Adenosine Deaminase Test

Deep brain stimulation in Parkinson’s disease

Abstract: Deep brain stimulation (DBS) is a widely accepted therapy for medically refractory Parkinson’s disease (PD). Both globus pallidus internus (GPi) and subthalamic nucleus (STN) stimulation are safe and effective in improving the symptoms of PD and reducing dyskinesias. STN DBS is the most commonly performed surgery for PD as compared to GPi DBS. Ventral intermediate nucleus (Vim) DBS is infrequently used as an alternative for tremor predominant PD patients.

Patient selection is critical in achieving good outcomes. Differential diagnosis should be emphasized as well as neurological and nonneurological comorbidities. Good response to a levodopa challenge is an important predictor of favorable long-term outcomes. The DBS surgery is typically performed in an awake patient and involves stereotactic frame application, CT/MRI imaging, anatomical targeting, physiological confirmation, and implantation of the DBS lead and pulse generator. Anatomical targeting consists of direct visualization of the target in MR images, formula-derived coordinates based on the anterior and posterior commissures, and reformatted anatomical stereotactic atlases. Physiological verification is achieved most commonly via microelectrode recording followed by implantation of the DBS lead and intraoperative test stimulation to assess benefits and side effects. The various aspects of DBS surgery will be discussed.

Key words: deep brain stimulation (DBS); Parkinson’s disease(PD),  stereotaxis

Introduction

Parkinson's disease is a slowly progressive, neurodegenerative disease characterized by tremor, rigidity, bradykinesia and postural instability. It is the most common movement disorder in middle or late life with a prevalence of about 0.3% of the general population, rising to 1% in people over 60 years of age. Approximately 130 000 people suffer from it in the UK and it presents an increasing burden in our ageing population. Pathological findings in Parkinson's disease demonstrate greatly diminished neuromelanin pigmented neurons in the substantia nigra of the basal ganglia with associated gliosis, and Lewy bodies present in many remaining neurons.

James Parkinson, in his original 1817 Essay on The Shaking Palsy, gave an account of six patients in which he noted signs of tremor, festinating gait and flexed posture.  Nearly two centuries from Parkinson's observations, and almost four decades after Cotzias' dramatic demonstration of levodopa's efficacy, the limitations and complications of levodopa treatment for Parkinson's disease have become well documented Five years after initiation of therapy, a majority of patients develop medication related motor complications, namely levodopa induced dyskinesias (LID) and motor fluctuations. Deep brain stimulation (DBS) has been developed primarily to address these treatment related motor complications and therapeutic failures.

Pathophysiology of PD

The loss of dopaminergic neurons in the substantia nigra, the main functional characteristic of PD, affects the circuit described above and leads to the cardinal motor symptoms of PD. While the exact mechanism of this process is unknown, animal research as well as human recordings have provided functional and biochemical evidence that bradykinesia in PD results from excessive activity in the STN and the GPi. This leads to an exaggerated beta (10-30 Hz) synchronization within and between structures in the basal ganglia circuitry  that could also contribute to rigidity and akinesia.

The pathophysiology of rest tremor in PD is less clear and probably more complicated. This symptom most likely results from a dysfunction of both the striato-pallidal-thalamocortical and the cerebellodentato-thalamocortical circuits, with hyperactivity and hypersynchronization between central oscillators.

Possible mechanism of action of DBS

DBS acts through delivering an electrical current in a specific target area of the brain. This current can be modulated through modification of voltage, frequency and duration of each electrical pulse delivered. The delivered energy creates an electrical field of variable size and shape according to the parameters used for stimulation. Although initially believed to stimulate the target, thus the name of the whole process, it seems that

