RESUMEN
The identification of genomic imbalances in young patients can affect medical management by allowing early intervention for developmental delay and by identifying patients at risk for unexpected medical complications. Using a 105K-feature oligonucleotide array, we identified a 7.25 Mb deletion at 10q22.3q23.2 in six unrelated patients. Deletions of this region have been described in individuals with cognitive and behavioral abnormalities, including autistic features, and may represent a recurring genetic syndrome. All four patients in this study for whom clinical information was available had mild dysmorphic features and three had developmental delay. Of note is the emerging clinical phenotype in these individuals with similar dysmorphic features such as macrocephaly, hypertelorism, and arachnodactyly, and neurodevelopmental delay that includes failure to thrive, hypotonia, and feeding difficulties in the neonatal period, and receptive and expressive language delay with global neurodevelopmental delay after the neonatal period. However, there is no pattern of abnormalities, craniofacial, behavioral, or otherwise, that would have aroused clinical suspicion of a specific syndrome. Finally, the patients' deletions encompass BMPR1A but not PTEN, and these patients may be at risk for colon cancer and should be referred for appropriate prophylactic care and surveillance. Of the two patients in this study who had colonoscopy following the array results, neither had polyps. Therefore, the magnitude of the increased risk for colon cancer is currently unknown.
Asunto(s)
Cromosomas Humanos Par 10/genética , Genoma Humano/genética , Inestabilidad Genómica/genética , Adolescente , Preescolar , Deleción Cromosómica , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Embarazo , RecurrenciaRESUMEN
We report the identification of microdeletions of 16q11.2q12.2 by microarray-based comparative genomic hybridization (aCGH) in two individuals. The clinical features of these two individuals include hypotonia, gastroesophageal reflux, ear anomalies, and toe deformities. Other features include developmental delay, mental retardation, hypothyroidism, and seizures. The identification of common clinical features in these two individuals and those of one other report suggests microdeletion of 16q12.1q12.2 is a rare, emerging syndrome. These results illustrate that aCGH is particularly suited to identify rare chromosome abnormalities in patients with apparently non-syndromic idiopathic mental retardation and birth defects.
Asunto(s)
Anomalías Múltiples/genética , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 16/genética , Eliminación de Gen , Adolescente , Adulto , Femenino , Genotipo , Humanos , Hibridación Fluorescente in Situ , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , SíndromeRESUMEN
OBJECTIVE: Array-based comparative genomic hybridization (array CGH) is an emerging technology that allows for the genome-wide detection of DNA copy number changes (CNC) such as deletions or duplications. In this study, array-based CGH was applied to a consecutive series of children with previously undiagnosed non-syndromal global developmental delay (GDD) to assess potential etiologic yield. METHODS: The children in this study were drawn from a previously reported consecutive series of children with well-defined GDD. Almost all subjects had undergone prior karyotyping and neuroimaging studies with non-diagnostic results. Array-based CGH was undertaken using the SignatureChip(R) (1887 BACs representing 622 loci) with abnormalities verified by subsequent FISH analysis and testing of parents to distinguish between pathogenic and familial non-pathogenic variants. RESULTS: On CGH analysis in our study, 6 of 94 children (6.4%) had a causally related pathogenic CNC. Three were sub-telomeric in location. An analysis of a variety of clinical factors revealed that only the presence of minor dysmorphic features (<3) was predictive of etiologic yield on CGH analysis (4/26 vs. 2/68, P = 0.05). Severity of delay was not found to be predictive. INTERPRETATION: In children with non-syndromal GDD, array-based CGH has an etiologic yield of 6.4%. This suggests that this emerging technology may be of diagnostic value when applied subsequent to detailed history, physical examination, and targeted laboratory testing. Array CGH may merit consideration as a first-tier test in the context of a child with unexplained GDD.
