Michele Tagliati

Deep Brain Stimulation for Parkinson Disease: An Expert Consensus and Review of Key Issues

OBJECTIVE To provide recommendations to patients, physicians, and other health care providers on several issues involving deep brain stimulation (DBS) for Parkinson disease (PD). DATA SOURCES AND STUDY SELECTION An international consortium of experts organized, reviewed the literature, and attended the workshop. Topics were introduced at the workshop, followed by group discussion. DATA EXTRACTION AND SYNTHESIS A draft of a consensus statement was presented and further edited after plenary debate. The final statements were agreed on by all members. CONCLUSIONS (1) Patients with PD without significant active cognitive or psychiatric problems who have medically intractable motor fluctuations, intractable tremor, or intolerance of medication adverse effects are good candidates for DBS. (2) Deep brain stimulation surgery is best performed by an experienced neurosurgeon with expertise in stereotactic neurosurgery who is working as part of a interprofessional team. (3) Surgical complication rates are extremely variable, with infection being the most commonly reported complication of DBS. (4) Deep brain stimulation programming is best accomplished by a highly trained clinician and can take 3 to 6 months to obtain optimal results. (5) Deep brain stimulation improves levodopa-responsive symptoms, dyskinesia, and tremor; benefits seem to be long-lasting in many motor domains. (6) Subthalamic nuclei DBS may be complicated by increased depression, apathy, impulsivity, worsened verbal fluency, and executive dysfunction in a subset of patients. (7) Both globus pallidus pars interna and subthalamic nuclei DBS have been shown to be effective in addressing the motor symptoms of PD. (8) Ablative therapy is still an effective alternative and should be considered in a select group of appropriate patients.

Gene delivery of AAV2-neurturin for Parkinson's disease: a double-blind, randomised, controlled trial

BACKGROUND In an open-label phase 1 trial, gene delivery of the trophic factor neurturin via an adeno-associated type-2 vector (AAV2) was well tolerated and seemed to improve motor function in patients with advanced Parkinsons disease. We aimed to assess the safety and efficacy of AAV2-neurturin in a double-blind, phase 2 randomised trial. METHODS We did a multicentre, double-blind, sham-surgery controlled trial in patients with advanced Parkinsons disease. Patients were randomly assigned (2:1) by a central, computer generated, randomisation code to receive either AAV2-neurturin (5·4 × 10¹¹ vector genomes) injected bilaterally into the putamen or sham surgery. All patients and study personnel with the exception of the neurosurgical team were masked to treatment assignment. The primary endpoint was change from baseline to 12 months in the motor subscore of the unified Parkinsons disease rating scale in the practically-defined off state. All randomly assigned patients who had at least one assessment after baseline were included in the primary analyses. This trial is registered at ClinicalTrials.gov, NCT00400634. RESULTS Between December, 2006, and November, 2008, 58 patients from nine sites in the USA participated in the trial. There was no significant difference in the primary endpoint in patients treated with AAV2-neurturin compared with control individuals (difference -0·31 [SE 2·63], 95% CI -5·58 to 4·97; p=0·91). Serious adverse events occurred in 13 of 38 patients treated with AAV2-neurturin and four of 20 control individuals. Three patients in the AAV2-neurturin group and two in the sham surgery group developed tumours. INTERPRETATION Intraputaminal AAV2-neurturin is not superior to sham surgery when assessed using the UPDRS motor score at 12 months. However, the possibility of a benefit with additional targeting of the substantia nigra and longer term follow-up should be investigated in further studies. FUNDING Ceregene and Michael J Fox Foundation for Parkinsons Research.

