Complex Dynamics in the Basal Ganglia: Health and Disease Beyond the Motor System.

The rate and oscillatory hypotheses are the two main current frameworks of basal ganglia pathophysiology. Both hypotheses have emerged from research on movement disorders sharing similar conceptualizations. These pathological conditions are classified either as hypokinetic or hyperkinetic, and the electrophysiological hallmarks of basal ganglia dysfunction are categorized as prokinetic or antikinetic. Although nonmotor symptoms, including neurobehavioral symptoms, are a key manifestation of basal ganglia dysfunction, they are uncommonly accounted for in these models. In patients with Parkinson's disease, the broad spectrum of motor symptoms and neurobehavioral symptoms challenges the concept that basal ganglia disorders can be classified into two categories. The profile of symptoms of basal ganglia dysfunction is best characterized by a breakdown of information processing, accompanied at an electrophysiological level by complex alterations of spiking activity from basal ganglia neurons. The authors argue that the dynamics of the basal ganglia circuit cannot be fully characterized by linear properties such as the firing rate or oscillatory activity. In fact, the neuronal spiking stream of the basal ganglia circuit is irregular but has temporal structure. In this context, entropy was introduced as a measure of probabilistic irregularity in the temporal organization of neuronal activity of the basal ganglia, giving place to the entropy hypothesis of basal ganglia pathology. Obtaining a quantitative characterization of irregularity of spike trains from basal ganglia neurons is key to elaborating a new framework of basal ganglia pathophysiology.

A disease-specific metabolic brain network associated with corticobasal degeneration.

Corticobasal degeneration is an uncommon parkinsonian variant condition that is diagnosed mainly on clinical examination. To facilitate the differential diagnosis of this disorder, we used metabolic brain imaging to characterize a specific network that can be used to discriminate corticobasal degeneration from other atypical parkinsonian syndromes. Ten non-demented patients (eight females/two males; age 73.9 ± 5.7 years) underwent metabolic brain imaging with (18)F-fluorodeoxyglucose positron emission tomography for atypical parkinsonism. These individuals were diagnosed clinically with probable corticobasal degeneration. This diagnosis was confirmed in the three subjects who additionally underwent post-mortem examination. Ten age-matched healthy subjects (five females/five males; age 71.7 ± 6.7 years) served as controls for the imaging studies. Spatial covariance analysis was applied to scan data from the combined group to identify a significant corticobasal degeneration-related metabolic pattern that discriminated (P < 0.001) the patients from the healthy control group. This pattern was characterized by bilateral, asymmetric metabolic reductions involving frontal and parietal cortex, thalamus, and caudate nucleus. These pattern-related changes were greater in magnitude in the cerebral hemisphere opposite the more clinically affected body side. The presence of this corticobasal degeneration-related metabolic topography was confirmed in two independent testing sets of patient and control scans, with elevated pattern expression (P < 0.001) in both disease groups relative to corresponding normal values. We next determined whether prospectively computed expression values for this pattern accurately discriminated corticobasal degeneration from multiple system atrophy and progressive supranuclear palsy (the two most common atypical parkinsonian syndromes) on a single case basis. Based upon this measure, corticobasal degeneration was successfully distinguished from multiple system atrophy (P < 0.001) but not progressive supranuclear palsy, presumably because of the overlap (∼ 24%) that existed between the corticobasal degeneration- and the progressive supranuclear palsy-related metabolic topographies. Nonetheless, excellent discrimination between these disease entities was achieved by computing hemispheric asymmetry scores for the corticobasal degeneration-related pattern on a prospective single scan basis. Indeed, a logistic algorithm based on the asymmetry scores combined with separately computed expression values for a previously validated progressive supranuclear palsy-related pattern provided excellent specificity (corticobasal degeneration: 92.7%; progressive supranuclear palsy: 94.1%) in classifying 58 testing subjects. In conclusion, corticobasal degeneration is associated with a reproducible disease-related metabolic covariance pattern that may help to distinguish this disorder from other atypical parkinsonian syndromes.