Asunto(s)
Discapacidades del Desarrollo/genética , Dosificación de Gen , Hibridación de Ácido Nucleico/métodos , Preescolar , Aberraciones Cromosómicas , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/etiología , Salud de la Familia , Humanos , Hibridación Fluorescente in Situ , Padres , FenotipoRESUMEN
Microarray-based comparative genomic hybridization (array CGH) merges molecular diagnostics with traditional chromosome analysis and is transforming the field of cytogenetics. Prospective studies of individuals with developmental delay and dysmorphic features have demonstrated that array CGH has the ability to detect any genomic imbalance including deletions, duplications, aneuploidies and amplifications. Detection rates for chromosome abnormalities with array CGH range from 5-17% in individuals with normal results from prior routine cytogenetic testing. In addition, copy number variants (CNVs) were identified in all studies. These CNVs may include large-scale variation and can confound the diagnostic interpretations. Although cytogeneticists will require additional training and laboratories must become appropriately equipped, array CGH holds the promise of being the initial diagnostic tool in the identification of visible and submicroscopic chromosome abnormalities in mental retardation and other developmental disabilities.
Asunto(s)
Biología Computacional/métodos , Análisis Citogenético/métodos , Análisis Citogenético/tendencias , Hibridación de Ácido Nucleico , Aberraciones Cromosómicas , Trastornos de los Cromosomas/diagnóstico , Análisis Citogenético/instrumentación , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Análisis de Secuencia por Matrices de Oligonucleótidos , Translocación GenéticaRESUMEN
Comprehensive and reliable testing is an important component of counseling and management in clinical genetics. Identification of imbalances of chromosomal segments has uncovered new genes and has established phenotype/genotype correlations for many syndromes with previously unidentified causes. Conventional cytogenetics has proven to be useful for the detection of large aberrations, but its resolution limits the identification of submicroscopic alterations. Comparative genomic hybridization (CGH) on a microarray-based platform has the potential to detect and characterize both microscopic and submicroscopic chromosomal abnormalities. Nine cases of aberrations involving chromosome 18 are used to illustrate the use and clinical potential of array CGH.
Asunto(s)
Cromosomas Humanos Par 18 , Reordenamiento Génico , Enfermedades Genéticas Congénitas/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Niño , Cromosomas Artificiales Bacterianos , Anomalías Congénitas/genética , Enfermedades Genéticas Congénitas/clasificación , Humanos , Valores de ReferenciaAsunto(s)
Agonistas de Dopamina/efectos adversos , Terapia por Estimulación Eléctrica , Levodopa/efectos adversos , Enfermedad de Parkinson/terapia , Núcleo Subtalámico , Confusión/etiología , Depresión/inducido químicamente , Agonistas de Dopamina/uso terapéutico , Estudios de Seguimiento , Levodopa/uso terapéutico , Trastornos del Humor/etiología , Síndrome Neuroléptico Maligno/prevención & control , Calidad de Vida , Trastorno de la Conducta Social/inducido químicamente , Síndrome de Abstinencia a Sustancias/etiología , Núcleo Subtalámico/fisiología , Tiempo , Resultado del TratamientoAsunto(s)
Cromosomas Artificiales Bacterianos/genética , Genoma Humano , Genómica/métodos , Mapeo Cromosómico , Cromosomas Humanos X/genética , Cromosomas Humanos Y/genética , ADN/genética , Femenino , Genómica/estadística & datos numéricos , Humanos , Discapacidad Intelectual/genética , Masculino , Hibridación de Ácido Nucleico , Análisis de Secuencia por Matrices de Oligonucleótidos , Sensibilidad y EspecificidadRESUMEN
The authors report a patient with advanced PD, successfully treated by bilateral stimulation of the subthalamic nucleus, who developed acute transient aggressive behavior during intraoperative electrical test stimulation. The electrode responsible for this abnormal behavior was located within the lateral part of the posteromedial hypothalamic region (triangle of Sano). The authors suggest that affect can be dramatically modulated by the selective manipulation of deep brain structures.