DBS actually excites the neuronal fibers, but inhibits the neural cells. In fact, GPi DBS decreases the GPi mean firing rate back to a normal range in animal models as well as PD patients, and high frequency DBS has a similar effect as dopamine replacement therapies, and promotes faster (about 70 Hz) nonhypersynchronous activity in the basal ganglia, correlated with clinical improvement. This might be achieved through stimulation of bypassing inhibitory pathways, synaptic inhibition, depolarizing blockade, synaptic depression, and simulation-induced disruption of pathological network activity. Overall, this leads to modifications of the firing rate and pattern of neurons in the basal ganglia, as well as local release of neurotransmitters such as glutamate and adenosine. In addition, it seems that DBS also increases blood flow and stimulates neurogenesis. Over the last few years, functional imaging, specifically functional magnetic resonance imaging (fMRI), positron emission tomography (PET) and single-photon emission computed tomography (SPECT), has been used in an attempt to clarify the mechanism of action of DBS. In fMRI, blood-oxygen-level-dependent (BOLD) signals are acquired, and oxygenated blood marks areas of neural stimulation or inhibition. On the other hand, PET and SPECT allow for imaging of multiple activity markers, such as blood flow, glucose and oxygen metabolism. While fMRI is less powerful than nuclear medicine techniques, it provides a much better spatial and temporal resolution. Because of the suspected inhibitory DBS effects in electrophysiological studies, reduced STN blood flow or glucose metabolism would have been expected on functional imaging. However, the opposite has been found to be true in an overwhelming majority of imaging studies to date. In addition, BOLD activation in the area surrounding the electrode has been reported, despite the electrode imaging artifact preventing direct observation of the STN around the electrode. This discrepancy between apparent STN inhibition in single-cell studies and activation in imaging studies might be explained by a few hypotheses. First, electrophysiological recordings identify short neuronal modulation (in the order of milliseconds) while neuroimaging methods may reflect the summed activity changes over seconds to minutes. Second, non-neuronal contributions to the change in blood flow and/or glucose metabolism cannot be excluded, and could confound the results of neuroimaging.

Finally, it is possible that PET and fMRI actually detect the increased activity in the axons, rather than in the cell bodies. Complicating matters further, some imaging studies after STN DBS have showed increased

activity in the GPi while others reported decreased activity in that nucleus. In summary, it is still unclear how exactly DBS affects the firing rate and pattern of neurons and how these changes actually modify the symptoms of Parkinson’s disease. DBS is presently more of an empirically proven treatment in search of physiological explanation.

The effect of DBS on the cardinal symptoms of PD have been established in three randomized controlled clinical trials --- 

TABLE 1

PATIENT SELECTION for DBS in PD

Patient selection is a critical first step as poorly chosen candidates may not have optimal benefits and have increased morbidity. Several factors must be considered before determining if a patient is an appropriate candidate for DBS surgery. A multidisciplinary approach involving the neurosurgeon, neurologist, and neuropsychologist is important to determine the appropriate surgical candidate. It is also important that the diagnosis of idiopathic PD be confirmed prior to proceeding with DBS surgery. Key to this assessment is evaluating the surgical candidate in both the on and off medication states with a corroborating levodopa challenge. Perhaps the best prognostic indicator of a patient’s suitability for DBS surgery is their response to levodopa.In general, a levodopa challenge following a 12-hour medication withdrawal should provide at least a 33% improvement in the motor section of the Unified Parkinson’s Disease Rating Scale (UPDRS).

                     In our institute, we follow a simple chart(below) for screening of patients for DBS in PD.

PREOPERATIVE MANAGEMENT

A full medical assessment is a necessary part of the preoperative evaluation, as advanced PD patients tend to be elderly with significant comorbidities. Major issues are---

Anticoagulation/antiplatelets--- The risk of discontinuing medications that affect anticoagulation and

platelet aggregation should be weighed against the potential benefits in the quality of life offered by DBS surgery. However, timely discontinuation of these latter medications is mandatory for stereotactic surgery since intracerebral hematomas are the most serious of all potential complications from DBS. Any anticlotting medications, including aspirin, ticlopidine, clopidogrel, and all nonsteroidal anti-inflammatory drugs should be discontinued at least 7 to 10 days preoperatively to ensure the return of normal blood clotting function.

Arterial hypertension can also increase the risk of intracranial bleeding during stereotactic procedures and must be controlled in the weeks prior to surgery.

A prolonged discussion on the short- and long-term effects of DBS on Parkinson’s disease should be carried out with the patient, family, and caregivers.

The night prior to DBS surgery, the antiparkinsonian medications are typically held to pronounce the Parkinson’s symptoms at the time of surgery to see the clinical effects on symptoms during surgery and the families must be counselled regarding their role in facilitating the patient.

Target selection

The two main targets considered for DBS in PD are the STN and the GPi. current tendency is to prefer targeting the STN because of a greater improvement in the OFF phase motor symptoms as well as a higher chance to decrease the medication dosage and a lower battery consumption linked to the use of lower voltage in the STN compared to the GPi DBS. GPi can be the preferred target if LID is the main complaint. GPi DBS might be preferred for patients with mild cognitive impairment and psychiatric symptoms. Because STN DBS might have a higher rate of cognitive decline and/or depression and worsening of verbal fluency in some studies.

