RESUMO
OBJECTIVE: The study was undertaken to identify a monogenic cause of early onset, generalized dystonia. METHODS: Methods consisted of genome-wide linkage analysis, exome and Sanger sequencing, clinical neurological examination, brain magnetic resonance imaging, and protein expression studies in skin fibroblasts from patients. RESULTS: We identified a heterozygous variant, c.388G>A, p.Gly130Arg, in the eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2) gene, segregating with early onset isolated generalized dystonia in 5 patients of a Taiwanese family. EIF2AK2 sequencing in 191 unrelated patients with unexplained dystonia yielded 2 unrelated Caucasian patients with an identical heterozygous c.388G>A, p.Gly130Arg variant, occurring de novo in one case, another patient carrying a different heterozygous variant, c.413G>C, p.Gly138Ala, and one last patient, born from consanguineous parents, carrying a third, homozygous variant c.95A>C, p.Asn32Thr. These 3 missense variants are absent from gnomAD, and are located in functional domains of the encoded protein. In 3 patients, additional neurological manifestations were present, including intellectual disability and spasticity. EIF2AK2 encodes a kinase (protein kinase R [PKR]) that phosphorylates eukaryotic translation initiation factor 2 alpha (eIF2α), which orchestrates the cellular stress response. Our expression studies showed abnormally enhanced activation of the cellular stress response, monitored by PKR-mediated phosphorylation of eIF2α, in fibroblasts from patients with EIF2AK2 variants. Intriguingly, PKR can also be regulated by PRKRA (protein interferon-inducible double-stranded RNA-dependent protein kinase activator A), the product of another gene causing monogenic dystonia. INTERPRETATION: We identified EIF2AK2 variants implicated in early onset generalized dystonia, which can be dominantly or recessively inherited, or occur de novo. Our findings provide direct evidence for a key role of a dysfunctional eIF2α pathway in the pathogenesis of dystonia. ANN NEUROL 2021;89:485-497.
Assuntos
Distúrbios Distônicos/genética , Fibroblastos/metabolismo , eIF-2 Quinase/genética , Adolescente , Adulto , Idade de Início , Povo Asiático , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Distúrbios Distônicos/metabolismo , Distúrbios Distônicos/fisiopatologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , População Branca , Sequenciamento do Exoma , Adulto Jovem , eIF-2 Quinase/metabolismoRESUMO
BACKGROUND: Huntington's disease (HD) is a neurodegenerative disorder characterized by involuntary movements, cognitive decline, and behavioral changes. The complex constellation of clinical symptoms still makes the therapeutic management challenging. In the new era of functional neurosurgery, deep brain stimulation (DBS) may represent a promising therapeutic approach in selected HD patients. METHODS: Articles describing the effect of DBS in patients affected by HD were selected from Medline and PubMed by the association of text words with MeSH terms as follows: "Deep brain stimulation," "DBS," and "HD," "Huntington's disease," and "Huntington." Details on repeat expansion, age at operation, target of operation, duration of follow-up, stimulation parameters, adverse events, and outcome measures were collected. RESULTS: Twenty eligible studies, assessing 42 patients with HD, were identified. The effect of globus pallidus internus (GPi) DBS on Unified Huntington's Disease Rating Scale (UHDRS) total score revealed in 10 studies an improvement of total score from 5.4 to 34.5%, and in 4 studies, an increase of motor score from 3.8 to 97.8%. Bilateral GPi-DBS was reported to be effective in reducing Chorea subscore in all studies, with a mean percentage reduction from 21.4 to 73.6%. CONCLUSIONS: HD patients with predominant choreic symptoms may be the best candidates for surgery, but the role of other clinical features and of disease progression should be elucidated. For this reason, there is a need for more reliable criteria that may guide the selection of HD patients suitable for DBS. Accordingly, further studies including functional outcomes as primary endpoints are needed.
