly greater in the group of children with streptococcus-associated OCD and/or tics than in the healthy children. The differences were similar to those found previously for subjects with Sydenham's chorea compared with normal subjects. CONCLUSIONS: These results support the hypothesis that there is a distinct subgroup of subjects with OCD and/or tics who have enlarged basal ganglia. These findings are consistent with the hypothesis of an autoimmune response to streptococcal infection.     

The psychiatric symptoms of rheumatic fever

OBJECTIVE: This study examined the frequency and age at onset of psychiatric disorders among children with rheumatic fever, Sydenham's chorea, or both and a comparison group. METHOD: Twenty children with rheumatic fever, 22 with Sydenham's chorea, and 20 comparison children were assessed by means of a semistructured interview and rating scales for tic disorders and obsessive-compulsive disorder. RESULTS: Obsessive-compulsive symptoms were more frequent in both the Sydenham's chorea and rheumatic fever groups than in the comparison group. The Sydenham's chorea group had a higher frequency of major depressive disorder, tic disorders, and attention deficit hyperactivity disorder (ADHD) than both the comparison and rheumatic fever groups. ADHD symptoms were associated with a higher risk of developing Sydenham's chorea. CONCLUSIONS: Both the rheumatic fever and Sydenham's chorea groups were associated with a higher risk of developing neuropsychiatric disorders than the comparison group. ADHD appears to be a risk factor for Sydenham's chorea in children with rheumatic fever.     

Metabolic alterations in medication-free patients with bipolar disorder: a 3T CSF-corrected magnetic resonance spectroscopic imaging study

The objective of this study was to determine whether cerebrospinal fluid(CSF)-corrected concentrations of N-acetylaspartate are lower in several brain regions of drug- and medication-free subjects with bipolar disorder as compared with matched healthy controls. Bipolar subjects (n=21) and age- and sex-matched healthy control (n=21) were studied using proton magnetic resonance spectroscopic imaging on a 3T magnetic resonance (MR) scanner. Spectra were quantified using the LCModel, and metabolite values were CSF-corrected to yield metabolite concentrations. Fourteen regions of interest and five metabolite concentrations in each subject were selected for statistical analysis. We found that bipolar subjects had significantly decreased N-acetylaspartate concentrations in both caudate heads and the left lentiform nucleus. Choline and creatine in the head of the right caudate were also significantly decreased in bipolar subjects. Significantly increased myo-inositol was found in the left caudate head in bipolar subjects. Bipolar subjects showed significantly decreased glutamate/glutamine concentrations in the frontal white matter bilaterally and in the right lentiform nucleus. No differences were found for other metabolites examined. These preliminary findings suggest decreased neuronal density or viability in the basal ganglia and neurometabolic abnormalities in the frontal lobes of subjects with bipolar disorder.     

Basal Ganglia volumes in patients with Gilles de la Tourette syndrome

BACKGROUND: Despite strong circumstantial evidence that the pathophysiology of Gilles de la Tourette syndrome (TS) involves structural and functional disturbances of the basal ganglia, inconsistent findings from relatively small in vivo TS imaging studies have supported contradictory conclusions concerning the role of abnormal anatomical characteristics of the basal ganglia in the pathophysiology of TS. METHODS: Basal ganglia volumes were measured on high-resolution magnetic resonance images acquired for 154 children and adults with TS and 130 healthy control subjects. Repeated-measures analyses tested hypotheses concerning regional specificity, age effects, and abnormal asymmetries in the basal ganglia of subjects with TS. Subjects with prior neuroleptic exposure had larger basal ganglia volumes and were excluded from further statistical analyses. RESULTS: Caudate nucleus volumes were significantly (P =.008) smaller in children and adults with TS. Lenticular nucleus volumes also were smaller in adults with TS and in children with TS who were diagnosed as having comorbid obsessive-compulsive disorder. Regional anatomical asymmetries did not differ across groups. Regional volumes did not correlate significantly with the severity of tic, obsessive-compulsive disorder, or attention-deficit/hyperactivity disorder symptoms. CONCLUSIONS: Reduced caudate nucleus volumes may be a good candidate marker for a trait abnormality in the structure of the basal ganglia in persons with TS. Smaller lenticular nucleus volumes may be an additional marker for the presence of comorbid obsessive-compulsive disorder and for the persistence of tic symptoms into adulthood. Brain regions other than the basal ganglia may have greater clinical relevance in determining the severity of tic symptoms.