Neurologic Manifestations of HIV Infection

In the early 1980s, as the systemic manifestations of the acquired immunodeficiency syndrome (AIDS) were first described, investigators realized that human immunodeficiency virus (HIV) type 1 infection could affect the nervous system at every level [1-3]. Neurologic disorders associated with HIV infection include central nervous system infections, neoplasms, vascular complications, peripheral neuropathies, and myopathies (Table 1). In the past decade, basic and clinical research advances produced much new information. We review the clinical features, pathogenetic mechanisms, and treatment of neurologic disorders associated with HIV infection. Table 1. Major Neurologic Manifestations of HIV Infection HIV Dementia Clinical Features One of the most frequent and enigmatic neurologic complications of HIV infection is HIV dementia (also called AIDS dementia complex, subacute encephalitis, HIV encephalopathy, and HIV-1-associated cognitive/motor complex). The symptoms of HIV dementia can be subdivided into three main categories: cognitive, motor, and behavioral [4]. The primary cognitive symptom is forgetfulness associated with slowed mental and motor abilities. Loss of balance and leg weakness are early motor signs. The most commonly observed behavioral symptoms are apathy and social withdrawal, which are often mistakenly diagnosed as depression. Sometimes organic psychosis, such as acute mania, may be a primary manifestation of HIV dementia [5]. Early in the course of HIV dementia, symptoms and signs may be too subtle to establish a definitive clinical diagnosis. Neuropsychological tests are useful to show early cognitive dysfunction and to provide quantitative markers of disease progression [6-8]. As dementia advances, cognitive impairment becomes more obvious, with psychomotor retardation and marked behavioral abnormalities. By this time, objective neurologic signs such as paraparesis, incontinence, tremor, and seizures are more common. Sidtis and Price [9] developed a staging system for AIDS dementia complex that classifies patients from normal (grade 0) to end-stage vegetative state (grade 4). Grade 0.5 (subclinical dementia) comprises patients whose disease may be difficult to diagnose. These persons often have equivocal cognitive complaints, accompanied by relatively normal results of neurologic examinations. Because it is not clear if dementia will develop in patients at this early stage, clinical research trials generally have required that patients have objective neurologic impairment (that is, stage 1) for entry into studies of HIV dementia treatment [10]. In 1992, 7.3% of patients with AIDS in the Centers for Disease Control and Prevention (CDC) database were reported to have HIV dementia [11]. However, this Figure is probably an underestimate because CDC figures generally reflect the incidence of a disorder as the initial manifestation of AIDS, whereas dementia often occurs late in the course of HIV disease, following other AIDS-defining events [11]. The Multicenter AIDS Cohort Study found a prevalence of HIV dementia of 0.4% during the asymptomatic phase [12], whereas retrospective studies found HIV dementia during the late stages of HIV disease in 7.5% to 27% of patients [3, 13, 14]. McArthur and colleagues [15] reported a 7% annual incidence of HIV dementia during the first 2 years after AIDS diagnosis. The onset and progression of HIV dementia varies. Most commonly, dementia occurs late in HIV disease, when CD4 lymphocyte counts are less than 200 cells/mm3. Neurologic deficits usually progress insidiously, although rapid progression may occur. Some controversy exists about how early in HIV infection neuropsychological impairment occurs. Grant and colleagues [16] reported substantial neuropsychological impairment in a few otherwise asymptomatic persons with HIV infection. However, these results were not confirmed by the Multicenter AIDS Cohort Study [12], which found HIV dementia in fewer than 1% of asymptomatic persons with positive HIV serum test results and no significant difference in results of neurologic examinations and neuropsychological tests and brain-imaging abnormalities among persons who were seropositive early in the course of HIV disease and a seronegative matched control group. Although a comprehensive review of this complex subject is beyond the scope of this article, most investigators believe that severe neuropsychological impairment is rare in early HIV infection if other potential confounding factors (substance abuse, age, and education, for example) are excluded [17, 18]. Diagnostic Studies No laboratory or neuroimaging study results are specific for HIV dementia, which is a diagnosis of exclusion. Blood and cerebrospinal fluid studies are helpful to screen for systemic infections (that is, VDRL, cryptococcal antigen). Other cerebrospinal fluid abnormalities are frequently present and include elevated total protein, mild pleocytosis, increased total