Assuntos
Coreia , Estimulação Encefálica Profunda , Doença de Huntington , Globo Pálido , Humanos , Doença de Huntington/terapia , Resultado do TratamentoRESUMO
The impact of coronavirus disease 2019 (COVID-19) on clinical features of Parkinson's disease (PD) has been poorly characterized so far. Of 141 PD patients resident in Lombardy, we found 12 COVID-19 cases (8.5%), whose mean age and disease duration (65.5 and 6.3 years, respectively) were similar to controls. Changes in clinical features in the period January 2020 to April 2020 were compared with those of 36 PD controls matched for sex, age, and disease duration using the clinical impression of severity index for PD, the Movement Disorders Society Unified PD Rating Scale Parts II and IV, and the nonmotor symptoms scale. Motor and nonmotor symptoms significantly worsened in the COVID-19 group, requiring therapy adjustment in one third of cases. Clinical deterioration was explained by both infection-related mechanisms and impaired pharmacokinetics of dopaminergic therapy. Urinary issues and fatigue were the most prominent nonmotor issues. Cognitive functions were marginally involved, whereas none experienced autonomic failure. © 2020 International Parkinson and Movement Disorder Society.
Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/complicações , Infecções por Coronavirus/virologia , Doença de Parkinson/fisiopatologia , Pneumonia Viral/complicações , Pneumonia Viral/virologia , COVID-19 , Estudos de Casos e Controles , Cognição/fisiologia , Transtornos Cognitivos/virologia , Depressão/psicologia , Depressão/virologia , Humanos , Pandemias , Doença de Parkinson/complicações , Doença de Parkinson/virologia , SARS-CoV-2RESUMO
Mitochondrial dynamics and quality control are crucial for neuronal survival and their perturbation is a major cause of neurodegeneration. m-AAA complex is an ATP-dependent metalloprotease located in the inner mitochondrial membrane and involved in protein quality control. Mutations in the m-AAA subunits AFG3L2 and paraplegin are associated with autosomal dominant spinocerebellar ataxia (SCA28) and autosomal recessive hereditary spastic paraplegia (SPG7), respectively. We report a novel m-AAA-associated phenotype characterized by early-onset optic atrophy with spastic ataxia and L-dopa-responsive parkinsonism. The proband carried a de novo AFG3L2 heterozygous mutation (p.R468C) along with a heterozygous maternally inherited intragenic deletion of SPG7. Functional analysis in yeast demonstrated the pathogenic role of AFG3L2 p.R468C mutation shedding light on its pathogenic mechanism. Analysis of patient's fibroblasts showed an abnormal processing pattern of OPA1, a dynamin-related protein essential for mitochondrial fusion and responsible for most cases of hereditary optic atrophy. Consistently, assessment of mitochondrial morphology revealed a severe fragmentation of the mitochondrial network, not observed in SCA28 and SPG7 patients' cells. This case suggests that coincidental mutations in both components of the mitochondrial m-AAA protease may result in a complex phenotype and reveals a crucial role for OPA1 processing in the pathogenesis of neurodegenerative disease caused by m-AAA defects.
Assuntos
Proteases Dependentes de ATP/genética , ATPases Associadas a Diversas Atividades Celulares/genética , GTP Fosfo-Hidrolases/metabolismo , Metaloendopeptidases/genética , Mitocôndrias/patologia , Mutação , Atrofia Óptica/patologia , Transtornos Parkinsonianos/patologia , Adulto , Linhagem Celular , Feminino , Humanos , Masculino , Mitocôndrias/genética , Mitocôndrias/metabolismo , Atrofia Óptica/genética , Atrofia Óptica/metabolismo , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/metabolismo , Linhagem , Leveduras/genéticaRESUMO
Mutations in PSEN1 are responsible for familial Alzheimer's disease (FAD) inherited as autosomal dominant trait, but also de novo mutations have been rarely reported in sporadic early-onset dementia cases. Parkinsonism in FAD has been mainly described in advanced disease stages. We characterized a patient presenting with early-onset dystonia-parkinsonism later complicated by dementia and myoclonus. Brain MRI showed signs of iron accumulation in the basal ganglia mimicking neurodegeneration with brain iron accumulation (NBIA) as well as fronto-temporal atrophy. Whole exome sequencing revealed a novel PSEN1 mutation and segregation within the family demonstrated the mutation arose de novo.We suggest considering PSEN1 mutations in cases of dystonia-parkinsonism with positive DAT-Scan, later complicated by progressive cognitive decline and cortical myoclonus even without a dominant family history.