Biotin-responsive basal ganglia disease should be renamed biotin-thiamine-responsive basal ganglia disease: a retrospective review of the clinical, radiological and molecular findings of 18 new cases.

BACKGROUND: Biotin-responsive basal ganglia disease (BBGD) is an autosomal recessive neurometabolic disorder. It is characterized by sub acute encephalopathy with confusion, seizure, dysarthria and dystonia following a history of febrile illness. If left untreated with biotin, the disease can progress to severe quadriparesis and even death. METHOD: A retrospective chart review of 18 patients with BBGD from two tertiary institutions describing their clinical, magnetic resonance imaging and molecular findings was conducted. RESULT: Eighteen children from 13 families seen over a period of nine years (2003-2012) were included. (Age range: 14month to 23 years, M: F: 1:1). The clinical features included sub acute encephalopathy, ataxia (n= 18), seizures (n= 13) dystonia (n=12) ,dysarthria (n= 9), quadriparesis and hyperreflexia (n=9). Magnetic resonance imaging demonstrated abnormal signal intensity with swelling in the basal ganglia during acute crises (n= 13/13) and atrophy of the basal ganglia and necrosis during follow up (n= 13/13). One-third of the present patients showed the recurrence of acute crises while on biotin therapy alone, but after the addition of thiamine, crises did not recur. All of the patients have a homozygous missense mutation in exon 5 of the SLC19A3 gene. The frequency of acute crises, delay in diagnosis and initiation of treatment significantly influenced the outcome. On follow up, four patients died, two had spastic quadriplegia, six had normal outcome and the rest had speech and motor dysfunctions. CONCLUSION: Clinicians should suspect BBGD in any child presenting with sub acute encephalopathy, abnormal movement and MRI findings as described above. Both biotin and thiamine are essential for disease management. Since biotin alone could not prevent the recurrence of crises in some patients, a more appropriate term to describe the disease would be biotin-thiamine-responsive basal ganglia disease (BTBGD).

Does corticobasal degeneration exist? A clinicopathological re-evaluation.

The pathological findings of corticobasal degeneration are associated with several distinct clinical syndromes, and the corticobasal syndrome has been linked with a number of diverse pathologies. We have reviewed all the archival cases in the Queen Square Brain Bank for Neurological Disorders over a 20-year period with either a clinical diagnosis of corticobasal syndrome or pathological diagnosis of corticobasal degeneration in an attempt to identify the main diagnostic pitfalls. Of 19 pathologically confirmed corticobasal degeneration cases, only five had been diagnosed correctly in life (sensitivity=26.3%) and four of these had received an alternative earlier diagnosis. All five of these had a unilateral presentation, clumsy useless limb, limb apraxia and myoclonus, four had cortical sensory impairment and focal limb dystonia and three had an alien limb. Eight cases of corticobasal degeneration had been clinically diagnosed as progressive supranuclear palsy, all of whom had vertical supranuclear palsy and seven had falls within the first 2 years. On the other hand, of 21 cases with a clinical diagnosis of corticobasal syndrome, only five had corticobasal degeneration pathology, giving a positive predictive value of 23.8%; six others had progressive supranuclear palsy pathology, five had Alzheimer's disease and the remaining five had other non-tau pathologies. Corticobasal degeneration can present very commonly with a clinical picture closely resembling classical progressive supranuclear palsy or Richardson's syndrome, and we propose the term corticobasal degeneration-Richardson's syndrome for this subgroup. Cases of corticobasal degeneration-Richardson's syndrome have delayed onset of vertical supranuclear gaze palsy (>3 years after onset of first symptom) and the infrequent occurrence of predominant downgaze abnormalities, both of which can be helpful pointers to their underlying corticobasal degeneration pathology. Fourty-two per cent of corticobasal degeneration cases presented clinically with a progressive supranuclear palsy phenotype and 29% of cases with corticobasal syndrome had underlying progressive supranuclear palsy pathology. In contrast, in the Queen Square Brain Bank archival collection, corticobasal syndrome is a rare clinical presentation of progressive supranuclear palsy occurring in only 6 of the 179 pathologically diagnosed progressive supranuclear palsy cases (3%). Despite these diagnostic difficulties we conclude that corticobasal degeneration is a discrete clinicopathological entity but with a broader clinical spectrum than was originally proposed.