immunoglobulin fraction, intrathecal synthesis of anti-HIV IgG, and oligoclonal bands. However, similar cerebrospinal fluid abnormalities are also common in patients with HIV infection and no neurologic symptoms [19]. Once other potential causes of dementia are excluded, cerebrospinal fluid markers of immune activation, such as 2-microglobulin, neopterin, and quinolinate may be useful in diagnosing HIV dementia [20-23]. Radiologic studies are important to exclude other infectious or neoplastic processes, and they provide information supporting the diagnosis of HIV dementia. Neuroimaging studies generally show various amounts of cerebral atrophy, ventricular enlargement, and diffuse or multifocal white matter abnormalities Figure 1 [4, 24, 25]. Although these findings are nonspecific, several studies have shown a close correlation between the amount of cerebral atrophy on brain magnetic resonance imaging (MRI) scans and the severity of HIV dementia [26, 27]. However, other studies have not confirmed this association [14]. The clinical features of HIV dementia suggest predominantly subcortical disease [28], which is supported by neuroimaging [27] and morphometric [29] studies. Although multiple causes of cerebral atrophy are possible, Gelman [30] showed that an increased number of microglial cells in the cerebral cortex partially accounts for the ventricular expansion shown by computed tomographic scans. Figure 1. Left. Right. Neuropathologic Findings A spectrum of neuropathologic abnormalities has been described in persons with HIV dementia [31], including multinucleate giant cell and other inflammatory cell infiltration (HIV encephalitis), reactive gliosis, and diffuse white matter pallor (HIV leukoencephalopathy). A consensus conference determined that key components of the pathologic diagnosis of HIV encephalitis are multiple foci of microglia, macrophages, and multinucleate giant cells Figure 2 or the presence of HIV-infected cells in the central nervous system [32]. However, the pathologic changes in the brains of persons with HIV dementia are often less prominent than their clinical symptoms would predict. Even in patients with severe dementia, microglial nodules and nonspecific white matter pallor often are the only pathologic findings in the brain, without substantial multinucleate giant cell infiltration [31, 33]. Figure 2. HIV encephalitis. arrows Although white matter pallor has often been attributed to demyelination, another explanation is disease resulting from changes in the blood-brain barrier. Petito and Cash [34] described substantial extravasation of serum proteins in the brains of persons with HIV infection, regardless of whether HIV encephalitis was present. They suggested that cytokine-mediated alteration of the blood-brain barrier may contribute to viral entry into the brain, leading to the demyelination and gliosis observed in these patients. Power and associates [35] reported that patients with HIV dementia have considerable accumulation of serum proteins in the subcortical white matter glia and frontal cortical neurons compared with persons with HIV who have no dementia. Because evidence of primary demyelination was not found, the authors concluded that blood-brain barrier changes contribute to development of HIV dementia. Pathogenesis Identification of HIV as the pathogenetic agent in AIDS made this an obvious candidate as the cause of HIV dementia. Shaw and colleagues [36] initially identified human lymphotrophic virus type III (HIV-1) in the brains of persons with HIV dementia using DNA Southern blot and in situ hybridization. Masliah and coworkers [37] reported abundant HIV gp41 antigen with immunohistochemical techniques in autopsy specimens from the brains of two thirds of 107 persons with AIDS. The gp41 immune reactivity correlated with the loss of neocortical dendritic area and synapses. The polymerase chain reaction has been proposed as a powerful technique to identify HIV-1 DNA in the brain [38]. Using the polymerase chain reaction, Boni and associates [39] reported the presence of HIV-1 in the central nervous system of two thirds of 39 patients with AIDS, with a correlation between the viral DNA load and the presence of encephalopathy. The human immunodeficiency virus predominantly infects cells of the lymphoreticular system. Although HIV invasion of the central nervous system may occur soon after primary infection [19, 40], what mediates the passage of the virus into the brain is uncertain. The virus may be carried into the brain by infected peripheral monocytes (the so-called Trojan horse theory [41]) or may be transported by infected T cells through a disrupted blood-brain barrier [42]. Wiley and colleagues [43] showed that HIV-infected cells are predominantly located in the deep white matter and are mostly of the monocyte-macrophage series; sometimes infected endothelial cells were identified. 2-Microglobulin, a low-molecular-weight protein expressed on the surface of nucleated cells (particula