Assuntos
Disfunção Cognitiva/genética , Distonia/genética , Mutação/genética , Transtornos Parkinsonianos/genética , Presenilina-1/genética , Doença de Alzheimer/genética , Encéfalo/metabolismo , Distonia/complicações , Feminino , Humanos , Masculino , Transtornos Parkinsonianos/complicações , FenótipoRESUMO
INTRODUCTION: Parkin disease (PARK2, OMIM 602544) is an autosomal-recessive early-onset parkinsonism characterized by an early occurrence of lower limb dystonia. The aim of this study was to analyze spatiotemporal, kinematic, and kinetic gait parameters in patients with parkin disease in the OFF and ON conditions compared to healthy age-matched controls. METHODS: Fifteen patients with parkin disease and 15 healthy age-matched controls were studied in a gait analysis laboratory with an integrated optoelectronic system. Spatiotemporal, kinematic, and kinetic gait parameters at a self-selected speed were recorded in the OFF and ON conditions. A jerk index was computed to quantify the possible reduction of smoothness of joint movements. RESULTS: Compared to controls, parkin patients had, either in the OFF or in the ON conditions, significant reduction of walking velocity, increased step width, and decreased percentage of double support. Kinematic analysis in both conditions showed: increased ankle dorsiflexion and knee flexion at the initial contact; maximal flexion and increased range of motion in mid stance; increased hip flexion and max extension in stance at pelvis; and increased mean tilt antiversion. Kinetics showed increased hip and knee power generation in stance in either condition. The jerk index was increased at all joints both in OFF and ON. There were no correlations between individual gait parameters and clinical ratings. CONCLUSION: Parkin patients have an abnormal gait pattern that does not vary between the OFF and the ON conditions. Variations recorded with instrumented analysis are more evident for kinematic than kinetic parameters at lower limbs. Severity of dystonia does not correlate with any individual kinematic parameter. © 2016 International Parkinson and Movement Disorder Society.
Assuntos
Distonia/fisiopatologia , Transtornos Neurológicos da Marcha/fisiopatologia , Doença de Parkinson/fisiopatologia , Ubiquitina-Proteína Ligases , Adulto , Fenômenos Biomecânicos , Distonia/etiologia , Feminino , Transtornos Neurológicos da Marcha/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Doença de Parkinson/genéticaRESUMO
BACKGROUND: Multiplications of the SNCA gene that encodes alpha-synuclein are a rare cause of autosomal dominant Parkinson's disease (PD). METHODS: Here, we describe 2 novel families in which there is autosomal dominant PD associated with SNCA duplication, and we compare the clinical features of all known patients carrying 3 or 4 SNCA copies. RESULTS: Affected members in family A presented with early onset PD that was variably associated with nonmotor features, such as dysautonomia, cognitive deficits, and psychiatric disturbances. In family B, the clinical presentation ranged from early onset PD-dementia with psychiatric disturbances to late onset PD with mild cognitive impairment. CONCLUSIONS: The presence of 4 SNCA copies is associated with a rich phenotype, characterized by earlier onset of motor and nonmotor features compared with patients who bear 3 SNCA copies. The clinical spectrum associated with SNCA duplications is wide, even within a single family, suggesting a role for as yet unidentified genetic or environmental modifiers.