Do MRI features distinguish Wilson's disease from other early onset extrapyramidal disorders? An analysis of 100 cases.

Magnetic resonance imaging (MRI) is frequently used in the evaluation of various extrapyramidal disorders. Among the plethora of MRI features in Wilson's disease (WD), only "face of the giant panda" sign has been recognized to distinguish WD from other early onset extrapyramidal disorders (EOEPD). To ascertain the value of various MRI features in differentiating neuropsychiatric form of WD from other EOEPD. This retrospective analysis included 100 patients (M:F = 56:44) of EOEPD (5-40 years), who had undergone MRI during Jan'03 to Nov'08. Their clinical features were recorded and the following MR sequences were analyzed: T1WI, T2WI, FLAIR. Fifty-six patients had WD (M:F = 28:30, age at onset: 14 +/- 6.8 years) and 44 had other EOEPD (M:F = 27:17, age at onset: 19 +/- 9.8 years) that included Huntington's disease--4, young-onset Parkinson's disease--7, mitochondrial disorders--2, Hallervorden-Spatz disease--8, non-Wilsonian hepatolenticular degeneration--2, toxic/metabolic disorder--1, and others--20. The duration of illness at the time of MRI was comparable (WD: 3.1 +/- 4.9 years; Other EOEPD: 2.8 +/- 2.4 years). MR signal characteristics varied in topography and severity in both the groups. All the patients of WD had signal abnormalities in MRI, as against 16/44 of the other EOEPD group. The following MR observations were noted exclusively in WD: "Face of giant panda" sign (14.3%), tectal plate hyperintensity (75%), central pontine myelinolysis (CPM)-like abnormalities (62.5%), and concurrent signal changes in basal ganglia, thalamus, and brainstem (55.3%). Besides "Face of giant panda" sign, hyperintensities in tectal-plate and central pons (CPM-like), and simultaneous involvement of basal ganglia, thalamus, and brainstem are virtually pathognomonic of WD.

Germinomas in the basal ganglia: magnetic resonance imaging classification and the prognosis.

Germinoma in the basal ganglia (BG) is notorious for its diagnostic difficulty. Clinical and radiological features of this disease are quite diverse, but have not been well characterized with respect to prognosis. We retrospectively reviewed the clinical course and treatment outcomes of 17 patients with a BG germinoma. The initial magnetic resonance imaging (MRI) features were classified. Clinical features and treatment outcomes were then analyzed with this classification scheme. A Type 1 lesion was defined as a subtle lesion with faint or no contrast enhancement (six patients). Type 2, 3, and 4 lesions were defined as contrast-enhancing lesions and were differentiated by the lesion size and the presence of subependymal seeding (11 patients). Type 1 lesions were distinct from the other lesions. Patients with a Type 1 lesion had a significantly longer time from the initial MRI to diagnosis than patients with Type 2, 3, and 4 lesions (P = 0.012). The actuarial progression-free survival and overall survival of patients 5 years after diagnosis were 66 and 77%, respectively. The presence of a Type 1 lesion (P = 0.004), a longer time delay in the diagnosis (P = 0.038), and radiation therapy without complete ventricular coverage (P = 0.010) were significantly associated with tumor progression. Profound motor deficits at diagnosis were associated with deterioration in motor function after tumor remission (P = 0.035). Early diagnosis of BG germinomas could affect the ability to control a tumor and neurological outcomes. In particular, high clinical suspicion and active diagnostic procedures are recommended. For optimal treatment, radiation fields should include entire ventricles even if there is no subependymal seeding.

Baroreflex sensitivity and power spectral analysis during autonomic testing in different extrapyramidal syndromes.