Asunto(s)
Agresión , Terapia por Estimulación Eléctrica/efectos adversos , Hipotálamo Posterior/fisiología , Complicaciones Intraoperatorias/etiología , Enfermedad de Parkinson/terapia , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/cirugíaRESUMEN
OBJECTIVE: To describe a reversible neurological condition resembling a crossed midbrain syndrome resulting from high frequency stimulation (HFS) in the midbrain. METHODS: Postoperative evaluation of quadripolar electrodes implanted in the area of the subthalamic nucleus of 25 patients with Parkinson's disease (PD) successfully treated by HFS. RESULTS: Four of the 25 patients experienced reversible acute diplopia, with dystonic posture and tremor in the contralateral upper limb when the white matter between the red nucleus and the substantia nigra was stimulated. The motor signs resembled those caused by lesions of the red nucleus. The ipsilateral resting eye position was "in and down" (three patients) or "in" (one patient). Enophthalmos was seen. Abduction was impaired and vertical eye movements were limited, but adduction was spared. The movements of the controlateral eye were normal. The ocular signs could be best explained by sustained hyperactivity of the extrinsic oculomotor nerve. Simultaneous tonic contraction of the superior rectus, the inferior rectus, and inferior oblique may cause the enophthalmos and partial limitation of upward and downward eye movements. Antagonist tonic contraction of the ipsilateral medial rectus severely impairs abduction. CONCLUSION: This crossed midbrain syndrome, possibly resulting from simultaneous activation of oculomotor nerve and lesion-like inhibition of the red nucleus suggests that high frequency stimulation has opposite effects on grey and white matter.
Asunto(s)
Terapia por Estimulación Eléctrica/efectos adversos , Mesencéfalo/fisiología , Nervio Oculomotor/fisiología , Enfermedad de Parkinson/terapia , Terapia por Estimulación Eléctrica/métodos , Electrodos , Movimientos Oculares/fisiología , Humanos , Masculino , Persona de Mediana Edad , Núcleo Subtalámico/fisiología , SíndromeRESUMEN
Dyskinesia is a frequent and disabling side effect in patients with Parkinson's disease treated with chronic dopa-therapy. Preclinical data in the 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) monkey suggest that alpha-2 antagonists may reduce dihydroxyphenylalanine (L-DOPA)-induced dyskinesia. We assessed, in a pilot randomised placebo-controlled study, the effects of single oral doses (10 mg, 20 mg, and 40 mg) of idazoxan, an alpha-2 antagonist, on motor parkinsonian disability and L-DOPA-induced dyskinesia following an acute oral challenge of L-DOPA in 18 patients with Parkinson's disease. The severity of L-DOPA-induced dyskinesia improved after 20 mg idazoxan pretreatment, while there was no concommittant deterioration in the antiparkinsonian response to L-DOPA. These results suggest that blocking alpha-2 receptors in patients with Parkinson's disease might improve L-DOPA-induced dyskinesia without the cost of a return of parkinsonian symptomatology. Further studies are required to assess whether this property could have potential therapeutic applications in the long-term management of dyskinetic patients with Parkinson's disease.
Asunto(s)
Antagonistas Adrenérgicos alfa/uso terapéutico , Antiparkinsonianos/efectos adversos , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Idazoxan/uso terapéutico , Levodopa/efectos adversos , Enfermedad de Parkinson/tratamiento farmacológico , Administración Oral , Antagonistas Adrenérgicos alfa/efectos adversos , Anciano , Antiparkinsonianos/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Idazoxan/efectos adversos , Levodopa/uso terapéutico , Masculino , Persona de Mediana Edad , Examen Neurológico/efectos de los fármacos , Proyectos PilotoRESUMEN
High-frequency stimulation of the subthalamic nucleus (STN) was used to investigate the relationship of sleep disorders with motor handicap in PD. In 10 insomniac patients with PD, stimulation reduced nighttime akinesia by 60% and completely suppressed axial and early morning dystonia, but did not alleviate periodic leg movements (n = 3) or REM sleep behavior disorders (n = 5). Total sleep time increased by 47%; wakefulness after sleep onset decreased by 51 minutes. Insomnia in patients with PD may predominantly result from nighttime motor disability.