Assuntos
Duplicação Gênica/genética , Transtornos Parkinsonianos/genética , alfa-Sinucleína/genética , Adulto , Idoso , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
BACKGROUND: Preclinical and clinical evidence suggests that impaired gamma-aminobutyric (GABA) control, leading to disinhibition within the sensorimotor system, might play a role in dystonia. Aim of this study is the in vivo assessment of the GABAergic system in dystonia using positron emission tomography (PET) and (11) C-flumazenil, a selective GABA(A) receptor ligand. METHODS: Fourteen subjects with primary dystonia (9 carriers of the DYT1 mutation and 5 sporadic cases) were compared to 11 controls, using a simplified reference tissue model to measure binding potential. RESULTS: Voxel-based analyses showed a reduction in GABA(A) receptor expression/affinity both in DYT1 carriers and sporadic patients in primary motor and premotor cortex, primary and secondary somatosensory cortex, and in the motor component of the cingulate gyrus. CONCLUSIONS: Dysfunction of GABA(A) receptors in sensorimotor systems in primary (genetic and sporadic) dystonia supports the view that lack of GABAergic control may be associated with the generation of dystonic movements.
Assuntos
Córtex Cerebral/metabolismo , Distúrbios Distônicos/patologia , Receptores de GABA-A/metabolismo , Adulto , Análise de Variância , Mapeamento Encefálico , Córtex Cerebral/diagnóstico por imagem , Distúrbios Distônicos/diagnóstico , Distúrbios Distônicos/diagnóstico por imagem , Distúrbios Distônicos/genética , Feminino , Flumazenil/farmacocinética , Moduladores GABAérgicos/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Chaperonas Moleculares/genética , Cintilografia , Deleção de Sequência/genética , Repetições de Trinucleotídeos/genéticaRESUMO
OBJECTIVES: Levodopa-Carbidopa Intrajejunal gel (LCIG) infusion is an effective intervention for people with advanced Parkinson's disease (PD). Although age may not be a limiting factor for LCIG implant, no data are available on late elderly PD (LE-PD) subjects. In this cross-sectional, we aimed to demonstrate if older age may impact on quality of life (QoL), motor and non-motor symptoms severity, and profile of side effects in PD treated with LCIG. METHODS: Out of 512 PD subjects treated with LCIG at 9 Italian PD centers, we selected 25 LE-PD defined as age ≥ 80 years at last follow-up who were available to attend the study visit. Twenty-five PD patients (Control-PD, defined as age < 75 years at last follow-up) matched to LE-PD by disease and LCIG duration served as control group. The following motor and non-motor variables were ascertained: quality of life (PDQ-8), time spent in ON, wearing-off Questionnaire, Unified PD Rating Scale, freezing of gait questionnaire, Parkinson's disease sleep scale-2, Non Motor Symptoms Scale (NMSS), and MOCA. RESULTS: No statistically significant differences were found between LE-PD and Control-PD on PDQ-8 and several motor and non-motor variables. LE-PD had less frequent and milder impulsive-compulsive behaviors and milder dyskinesia. At multivariable regression, worse quality of life was associated with UPDRS-III and NMSS scores but not to age at study visit and age at LICG implant. Rate of adverse effects was similar in both groups. Drop-out rate calculated in the whole PD cohort was comparable between the two groups. CONCLUSION: Our data provide evidence that valuable LCIG infusion might be achieved in late elderly PD.
Assuntos
Transtornos Neurológicos da Marcha , Doença de Parkinson , Idoso , Idoso de 80 Anos ou mais , Antiparkinsonianos , Carbidopa , Estudos Transversais , Combinação de Medicamentos , Géis , Humanos , Itália , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Qualidade de VidaRESUMO
INTRODUCTION: Specific pre-existing medical conditions (e.g. hypertension or obesity), advanced age and male sex appear linked to more severe manifestations of SARS Co-V2 infection, thus raising the question of whether Parkinson's disease (PD) poses an increased risk of morbidity and mortality in COVID-19 patients. METHODS: In order to describe the outcome of COVID-19 in multi-centre a cohort of PD patients and explore its potential predictors, we gathered the clinical information of 117 community-dwelling patients with COVID-19 followed in 21 tertiary centres in Italy, Iran, Spain, and the UK. RESULTS: Overall mortality was 19.7%, with a significant effect of co-occurrence of dementia, hypertension, and PD duration. CONCLUSIONS: The frailty caused by advanced PD poses an increased risk of mortality during COVID-19.