Surgical technique

The basic components of DBS implantation surgery involve frame placement, anatomical targeting, physiological mapping, evaluation of macrostimulation thresholds for improvement in motor symptoms or induction of side effects, implantation of the DBS electrode and implantable pulse generator (IPG).

Head-frame placement

The CRW frame is the most commonly used followed by the Leksell frame. Placement of the frame is done under local anesthesia unless anxiety or uncontrollable movements necessitate the use of sedation or general anesthesia.

Leksell stereotactic frame  placed over the head of a patient showing the correct method for placement of the Leksell head-frame. The frame should be placed parallel to orbito-meatal line in order to approximate the AC-PC plane. It is attached to the patient’s head using four pins under local anesthesia.

Imaging and anatomic targeting

Computerized Tomography (CT) scans and MRI are the two main imaging modalities used for targeting when performing DBS implantations. A thin cut stereotactic CT (_2 mm slices with no gap and no gantry tilt) is obtained after frame placement and is then fused with the stereotactic MRI on a planning station (Stealth station). The advantage of fusing the CT with MRI is the ability to avoid image-distortions inherent to MR imaging adding to the stereotactic accuracy. To better define the STN, T2-weighted images (TR 2800, TE 90, flip angle 90˚, slice thickness 2.0 mm) were obtained.

The AC and the PC were marked and the centre of the AC–PC line determined. The next step is planning the entry point and trajectory. The strategy here is to avoid surface and sub-cortical vessels. After trajectory planning, the patient is placed supine on the operating table and the frame attached to the table using an adaptor. Prophylactic antibiotics are given at least 30 min prior to incision. The head is prepped and draped in a sterile fashion. Under local anesthesia, a burr-hole is placed on the calculated entry point marked on the skull. The entry point is determined by the calculated arc and ring angles. Hemostasis is achieved with bone wax and bipolar cautery.

A Medronic Stim-Loc anchoring device (Medtronic, Minneapolis, MN) burr-hole base ring is then placed on the burr-hole and secured with two screws which are used at the end of the procedure to anchor the DBS electrode.

The dura is then cauterized and opened exposing the underlying surface of the brain. The microdrive is then assembled and cannulae inserted 10 mm above the target to avoid lenticulostriate vessels found deeper. Gel- foam and fibrin glue is applied on dural hole to minimize cerebrospinal fluid (CSF) loss and air entry into the skull. Subsequently, microelectrode recording and stimulation is undertaken.

Microelectrode recording/ Mapping

Microelectrode mapping is used to precisely define the target STN and its boundaries as well as nearby critical structures. We believe microelectrode mapping is crucial in order to give one the best chance for optimal placement of the DBS lead given anatomical inaccuracies due to image distortion and intraoperative brain shifts secondary to CSF loss, and pneumocephalus that can lead to inaccuracies in defining the initial target coordinates and shifts in the target itself once the skull is opened. Microelectrode mapping is performed using platinum-iridium glass coated microelectrodes dipped in platinum black with an impedance of around 0.3–0.5 Mo. These platinum-iridium microelectrodes are capable of recording single unit activity and can also be used for micro-stimulation up to 100 mAwithout significant breakdown in their recording qualities.

As the recording electrode was advanced, entry into the STN was identified by a sudden increase in the density of cellular discharge, with the characteristic irregular pattern of discharge—spikes of different sizes, occurring at random intervals. On coming out of the STN a quiet period (background noise) was seen followed by recording from the substantia nigra if the recording was continued far enough, described as high frequency (50–60 spikes/s) discharge pattern.11 Characteristic STN recordings (visual and audio) were identified and the depth of the STN activity was noted. Identification of STN activity was only based on the visual identification. The centre of the point of best electrical activity was selected as the final target. The microelectrode was replaced with a permanent quadripolar macroelectrode (Medtronic electrode no. 3389) to target the centre of the STN electrical activity. The proximal part of this electrode consists of four nickel conductor wires insulated with a polytetrafluoroethylene jacket tubing. The distal part has four metallic noninsulated contacts of 1.5 mm spaced at 0.5 mm intervals. The diameter of the distal electrode is 1.27 mm. Based on the clinical response any of the four contacts can be used for stimulation. Macrostimulation using the DBS electrode itself is then used to determine benefits and side effects. In most cases lateral skull x rays were obtained at this point with image intensifier carefully positioned to locate the target point in the centre of the Leksell-G frame rings.