Outcome predictors of pallidal stimulation in patients with primary dystonia: the role of disease duration

Pallidal deep brain stimulation (DBS) is currently the most effective treatment for advanced, medically refractory dystonia. However, factors predicting clinical outcome are not well defined. We reviewed the clinical records of 39 consecutive patients with medically refractory primary dystonia who underwent pallidal DBS implants. Thirty-five patients were implanted bilaterally and four unilaterally. Seven patients had fixed skeletal deformities (FSD). The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) scores at baseline, 3 and 12 months after DBS were used to evaluate clinical outcome. We investigated the outcome predictive role of several demographic and clinical factors. FSD patients had a significantly inferior outcome at 12 months, mostly affected by axial scores. All other patients (n = 32) showed a remarkable improvement (median BFMDRS percentage improvement = 87.8). Only disease duration showed a significant correlation with DBS outcome at 3 and 12 months. No other demographic and baseline clinical features predicted DBS outcome. This study confirms that patients with primary, medically refractory dystonia are generally outstanding candidates for pallidal DBS, with the possible exception of axial FSD. Patients with shorter duration of disease may expect a better general outcome. No particular predictive value should be assigned to age at onset, age at surgery, severity of disease, DYT1 status and the presence of phasic or tonic involuntary movements.

Sixty hertz pallidal deep brain stimulation for primary torsion dystonia

Objective: To evaluate the safety and efficacy of 60 Hz deep brain stimulation (DBS) of the globus pallidus internus (GPi) in 15 consecutive patients with primary dystonia. Methods: We conducted a retrospective analysis of clinic charts relative to 15 consecutive patients with medically refractory primary dystonia who underwent stereotactic implantation of DBS leads within the GPi. Twelve had the DYT1 gene mutation. Frame-based MRI and intraoperative microelectrode recording were employed for targeting. All patients were treated exclusively with stimulation at 60 Hz from therapy outset. The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) served as the primary measure of symptom severity at baseline and 1, 3, 6, and 12 months after treatment. Results: All patients tolerated DBS treatment well and showed a progressive median improvement of their BFMDRS motor subscores from 38% at 1 month to 89% at 1 year (p < 0.001, Wilcoxon rank sum test). The disability subscores were similarly improved. The clinical response to DBS allowed seven patients to completely discontinue their medications; six additional patients had reduced their medications by at least 50%. Surgical complications were limited to two superficial infections, which were treated successfully. Conclusions: Stimulation of the internal globus pallidus at 60 Hz is safe and effective for treating medically refractory primary dystonia.

Emergence of restless legs syndrome during subthalamic stimulation for Parkinson disease.

The authors systematically studied the emergence of restless legs syndrome (RLS) after subthalamic nucleus (STN) deep brain stimulation (DBS) for Parkinson disease (PD). Postoperatively, 11 of 195 patients with STN DBS reported new problematic symptoms of RLS. The mean reduction in antiparkinsonian medication was 74%. The mean RLS score at diagnosis was 15 (±5.9) of a possible 24 points and after symptomatic drug therapy 4.3 (±3.1) points. Reduction of antiparkinsonian medication during STN DBS may unmask symptoms of RLS and complicate therapy of both RLS and PD.