Asunto(s)
Enfermedad de Parkinson/fisiopatología , Sueño/fisiología , Núcleo Subtalámico/fisiopatología , Adulto , Estimulación Eléctrica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tiempo de Reacción/fisiologíaRESUMEN
Our objective was to elaborate a functional map of the globus pallidus by correlating the intrapallidal localization of quadripolar electrodes implanted in parkinsonian patients with the clinical effect of the stimulation of each contact. Five patients with L-DOPA-responsive Parkinson's disease presenting severe motor fluctuations and L-DOPA-induced dyskinesias were treated by continuous bilateral high-frequency stimulation of the globus pallidus. The effects of stimulation on parkinsonian disability were tested through each of the four stimulating contacts of each electrode. The anatomical localization of each of the stimulating contacts was determined by confronting the pre- and post-operative magnetic resonance imaging with the anatomical atlas of Schaltenbrand and Wharen.(34) The registration procedure comprised digitization of the atlas, the use of deformation tools to fit atlas sections with magnetic resonance imaging sections, and three-dimensional reconstruction of both the atlas and the magnetic resonance imaging sections. Analysis of the 32 stimulating contacts tested did not reveal a somatotopic organization in the pallidal region investigated but demonstrated that high-frequency stimulation had contrasting effects depending on whether it was applied to the external or the internal pallidum. Akinesia was improved by stimulation of the external pallidum but worsened by stimulation of the internal pallidum. In contrast, parkinsonian rigidity was improved by stimulation of either part of the pallidum. The areas in the internal pallidum where stimulation worsened akinesia were those in which stimulation reduced or suppressed L-DOPA-induced dyskinesias. Conversely, stimulation applied to the external pallidum induced dyskinesias. The fact that rigidity was improved by stimulation of the internal and external pallidum suggests that the neuronal bases of parkinsonian rigidity are different from those of akinesia and dyskinesias. The effect on akinesia and dyskinesias is in agreement with the current model of basal ganglia circuitry(10) if high-frequency stimulation activates rather than inhibits pallidal neurons, a possibility which is very likely since there are marked anatomical, biochemical and electrophysiological differences between the globus pallidus and the subthalamic nucleus. This study demonstrates that high-frequency stimulation of the globus pallidus in parkinsonian patients has contrasting effects depending on whether it is applied to the external or the internal part of this nucleus. The effect on akinesia and dyskinesias suggests that stimulation activates pallidal neurons, a result which challenges the generally accepted concept that high-frequency stimulation inactivates neurons in the region stimulated.
Asunto(s)
Globo Pálido/fisiopatología , Vías Nerviosas/fisiopatología , Enfermedad de Parkinson/terapia , Adulto , Anciano , Mapeo Encefálico , Discinesias/patología , Discinesias/fisiopatología , Discinesias/terapia , Terapia por Estimulación Eléctrica , Globo Pálido/patología , Humanos , Persona de Mediana Edad , Vías Nerviosas/patología , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Recuperación de la Función/fisiología , Resultado del TratamientoRESUMEN
High-frequency thalamic stimulation alleviates tremor in Parkinson's disease (PD) and essential tremor (ET). The origin of thalamic myoclonus is unexplained and the effects of low-frequency thalamic stimulation on movement control are still unknown. We studied the effects of stimulation at a low frequency of 15 Hz in five drug-free patients (3 PD, 2 ET) 6 months after thalamic implantation of quadripolar electrodes (unilateral in four patients, bilateral in one patient). Clinical, electrophysiological, and videotaped assessment, using a monopolar 15 Hz frequency (3 V, 90 micros) stimulation current applied simultaneously through two adjacent contacts of the electrode, was performed. We observed myoclonus and irregular jerky tremor in the upper limb contralateral to the site of stimulation. The jerks lasted less than 200 ms, were irregular and not synchronous with stimulation, were superimposed on rest or postural tremor, and increased in response to tactile, proprioceptive, or vibratory stimuli. The fact that this complex movement disorder can be induced by low-frequency stimulation in the ventral intermediate nucleus (Vim) of the thalamus suggests that it results, at least partly, from dysfunction of the Vim and possibly adjacent nuclei of the thalamus.
