BACKGROUND Increased neuronal activity in the subthalamic nucleus and the pars interna of the globus pallidus is thought to account for motor dysfunction in patients with Parkinson's disease. Although creating lesions in these structures improves motor function in monkeys with induced parkinsonism and patients with Parkinson's disease, such lesions are associated with neurologic deficits, particularly when they are created bilaterally. Deep-brain stimulation simulates the effects of a lesion without destroying brain tissue. METHODS We performed a prospective, double-blind, crossover study in patients with advanced Parkinson's disease, in whom electrodes were implanted in the subthalamic nucleus or pars interna of the globus pallidus and who then underwent bilateral high-frequency deep-brain stimulation. We compared scores on the motor portion of the Unified Parkinson's Disease Rating Scale when the stimulation was randomly assigned to be turned on or off. We performed unblinded evaluations of motor function preoperatively and one, three, and six months postoperatively. RESULTS Electrodes were implanted bilaterally in 96 patients in the subthalamic-nucleus group and 38 patients in the globus-pallidus group. Three months after the procedures were performed, double-blind, crossover evaluations demonstrated that stimulation of the subthalamic nucleus was associated with a median improvement in the motor score (as compared with no stimulation) of 49 percent, and stimulation of the pars interna of the globus pallidus with a median improvement of 37 percent (P<0.001 for both comparisons). Between the preoperative and six-month visits, the percentage of time during the day that patients had good mobility without involuntary movements increased from 27 percent to 74 percent (P<0.001) with subthalamic stimulation and from 28 percent to 64 percent (P<0.001) with pallidal stimulation. Adverse events included intracranial hemorrhage in seven patients and infection necessitating removal of the leads in two. CONCLUSIONS Bilateral stimulation of the subthalamic nucleus or pars interna of the globus pallidus is associated with significant improvement in motor function in patients with Parkinson's disease whose condition cannot be further improved with medical therapy.

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Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson's disease.

High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN-HFS) is the preferred surgical treatment for advanced Parkinson's disease. In the 15 years since its introduction into clinical practice, many studies have reported on its benefits, drawbacks, and insufficiencies. Despite limited evidence-based data, STN-HFS has been shown to be surgically safe, and improvements in dopaminergic drug-sensitive symptoms and reductions in subsequent drug dose and dyskinesias are well documented. However, the procedure is associated with adverse effects, mainly neurocognitive, and with side-effects created by spread of stimulation to surrounding structures, depending on the precise location of electrodes. Quality of life improves substantially, inducing sudden global changes in patients' lives, often requiring societal readaptation. STN-HFS is a powerful method that is currently unchallenged in the management of Parkinson's disease, but its long-term effects must be thoroughly assessed. Further improvements, through basic research and methodological innovations, should make it applicable to earlier stages of the disease and increase its availability to patients in developing countries.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(08)70291-6.pdf

Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson's disease

Deep brain stimulation for Parkinson's disease.

UNLABELLED Tranexamic acid is a synthetic derivative of the amino acid lysine that exerts its antifibrinolytic effect through the reversible blockade of lysine binding sites on plasminogen molecules. Intravenously administered tranexamic acid (most commonly 10 mg/kg followed by infusion of 1 mg/kg/hour) caused reductions relative to placebo of 29 to 54% in postoperative blood losses in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB), with statistically significant reductions in transfusion requirements in some studies. Tranexamic acid had similar efficacy to aprotinin 2 x 10(6) kallikrein inhibitory units (KIU) and was superior to dipyridamole in the reduction of postoperative blood losses. Transfusion requirements were reduced significantly by 43% with tranexamic acid and by 60% with aprotinin in 1 study. Meta-analysis of 60 trials showed tranexamic acid and aprotinin, unlike epsilon-aminocaproic acid (EACA) and desmopressin, to reduce significantly the number of patients requiring allogeneic blood transfusions after cardiac surgery with CPB. Tranexamic acid was associated with reductions relative to placebo in mortality of 5 to 54% in patients with upper gastrointestinal bleeding. Meta-analysis indicated a reduction of 40%. Reductions of 34 to 57.9% versus placebo or control in mean menstrual blood loss occurred during tranexamic acid therapy in women with menorrhagia; the drug has also been used to good effect in placental bleeding, postpartum haemorrhage and conisation of the cervix. Tranexamic acid significantly reduced mean blood losses after oral surgery in patients with haemophilia and was effective as a mouthwash in dental patients receiving oral anticoagulants. Reductions in blood loss were also obtained with the use of the drug in patients undergoing orthotopic liver transplantation or transurethral prostatic surgery, and rates of rebleeding were reduced in patients with traumatic hyphaema. Clinical benefit has also been reported with tranexamic acid in patients with hereditary angioneurotic oedema. Tranexamic acid is well tolerated; nausea and diarrhoea are the most common adverse events. Increased risk of thrombosis with the drug has not been demonstrated in clinical trials. CONCLUSIONS Tranexamic acid is useful in a wide range of haemorrhagic conditions. The drug reduces postoperative blood losses and transfusion requirements in a number of types of surgery, with potential cost and tolerability advantages over aprotinin, and appears to reduce rates of mortality and urgent surgery in patients with upper gastrointestinal haemorrhage. Tranexamic acid reduces menstrual blood loss and is a possible alternative to surgery in menorrhagia, and has been used successfully to control bleeding in pregnancy.

Tranexamic acid: a review of its use in surgery and other indications.