Autonomic dysfunction has been frequently demonstrated in patients with extrapyramidal diseases by cardiovascular autonomic testing. In addition to classical testing, we applied the more detailed baroreflex and spectral analysis on three traditional cardiovascular tests in this study to get additional information on autonomic outflow. We recorded continuously blood pressure, electrocardiogram, and respiration in 35 patients with multiple system atrophy, 32 patients with progressive supranuclear palsy, 46 patients with idiopathic Parkinson's disease and in 27 corresponding healthy subjects during cardiovascular autonomic testing (metronomic breathing, Valsalva manoeuvre, head-up tilt). Baroreflex and spectral analyses were performed by using trigonometric regressive spectral analysis between and during the manoeuvres. Consistent with previous interpretations, our data showed an increase of sympathetic activity in head-up tilt and Valsalva test in healthy controls. This sympathetic activity was significantly decreased in patients with typical and atypical Parkinson syndromes. Significant modulation of baroreflex activity could be observed especially during metronomic breathing; again it was significantly lower in all patient groups. Baroreflex and spectral parameters could not only differentiate between patients and healthy controls, but also differentiate between clinically symptomatic (with autonomic dysfunction as eg. orthostatic hypotension) and asymptomatic patients. In conclusion, our approach allows the evaluation of autonomic variability during short and nonstationary periods of time and may constitute a useful advance in the assessment of autonomic function in both physiological and pathological conditions.

Error processing in normal aging and in basal ganglia disorders.

Recently it has been shown that effects of aging and pathologically induced changes of basal ganglia structures may have quite similar effects on cognitive functions mediated by the medial prefrontal cortex. The question appears, if this pattern may be assignable to other cognitive functions that are mediated via the basal ganglia and medial prefrontal brain areas. Error processing is a component of executive functions that also depends on these areas and especially on the anterior cingulate cortex (ACC). Hence we ask, if error processing functions are differentially modulated by normal aging and basal ganglia diseases. Error processing mechanisms in these groups were investigated using a cognitive event-related potential (ERP), the error negativity. Enrolling an extended sample of young and elderly controls, as well as patients with Parkinson's and Huntington's disease, we show that modulations of error processing differ between aging, different basal ganglia diseases. Despite that the examined basal ganglia disorder groups (Parkinson's and Huntington's disease) differ in their age they show similar modulations in error processing, suggesting that aging effects are overridden by pathogenic effects. The study shows that it may be valuable to compare aging not only to different forms of basal ganglia disorders in order to gain knowledge about age- and disease-related mechanisms and the effects of these on cognitive functions. Diseases of the basal ganglia may impact error processing above and beyond the effects of normal aging. Although many aging, Parkinson's disease and Huntington's disease studies on error processing functions have already been published, this study ties together several related observations across all of these groups in one experiment.

Frontotemporal dementia and related disorders: deciphering the enigma.

In the past century, particularly the last decade, there has been enormous progress in our understanding of frontotemporal dementia, a non-Alzheimer's type dementia. Large clinicopathological series have been published that have clearly demonstrated an overlap between the clinical syndromes subsumed under the term frontotemporal dementia and the progressive supranuclear palsy syndrome, corticobasal syndrome, and motor neuron disease. There have also been significant advancements in brain imaging, neuropathology, and molecular genetics that have led to different approaches to classification. Unfortunately, the field is complicated by a barrage of overlapping clinical syndromes and histopathological diagnoses that does not allow one to easily identify relations between individual clinical syndromic presentations and underlying neuropathology. This review deciphers this web of terminology and highlights consistent, and hence important, associations between individual clinical syndromes and neuropathology. These associations could ultimately allow the identification of appropriate patient phenotypes for future targeted treatments.

Circuits and circuit disorders of the basal ganglia.

Views of the anatomy and function of the basal ganglia and their role in motor and nonmotor disorders have undergone major revisions during the past decades. The basal ganglia are now appreciated as components of parallel, reentrant cortico-subcortical circuits, which originate from individual cortical areas, traverse the basal ganglia and thalamus, and terminate in their respective areas of origin in the frontal lobe. Further research and clinical experience have resulted in new insights and perspectives on the details of the circuitry and on the role of these structures in Parkinson disease and other basal ganglia disorders. On the basis of anatomical and physiological studies and the striking success of focused surgical interventions, it seems appropriate to view these varied clinical disorders as circuit disorders, resulting from pathologic disturbances in neuronal activity throughout specific cortico-subcortical loops.