Assuntos
COVID-19/mortalidade , Demência/epidemiologia , Hospitalização/estatística & dados numéricos , Hipertensão/epidemiologia , Doença de Parkinson/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Antiparkinsonianos/uso terapêutico , COVID-19/epidemiologia , Comorbidade , Estimulação Encefálica Profunda , Feminino , Humanos , Irã (Geográfico)/epidemiologia , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/terapia , Fatores de Risco , Índice de Gravidade de Doença , Espanha/epidemiologia , Fatores de Tempo , Reino Unido/epidemiologiaAssuntos
Distonia/etiologia , Transtornos Parkinsonianos/complicações , Adolescente , Adulto , Criança , Heterozigoto , Humanos , FenótipoAssuntos
Ceruloplasmina , Mutação da Fase de Leitura , Imageamento por Ressonância Magnética , Doenças Neurodegenerativas , Humanos , Ceruloplasmina/deficiência , Ceruloplasmina/genética , Ceruloplasmina/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/patologia , Distúrbios do Metabolismo do Ferro/genética , Distúrbios do Metabolismo do Ferro/diagnóstico , Distúrbios do Metabolismo do Ferro/diagnóstico por imagem , Distúrbios do Metabolismo do Ferro/patologia , Masculino , FemininoRESUMO
Heterozygous rare variants in the PINK1 gene, as well as in other genes causing autosomal recessive parkinsonism, have been reported both in patients and healthy controls. Their pathogenic significance is uncertain, but they have been suggested to represent risk factors to develop Parkinson disease (PD). The few large studies that assessed the frequency of PINK1 heterozygotes in cases and controls yielded controversial results, and the phenotypic spectrum is largely unknown. We retrospectively analyzed the occurrence of PINK1 heterozygous rare variants in over 1100 sporadic and familial patients of all onset ages and in 400 controls. Twenty patients and 6 controls were heterozygous, with frequencies (1.8% vs. 1.5%) not significantly different in the two groups. Clinical features of heterozygotes were indistinguishable to those of wild-type patients, with mean disease onset 10 years later than in carriers of two mutations but worse disease progression. A meta-analysis indicated that, in PINK1 heterozygotes, the PD risk is only slightly increased with a non significant odds ratio of 1.62. These findings suggest that PINK1 heterozygous rare variants play only a minor susceptibility role in the context of a multifactorial model of PD. Hence, their significance should be kept distinct from that of homozygous/compound heterozygous mutations, that cause parkinsonism inherited in a mendelian fashion.
Assuntos
Variação Genética , Doença de Parkinson/genética , Proteínas Quinases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genes Recessivos , Heterozigoto , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Doença de Parkinson/enzimologia , Fenótipo , Estudos Retrospectivos , Homologia de Sequência de AminoácidosRESUMO
Cerebral palsy (CP) is a heterogeneous group of syndromes that cause a non-progressive disorder of early onset, with abnormal control of movement and posture. Various aetiologies can cause the CP clinical spectrum, but all have a disruption of motor control in common. CP can be divided into four major types based on the motor disability: predominant spastic, dyskinetic, ataxic and mixed form. Dyskinetic CP (DCP) is the most common cause of acquired dystonia in children. The treatment of DCP is challenging because most individuals have mixed degrees of chorea, athetosis and dystonia. Pharmacological treatment is often unsatisfactory. Functional neurosurgery, in particular deep brain stimulation targeting the basal ganglia or the cerebellum, is emerging as a promising therapeutic approach in selected patients with DCP. We evaluated herein the effects of DBS on patients with DCP in a review of published patient data in the largest available studies.