Parkinson disease (PD) is an age-related neurodegenerative disorder that affects as many as 1-2% of persons aged 60 years and older. With the aging of the population, the frequency of PD is expected to increase dramatically in the coming decades. Current therapy is largely based on a dopamine replacement strategy, primarily using the dopamine precursor levodopa. However, chronic treatment is associated with the development of motor complications, and the disease is inexorably progressive. Further, advancing disease is associated with the emergence of features such as freezing, falling, and dementia which are not adequately controlled with dopaminergic therapies. Indeed, it is now appreciated that these nondopaminergic features are common and the major source of disability for patients with advanced disease. Many different therapeutic agents and treatment strategies have been evaluated over the past several years to try and address these unmet medical needs, and many promising approaches are currently being tested in the laboratory and in the clinic. As a result, there are now many new therapies and strategic approaches available for the treatment of the different stages of PD, with which the treating physician must be familiar in order to provide patients with optimal care. This monograph provides an overview of the management of PD patients, with an emphasis on pathophysiology, and the results of recent clinical trials. It is intended to provide physicians with an understanding of the different treatment options that are available for managing the different stages of the disease and the scientific rationale of the different approaches.

The scientific and clinical basis for the treatment of Parkinson disease (2009)

Forty patients with cranial bone defects after craniectomy underwent extensive cerebrospinal fluid (CSF) hydrodynamic investigations by means of a CSF infusion test before and after cranioplasty. The results of these investigations were related to the clinical signs of the patients before and after cranioplasty and to the size and location of the skull bone defect. Twenty-two patients were considered to have “the syndrome of the trephined” (ST). The remaining patients were either free of symptoms or had symptoms not related to ST.

Effect of cranioplasty on cerebrospinal fluid hydrodynamics in patients with the syndrome of the trephined.

Fifty-eight patients, 36 with essential tremor (ET) and 22 with Parkinson's disease (PD), received deep brain stimulation (DBS) in the thalamic ventral intermediate (Vim) nucleus. The mean follow-up was 17 months for ET and 21 months for PD patients. Stimulation parameters were adjusted as needed, at various intervals after surgery. Results were assessed using routine clinical evaluation and established outcome scales. All patients needed incremental increase in stimulation parameters at various intervals during the first 6-12 months after surgery. The mean voltage 1 week postoperatively was 1. 45 V in PD patients, and 1.37 V in ET patients. Twelve months later, the figures were 2.14 V in PD and 2.25 V in ET patients. At 1 year, the Essential Tremor Rating Scale (ETRS) improved from 54 to 28 (p < 0.0001). The motor part of the Unified Parkinson's Disease Rating Scale (UPDRS) improved from 37 to 26 (p < 0.01). Tremor items of the UPDRS improved more markedly (p < 0.0001). One week postoperatively 90% of PD, and 89% of ET patients were tremor free. One year later, 70% of PD and 60% of ET patients remained mostly tremor free. Upon switching off stimulation, there was a clear tendency for tremor rebound (p = 0.07) in the PD group, requiring continuous 24-hour stimulation in some patients. Permanent non-adjustable ataxia was induced by stimulation in 2 PD patients.

Tolerance and tremor rebound following long-term chronic thalamic stimulation for Parkinsonian and essential tremor.

Several recent publications have stated that the use of microelectrode recording (MER) during pallidotomy or deep brain stimulation (DBS) contributes to decreasing risks and side effects of surgery, a

Do Microelectrode Techniques Increase Accuracy or Decrease Risks in Pallidotomy and Deep Brain Stimulation

The occurrence of intracranial aneurysms (IAs) in the families of 579 consecutive patients with subarachnoid hemorrhage (SAH), of whom 485 had verified IAs, was studied retrospectively. IAs occurred in the families of 6.7% of the IA patients, but only 0.4% of their siblings had IAs. However, there were differences between the familial and nonfamilial IA patients, indicating that the familial patients are a specific small subpopulation of IA patients. The familial patients were younger, often had multiple aneurysms, and had aneurysms frequently located on arteries other than those in the nonfamilial group.

Intracranial aneurysms and heredity.

A randomized controlled clinical trial was carried out to study the effect of tranexamic acid (AMCA, Cyklokapron; AB Kabi, Stockholm, Sweden) in the prevention of early rebleeding after the rupture of an intracranial aneurysm. The incidence of vasospasm, hydrocephalus, cerebral ischemic and thromboembolic complications, morbidity, and mortality was also evaluated. The series comprises 59 patients, 30 treated with tranexamic acid and 29 controls. The treatment was stopped if there was rebleeding, operation, or discharge from the hospital. There were 6 recurrent hemorrhages in 6 patients in the tranexamic acid-treated group and 11 recurrences in 7 patients in the control group. Recurrent hemorrhages occurred later in tranexamic acid-treated patients than in controls. Five patients in each group died from rebleeding. Five additional treated patients and 2 controls died from cerebral ischemic dysfunction. The results suggest that tranexamic acid may protect patients with ruptured aneurysms from rebleeding for 1 or 2 weeks, but that it also may produce cerebral ischemic complications.

Harald Fodstad

Papers

Effect of cranioplasty on cerebrospinal fluid hydrodynamics in patients with the syndrome of the trephined.

Tolerance and tremor rebound following long-term chronic thalamic stimulation for Parkinsonian and essential tremor.

Do Microelectrode Techniques Increase Accuracy or Decrease Risks in Pallidotomy and Deep Brain Stimulation

Intracranial aneurysms and heredity.

Antifibrinolysis with tranexamic acid in aneurysmal subarachnoid hemorrhage: a consecutive controlled clinical trial.