Primitive reflex evaluation in the clinical assessment of extrapyramidal syndromes.

The aim of the present study was to evaluate the role of primitive reflexes (PRs) as additional alert sign in routine clinical practice in patients with extrapyramidal syndrome. We considered glabellar, snout, palmomental and grasp reflexes in patients with mild stage of Lewy body dementia (LBD), corticobasal degeneration, progressive supranuclear palsy or Parkinson disease (PD). We also enrolled mild Alzheimer disease (AD) patients, and healthy subjects, as controls. LBD patients showed the highest prevalence of PRs compared with the other groups. The odds ratio of the risk of LBD in PRs > or = 2 was 27.9 (95% CI 2.9-269.0) compared with control group, 14.6 (95% CI 2.7-79.6) compared with mild AD, and 19.7 (95% CI 3.7-104.3) compared with PD. These data suggest that the occurrence of combination of PRs might be an useful additional warning sign of possible diffuse Lewy body pathology more than other causes of extrapyramidal syndrome.

Extrapyramidal side effects with atypical neuroleptics in bipolar disorder.

OBJECTIVE: To examine, in a real-world clinical setting, the risk of extrapyramidal symptoms (EPS) with atypical neuroleptics in bipolar patients. METHODS: The authors assessed 51 individual patient trials of atypical neuroleptic agents (17 risperidone, 13 olanzapine, 11 quetiapine, 8 ziprasidone, and 2 aripiprazole) in 37 bipolar patients (type I or type II). Risk of EPS was assessed using the Abnormal Involuntary Movement Scale, Barnes Akathisia Rating Scale, and the Simpson-Angus Scale. Mean duration of treatment was 25.5 weeks (range 3-107 weeks) and 60.8% of patients were female. RESULTS: 62.7% of trials resulted in moderate to severe EPS. EPS and discontinuation frequencies were similar between specific neuroleptic agents or between high potency (risperidone/ziprasidone/aripiprazole; 52.9%, 27/51 trials) and low potency (quetiapine/olanzapine; 47.1%, 24/51 trials) agents. In a multiple regression model adjusted for confounders, akathisia was less common with low potency agents. Younger age was associated with more akathisia. 31.4% (11/35) of trials discontinued due to side effects. 7.8% (4/51) of trials led to mild de novo tardive dyskinesia. CONCLUSIONS: Over one-half of bipolar patients experienced EPS in this real world clinical setting. This rate is much higher than the 5-15% range reported in clinical trials, suggesting potential problems with clinical trial generalizability.

[Asymptomatic familial basal ganglia calcification with autosomal dominant inheritance: a family report].

We report here a pedigree of basal ganglia calcification with autosomal dominant inheritance. Following a traffic accident, the proband, a seven-year-old boy, was incidentally noted by cranial computed tomography to have calcification of the bilateral basal ganglia. Six affected members spanning three generations, aged from 5 to 57 years, also had calcification in various degree. None of them had clinical symptoms. There were neither abnormal data nor any characteristic physical symptoms associated with parathyroid disorders. There was no consanguinity. Both sexes were affected and the sex ratio was 0.5. Male-to-male transmission was documented. These findings suggested an autosomal dominant trait. The clinico-radiological findings in our pedigree were different from those of the previously reported cases of familial basal ganglia calcification, that infants were affected and that clinical symptoms were absent in elderly patients. These facts suggest our pedigree is a new type of familial basal ganglia calcification with autosomal dominant inheritance.

[Clinical aspects and therapy of dystonias]. / Klinik und Therapie der Dystonien.

Dystonia is characterized by slow, repetitive, involuntary, often twisting movements leading to sustained abnormal postures and can be focal or generalised. In most cases, etiology remains unrevealed, some cases are hereditary, others have metabolic origin or can be attributed to focal brain lesions. The most common types of dystonia, spasmodic torticollis and blepharospasm, can now be treated successfully, albeit symptomatically, with Botulinum toxin injections into the affected muscles. A practical guide to differential diagnostic and therapeutic strategies is presented.