Assuntos
Paralisia Cerebral/complicações , Paralisia Cerebral/terapia , Estimulação Encefálica Profunda/métodos , Distonia/etiologia , Distonia/terapia , Criança , Feminino , Humanos , MasculinoRESUMO
This study aimed to investigate phosphorylated α-synuclein (p-syn) in autonomic skin nerves of Parkinson disease (PD) patients with and without orthostatic hypotension (OH). We studied 28 PD patients with normal corrected Mini-Mental State Examination including 14 patients with neurogenic OH (PD + OH) and 14 matched patients did not complain of OH (PD - OH); 7 of whom were re-evaluated over a follow-up period (4 ± 2 years). Skin biopsy was performed in proximal and distal sites. PD + OH patients showed a higher p-syn deposition than PD - OH, with widespread autonomic cholinergic and adrenergic skin nerve involvement. Over the follow-up period, PD - OH patients showed an increase in motor dysfunction scores without autonomic symptoms and a slight increase of skin p-syn deposition but still lower than PD + OH, mainly restricted to adrenergic fibers of skin vessels (SV). In summary, PD + OH patients showed a wide involvement of p-syn deposits in autonomic cholinergic and adrenergic skin nerves compared with PD - OH, and PD - OH patients showed a lower load of skin p-syn restricted to adrenergic fibers of SV still persisting over the follow-up period. The data supported a different pathogenesis between PD + OH and PD - OH and may help to identify a specific diagnostic trait for PD + OH.
Assuntos
Hipotensão Ortostática/metabolismo , Doença de Parkinson/metabolismo , Pele/inervação , Pele/metabolismo , alfa-Sinucleína/metabolismo , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Feminino , Seguimentos , Humanos , Hipotensão Ortostática/diagnóstico , Hipotensão Ortostática/epidemiologia , Masculino , Pessoa de Meia-Idade , Fibras Nervosas/metabolismo , Doença de Parkinson/diagnóstico , Doença de Parkinson/epidemiologia , Fosforilação/fisiologiaRESUMO
The aim of this study was to report the most frequent psychosocial difficulties (PSDs) in patients with Parkinson disease (PD), to explore the relationship between PSDs, disability and quality of life (QoL), and to address the predictors of PSDs. Patients with PD were interviewed using a protocol composed of a questionnaire investigating PSDs (PARADISE 24), QoL, disability, comorbidity, and social support questionnaires, scales on resilience, personality traits, and empathy in physician. Most frequent PSDs were reported. Spearman's correlation was used to address the relationship between PARADISE 24 and QoL and disability measures. Multiple linear regression was performed to investigate predictors of PARADISE 24. Eighty patients were enrolled: 40% women, mean age 61.2 years. The most frequent PSDs were related to cognitive and motor slowness, tiredness, sleeping, facing all things to do, depressive mood, and anxiety. PARADISE 24 were correlated with disability (ρ=0.831) and QoL (ρ=-0.685). Lower QoL, higher disability, early age at onset, and shorter disease duration were significant predictors of PSDs (adjusted R=0.762). PARADISE 24 is an easy to use questionnaire that could contribute toward describing the impact of PD on patients' life more extensively, thus helping to define more tailored interventions.
Assuntos
Doença de Parkinson/psicologia , Idade de Início , Ansiedade/psicologia , Depressão/psicologia , Pessoas com Deficiência/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Apoio SocialRESUMO
OBJECTIVE: We performed a real-life observation of patients with Parkinson disease (PD) who received duodenal levodopa infusion (DLI) to determine which adverse events caused treatment discontinuation and when such events occurred. METHODS: All consecutive patients with PD treated at the Carlo Besta Neurological Institute were included. The patients were evaluated at baseline and after DLI at regular intervals. Their motor condition was assessed and adverse events were recorded. RESULTS: Thirty-five patients with PD (15 men and 20 women) were included. They received DLI implants between October 2007 and September 2013. Four patients died of causes unrelated to the procedure. At the end of the study, 21 patients (60%) were still on treatment. DLI provided efficacious motor control in all patients. Discontinuation was most frequently caused by device- or infusion-related adverse events. Ten patients of the remaining 31 discontinued DLI. There were 2 main causes of withdrawal: stoma infection (4 patients), and worsening of dyskinesias not manageable with infusion reduction (3 patients). In most patients, discontinuations occurred during the first year after implant. Risk of discontinuation was related to age at implant, but no other demographic or clinical variables. CONCLUSIONS: We identified 2 main causes leading to DLI withdrawal during the first year postimplant and suggest adopting measures to prevent such occurrences. Elderly patients are at higher risk of treatment discontinuation.