Asunto(s)
Estimulación Eléctrica/efectos adversos , Mioclonía/etiología , Enfermedad de Parkinson/fisiopatología , Tálamo/fisiopatología , Temblor/etiología , Núcleos Talámicos Ventrales/fisiopatología , Anciano , Brazo , Electrodos Implantados , Lateralidad Funcional , Humanos , Persona de Mediana Edad , Mioclonía/fisiopatología , Enfermedad de Parkinson/terapia , Tálamo/cirugía , Temblor/fisiopatologíaRESUMEN
BACKGROUND: Patients with PD can have disabling visual hallucinations associated with dopaminergic therapy. Sleep disorders, including vivid dreams and REM sleep with motor behaviors (RBD), are frequent in these patients. METHODS: The association of hallucinations and REM sleep both at night and during the day was examined in 10 consecutive nondemented patients with long-standing levodopa-responsive PD and hallucinations. Seven patients presented with paranoia and paranoid delusions. Overnight sleep recordings and standard multiple daytime sleep latency test were performed. The results were compared to those of 10 similar patients with PD not experiencing hallucinations. RESULTS: RBD was detected in all 10 patients with hallucinations and in six without. Although nighttime sleep conditions were similar in both groups, hallucinators tended to be sleepier during the day. Delusions following nighttime REM period and daytime REM onsets were observed in three and eight of the hallucinators, and zero and two of the others. Daytime hallucinations, coincident with REM sleep intrusions during periods of wakefulness, were reported only by hallucinators. Postmortem examination of the brain of one patient showed numerous Lewy bodies in neurons of the subcoeruleus nucleus, a region that is involved in REM sleep control. CONCLUSION: The visual hallucinations that coincide with daytime episodes of REM sleep in patients who also experience post-REM delusions at night may be dream imagery. Psychosis in patients with PD may therefore reflect a narcolepsy-like REM sleep disorder.
Asunto(s)
Alucinaciones/fisiopatología , Enfermedad de Parkinson/fisiopatología , Sueño REM/fisiología , Anciano , Encéfalo/patología , Deluciones/diagnóstico , Deluciones/patología , Deluciones/fisiopatología , Sueños/fisiología , Femenino , Alucinaciones/diagnóstico , Alucinaciones/patología , Humanos , Cuerpos de Lewy/patología , Masculino , Narcolepsia/diagnóstico , Narcolepsia/patología , Narcolepsia/fisiopatología , Neuronas/patología , Trastornos Paranoides/diagnóstico , Trastornos Paranoides/patología , Trastornos Paranoides/fisiopatología , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/patología , Percepción Visual/fisiologíaRESUMEN
Levodopa-induced dyskinesias (LIDs) in patients with Parkinson's disease are considered to result from the severity of dopaminergic denervation in the striatum, which is an irrevocable phenomenon, and sensitization induced by long-term intermittent administration of levodopa. Taking advantage of the 64% reduction of levodopa treatment allowed in 12 Parkinson's disease patients by continuous high-frequency stimulation of the subthalamic nucleus, we evaluated the severity of parkinsonian motor disability and LIDs during two levodopa challenges performed before the surgical implantation of the stimulation electrodes and after 8.8 months of continuous bilateral subthalamic nucleus stimulation that was interrupted 2 hours before the levodopa test. Motor disability during the "off" and "on" drug periods was unchanged. The severity of LIDs during the "on" period and dystonia during the "off" period decreased by 54% and 62%, respectively. The reduced severity of LIDs in the absence of subthalamic nucleus stimulation demonstrates that the sensitization phenomenon resulting from long-term intermittent levodopa administration is partially reversible.