Initial programming is always refined by using intra-operative macrostimulation data and a mono-polar review to identify the thresholds of stimulation for improvement in parkinsonian motor signs as well as the thresholds for inducing side effects at the level of each contact. The four variables that are used in programming are choice of contacts (0, 1, 2 or 3 used either as the cathode or anode), frequency of stimulation (hertz), pulse-width (ms) and amplitude (voltage).

POSTOPERATIVE MANAGEMENT

In the immediate hours after surgery, it is important to keep arterial blood pressure in the normal range. In addition, the patient’s preoperative drug regimen should be restarted immediately after surgery to avoid problems with dopaminergic withdrawal. Patients should undergo postoperative CT scans and/or MRI scans to assess the electrode location and intracranial status. In addition, plain X-rays are obtained to assess the location and geometry of the leads and hardware. Parkinson’s medications may need to be adjusted depending on the patient’s status. Cognitive and behavioral changes may occur in the postoperative period, particularly in older patients. Patients can be discharged as early as 24 hours after surgery, depending on their neurological and cognitive status.

Conclusion

For the last 50 years, levodopa has been the cornerstone of PD management. However, a majority of patients develop motor fluctuations and/or LID about 5 years after the initiation of therapy. DBS of the STN or the GPI grant to patients with PD improved quality of life and decreased motor complications, and has been approved as such by the Food and Drug Administration in the US in 2002. We reviewed the experience and available literature on DBS for Parkinson’s disease over the last decade and arrive at the following understandings.

The success of DBS surgery depends on the accurate placement of the leads and meticulous programming of the stimulation. Therefore, it is best accomplished by an experienced team of neurosurgeon, neurologist, and support staff dedicated to the treatment.

Reports of surgical complication rates and long-term side-effects of DBS are very variable, so benefits and potential adverse results should not be under- or over-emphasized.

While essentially equal in improving the motor symptoms of PD, STN and GPi might have their own benefits and risks, and the choice of the target should be individualized and adapted to the patient’s situation.

Knowledge to further improve DBS treatment for Parkinson’s disease, such as a more scientific and reliable protocol on programming, strategies to minimize cognitive and psychiatric complications, and the better

long-term maintenance of the implanted device, are still lacking.

Data on the impact of DBS on non-motor symptoms affecting the quality of life of PD patients, such as pain, speech or gastro-intestinal complaints, are still scarce. Further research in these areas will help make this useful treatment even more beneficial.

Coffee is loaded with beneficial nutrients and anti-oxidants that can improve your health. Despite the myriad varieties coffee is usually consumed in, black coffee and milk coffee seem to interest the largest audience. The comparison between the two can come to an end, if you know what exactly you are looking for:

1. For weight loss: If you want to shed a few kilos, you can add black coffee to your diet plan due to its low calorie content than the milk alternative. A cup of black coffee contains 20 kilo calories while a cuppa prepared with milk and sugar has about 60 kilo calories. Caffeine also increases metabolism in the body that may help you in burning more calories.
2. To reduce the risk of diabetes: Coffee intake lowers your blood sugar level and in turn reducing your risk for diabetes. Moreover, the nutrients in coffee help your body use insulin, a hormone essential to store and use sugar that is delivered by your food. Those who drink considerable amounts of either regular or decaffeinated coffee could less likely to develop diabetes as compared to those who drink little or no coffee. This relationship between substantial coffee intake and diabetes suggests that each cup of coffee that you drink reduces your risk of developing diabetes by 7 per cent, if taken regularly.
3. For a smarter you: The stimulant called caffeine is the world's most frequently consumed psychoactive ingredient. Caffeine is absorbed into your bloodstream and then travels into the brain where it blocks an inhibitory neurotransmitter known as Adenosine. This increases the amounts of other neurotransmitters like norepinephrine and dopamine, leading to an enhanced firing of neurons. Coffee improves your brain function including memory, mood, vigilance, energy levels, reaction times and general cognitive function.

Regular coffee with milk and sugar

Although it is not entirely healthy to take added sugar and milk (Basically, roughly three times the calorie content of black coffee), you can drink a cup of milk coffee per day. If you are a caffeine addict and want to cut down your coffee intake, you should consider drinking cafe latte rather than an Americano to decrease caffeine content and increase protein content by adding milk. Besides, drinking your coffee black, post evening keeps you wide awake also disrupting your circadian rhythm. You might want to sip on thick, milky coffee on such occasions. If you wish to discuss about any specific problem, you can consult a dietitian-nutritionist.

Normal pregnancy lasts for 38 to 42 weeks. However, there may be times during these weeks that you may have some physical issues such as vomiting, backache, and loose stools etc which require treatment with medicines.