Safety of MRI in patients with implanted deep brain stimulation devices

OBJECTIVE To survey the safety of MRI in PD patients implanted with DBS devices. BACKGROUND MRI in patients with DBS implants is useful to confirm electrode placement, optimize programming and investigating complications. However, several medical centers do not perform MRI studies in DBS patients because of safety concerns. The safety profile of MRI in DBS patients has not been documented in large clinical series. METHODS 42 NPF Centers of Excellence (COEs) were asked to complete a questionnaire on MRI use and DBS. RESULTS Investigators from 40 of 42 (95%) NPF COEs completed the survey and 23 (58%) reported that they were currently performing brain MRI in DBS patients, while 3 (7.5%) had done it in the past. The 17 COEs currently not performing post-operative MRI for DBS listed the following reasons: 1) industry guidelines and/or warnings (53%); 2) decision deferred to outside department (29%); 3) liability/risk/safety (18%); 4) no active DBS program (18%); 5) no available MRI (12%); and 6) insurance and reimbursement concerns (6%). A total of 3304 PD patients with one or more DBS leads had a brain MRI scan, and 177 DBS patients had MRI of other body regions. In one case MRI was associated with an IPG failure without neurological sequelae after IPG replacement. No other complications were reported. CONCLUSIONS these data provide evidence for a favorable risk/benefit ratio for brain MRI in patients with DBS implants. Further studies will need to address whether a re-assessment of more restrictive recommendations (i.e. very low SAR values) may be warranted.

Treatment of levodopa-induced motor complications.

Chronic levodopa treatment for Parkinsons disease patients is frequently associated with the development of motor complications such as end‐of‐dose wearing‐off and dyskinesias. In this review, we provide an overview of the strategies available for dealing with these problems. Medical management includes manipulation of levodopa dosing to establish the optimum treatment schedule, improving levodopa absorption, catechol‐O‐methyl transferase‐inhibition (COMT), Monoamine oxidase‐B (MAO‐B) inhibition, dopaminergic agonists, amantadine, and continuous dopaminergic infusions. Surgical procedures and particularly deep brain stimulation are also reviewed. It should be noted that none of these treatments has been shown to provide anti‐parkinsonian efficacy that is greater than what can be achieved with levodopa. We highlight the importance of initiating therapy with a treatment strategy that reduces the risk that a Parkinsons disease patient will develop motor complications in the first place. Key Words: Advanced PD, dyskinesias, motor fluctuations, levodopa, dopamine agonists, COMT inhibitors, MAO‐B inhibitors.

Deep brain stimulation for torsion dystonia in children

IntroductionDeep brain stimulation (DBS) at the internal globus pallidus (GPi) is an effective treatment for some patients with medically refractory torsion dystonia. In this article, we review the results of pallidal DBS surgery in children with dystonia. Details of the DBS procedure and programming of the DBS devices are discussed.DiscussionPallidal DBS is most effective in patients with primary generalized dystonia. Children and adolescents possessing the DYT1 gene mutation may respond best of all. The presence of static dystonic postures and/or fixed orthopedic contractures may limit the functional response to DBS and may require additional surgery.ConclusionAs a group, patients with secondary dystonias respond less well to DBS than patients with primary dystonia. However, patients with dystonia secondary to anoxic brain injury who have grossly intact basal ganglia anatomy may represent a subpopulation for whom pallidal DBS is a viable option.

Narrowing the DYT6 dystonia region and evidence for locus heterogeneity in the Amish-Mennonites.

The DYT6 gene for primary torsion dystonia (PTD) was mapped to chromosome 8p21‐q22 in two Amish–Mennonite families who shared a haplotype of marker alleles across a 40 cM linked region. The objective of this study was to narrow the DYT6 region, clinically characterize DYT6 dystonia in a larger cohort, and to determine whether DYT6 is associated with dystonia in newly ascertained multiplex families. We systematically examined familial Amish–Mennonite dystonia cases, identifying five additional members from the original families, as well as three other multiplex Amish–Mennonite families, and evaluated the known DYT6 haplotype and recombination events. One of the three new families carried the shared haplotype, whereas the region was excluded in the two other families, suggesting genetic heterogeneity for PTD in the Amish–Mennonites. Clinical features in the five newly identified DYT6 carriers were similar to those initially described. In contrast, affected individuals from the excluded families had a later age of onset (46.9 years vs. 16.1 years in the DYT6), and the dystonia was both more likely to be of focal distribution and begin in the cervical muscles. Typing of additional markers in the DYT6‐linked families revealed recombinations that now place the gene in a 23 cM region surrounding the centromere. In summary, the DYT6 gene is in a 23 cM region on chromosome 8q21‐22 and does not account for all familial PTD in Amish–Mennonites.