Asunto(s)
Antiparkinsonianos/efectos adversos , Discinesia Inducida por Medicamentos/etiología , Discinesia Inducida por Medicamentos/prevención & control , Terapia por Estimulación Eléctrica , Levodopa/efectos adversos , Enfermedad de Parkinson/tratamiento farmacológico , Adulto , Anciano , Evaluación de la Discapacidad , Discinesia Inducida por Medicamentos/diagnóstico , Electrodos Implantados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/terapia , Índice de Severidad de la Enfermedad , Núcleo Subtalámico/fisiologíaRESUMEN
OBJECT: Several methods are used for stereotactically guided implantation of electrodes into the subthalamic nucleus (STN) for continuous high-frequency stimulation in the treatment of Parkinson's disease (PD). The authors present a stereotactic magnetic resonance (MR) method relying on three-dimensional (3D) T1-weighted images for surgical planning and multiplanar T2-weighted images for direct visualization of the STN, coupled with electrophysiological recording and stimulation guidance. METHODS: Twelve patients with advanced PD were enrolled in this study of bilateral STN implantation. Both STNs were visible as 3D ovoid biconvex hypointense structures located in the upper mesencephalon. The coordinates of the centers of the STNs were determined with reference to the patient's anterior commissure-posterior commissure line by using a new landmark, the anterior border of the red nucleus. Electrophysiological monitoring through five parallel tracks was performed simultaneously to define the functional target accurately. Microelectrode recording identified high-frequency, spontaneous, movement-related activity and tremor-related cells within the STNs. Acute STN macrostimulation improved contralateral rigidity and akinesia, suppressed tremor when present, and could induce dyskinesias. The central track, which was directed at the predetermined target by using MR imaging, was selected for implantation of 19 of 24 electrodes. No surgical complications were noted. CONCLUSIONS: At evaluation 6 months after surgery, continuous STN stimulation was shown to have improved parkinsonian motor disability by 64% and 78% in the "off' and "on" medication states, respectively. Antiparkinsonian drug treatment was reduced by 70% in 10 patients and withdrawn in two patients. The severity of levodopa-induced dyskinesias was reduced by 83% and motor fluctuations by 88%. Continuous high-frequency stimulation of the STN applied through electrodes implanted with the aid of 3D MR imaging and electrophysiological guidance is a safe and effective therapy for patients suffering from severe, advanced levodopa-responsive PD.
Asunto(s)
Terapia por Estimulación Eléctrica/métodos , Electroencefalografía , Imagen por Resonancia Magnética , Enfermedad de Parkinson/terapia , Radiología Intervencionista , Técnicas Estereotáxicas , Núcleo Subtalámico , Anciano , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/efectos adversos , Antiparkinsonianos/uso terapéutico , Discinesia Inducida por Medicamentos/prevención & control , Terapia por Estimulación Eléctrica/instrumentación , Electrodos Implantados , Femenino , Estudios de Seguimiento , Humanos , Levodopa/efectos adversos , Masculino , Mesencéfalo/patología , Persona de Mediana Edad , Monitoreo Intraoperatorio , Movimiento , Enfermedad de Parkinson/tratamiento farmacológico , Planificación de Atención al Paciente , Núcleo Rojo/patología , Seguridad , Núcleo Subtalámico/patología , Temblor/fisiopatología , Temblor/terapiaRESUMEN
The presence of Y chromatin in individuals with Ullrich-Turner syndrome (UTS) confers a risk for gonadoblastoma. In mosaic cases, little is known about Y chromatin distribution in gonads. Fluorescence in situ hybridization (FISH) is a direct approach to assess the extent of Y chromatin mosaicism in gonads. Gonadal tissue from four patients with mosaic karyotypes were analyzed by routine cytogenetics and FISH with X and Y centromere probes. Y chromatin was present in gonads in varying percentages in these patients. The distribution of Y chromatin in gonads of UTS individuals did not completely correlate with that found in blood lymphocytes. The finding of Y chromatin in the blood samples from these patients prompted the development of a screening strategy in our cytogenetics laboratory to detect low-level Y chromatin mosaicism in patients with UTS.
Asunto(s)
Cromatina , Gónadas/química , Mosaicismo/genética , Síndrome de Noonan/genética , Cromosoma Y/genética , Adolescente , Niño , Femenino , Pruebas Genéticas , Gonadoblastoma/genética , Humanos , Hibridación Fluorescente in Situ , CariotipificaciónRESUMEN
OBJECTIVE: To assess the effects of high frequency stimulation of the subthalamic nucleus (STN) on axial symptoms occurring in advanced stages of Parkinson's disease (PD). METHODS: The efficacy of STN stimulation on total motor disability score (unified Parkinson's disease rating scale (UPDRS) part III) were evaluated in 10 patients with severe Parkinson's disease. The subscores were then studied separately for limb akinesia, rigidity, and tremor, which are known to respond to levodopa, and axial signs, including speech, neck rigidity, rising from a chair, posture, gait, and postural stability, which are known to respond less well to levodopa. Patients were clinically assessed in the "off" and "on" drug condition during a levodopa challenge test performed before surgical implantation of stimulation electrodes and repeated 6 months after surgery under continuous STN stimulation. A complementary score for axial symptoms from the "activities of daily living" (ADL)-that is, speech, swallowing, turning in bed, falling, walking, and freezing-was obtained from each patient's questionnaire (UPDRS, part II). RESULTS: Improvements in total motor disability score (62%), limb signs (62%), and axial signs (72%) obtained with STN stimulation were statistically comparable with those obtained with levodopa during the preoperative challenge (68%, 69%, and 59%, respectively). When levodopa and STN stimulation were combined there was a further improvement in total motor disability (80%) compared with preoperative levodopa administration. This consisted largely of an additional improvement in axial signs (84%) mainly for posture and postural stability, no further improvement in levodopa responsive signs being found. Axial symptoms from the ADL showed similar additional improvement when levodopa and STN stimulation were combined. CONCLUSION: These findings suggest that bilateral STN stimulation improves most axial features of Parkinson's disease and that a synergistic effect can be obtained when stimulation is used in conjunction with levodopa treatment.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Terapia por Estimulación Eléctrica , Levodopa/uso terapéutico , Destreza Motora , Enfermedad de Parkinson/fisiopatología , Núcleo Subtalámico/fisiología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Continuous high frequency stimulation of the ventral intermediate nucleus of the thalamus (Vim), delivered through surgically implanted quadripolar electrodes, alleviates tremor in Parkinson's disease (PD) and essential tremor (ET). The Vim is adjacent to the thalamic reticular nuclei, where sleep spindles originate according to animal models. In order to determine whether Vim stimulation affects sleep spindles, six patients (4 PD, 2 ET), aged 60-69 years, were recorded on a control night and a stimulation night (130 Hz, 2-3 V; right stimulation in five patients and bilateral stimulation in one patient). Stimulation did not modify sleep quality or architecture. Sleep spindles were present and symmetrical in five out of six patients under stimulation. However, in one patient with a sustained 'thalamotomy-like effect' that abolished tremor, spindles were asymmetrical even without stimulation. In each patient, spindle density was similar on both nights (mean+/- SEM: 2.25+/-0. 61 spindles per min of stage 2 sleep vs. 1.84+/-0.31). In an attempt to promote sleep two different patterns of stimulation were applied in the region of ventrooralis posterior and reticularis nuclei in five patients in the awake state. Continuous low frequency stimulation (5 Hz, 0.1 V), and repeated trains of 15 Hz for 1 s every 15 s mimicking the pattern of physiological spindles, each failed to induce sleep or cortical synchronization. We conclude that Vim stimulation, unlike thalamotomy, selectively reduces tremor without altering sleep or sleep spindles. Our results also suggest that low frequency stimulation applied in the region of the reticular nuclei does not induce sleep.