Therefore, monitoring and managing these physical conditions becomes necessary to ensure a normal delivery. Management consists of both medicines and rehabilitation. Medicines are considered to be the first line of treatment; however, the health care provider needs to take care while prescribing medicines during pregnancy taking into consideration the harmful effects they can have on both – the mother and the foetus.  Medicines pass on via the placenta from the mother to the foetus. Hence, before prescribing any medicine the provider should check the possibilities of the medicine causing any congenital defect. You should avoid medicines from the time of conception till the first 10 weeks, as this is the time when the foetus is most prone to the get permanent congenital deformities. Medicines given in the later stages (after 10 weeks) may cause systemic damage. For example NSAIDs (Non Steroidal Anti-Inflammatory Drugs) may lead to problems during labour or organ defects in the foetus.

Therefore, medicines should always be avoided during pregnancy. Still there are certain medicines, which can be taken but after consulting your physician. Let’s discuss the medicines that are safe during pregnancy.

The following is a list of medicines and their effects during pregnancy:

1. Analgesic Medicines

2. Opiates 

3. Anaesthetics 

4. Thrombolytics - The possible advantages of this class may balance the risk during pregnancy. Common medicines used are: Alteplase, Reteplase, Streptokinase, Urokinase.

5. Antidotes

6. Penicillins

7. Cardiac agents

8. Diabetes: Insulin is safe to use during diabetes.

9. Antacids

10. Corticosteroids: Advised for short term use

Always talk to your physician in case of any complication and before taking any medicine given above.

Which medicines are safe to use during Pregnancy?

Normal pregnancy lasts for 38 to 42 weeks. However, there may be times during these weeks that you may have some physical issues such as vomiting, backache, and loose stools etc which require treatment with medicines.

Therefore, monitoring and managing these physical conditions becomes necessary to ensure a normal delivery.Management consists of both medicines and rehabilitation.Medicines are considered to be the first line of treatment; however, the health care provider needs to take care while prescribing medicines during pregnancy taking into consideration the harmful effects they can have on both – the mother and the foetus.  Medicines pass on via the placenta from the mother to the foetus. Hence, before prescribing any medicine the provider should check the possibilities of the medicine causing any congenital defect. You should avoid medicines from the time of conception till the first 10 weeks, as this is the time when the foetus is most prone to the get permanent congenital deformities. Medicines given in the later stages (after 10 weeks) may cause systemic damage. For example NSAIDs (Non Steroidal Anti-Inflammatory Drugs) may lead to problems during labour or organ defects in the foetus.

Therefore, medicines should always be avoided during pregnancy. Still there are certain medicines, which can be taken but after consulting your physician. Let’s discuss the medicines that are safe during pregnancy.

The following is a list of medicines and their effects during pregnancy:

1. Analgesic Medicines

2. Opiates

3. Anaesthetics

4. Thrombolytics - The possible advantages of this class may balance the risk during pregnancy. Common medicines used are: Alteplase, Reteplase, Streptokinase, Urokinase.

5. Antidotes

6. Penicillins

7. Cardiac agents

8. Diabetes: Insulin is safe to use during diabetes.

9. Antacids

10. Corticosteroids: Advised for short term use

Always talk to your physician in case of any complication and before taking any medicine given above.

Green tea is believed to be one of the healthiest beverages. It is rich in nutrients and antioxidants, which have a positive effect on the body. Some of the benefits, which it provides are lesser risk of cancer, fat loss, and an improved function of the brain. The latest study about green tea reveal that it boosts memory and can make you smart!

Listed here are some of the most amazing health benefits of having green tea which have been backed by research:

1. The presence of bioactive compounds in green tea helps to improve the health. It is enriched with polyphenols like flavonoids and catechins, which are considered to be powerful antioxidants. These reduce the free radical formation in the body thereby, protecting the cells from damage.
2. The compounds found in green tea helps to improve the brain function, thus making you smarter. The main ingredient is caffeine. Though not as much as in coffee, it is enough to create a response. Caffeine blocks Adenosine, an inhibitory neurotransmitter and increases the neurons and thus the concentration of the neurotransmitters like the norepinephrine and dopamine. It also has an amino acid L-theanine which increases the activity of the inhibitory neurotransmitter GABA. Caffeine and L-theanine work together to improve the brain function.
3. The antioxidants found in green tea can actually lower the risk of cancer. The oxidative damages lead to cancer and antioxidants have a protective effect against cancer. As green tea is enriched with antioxidants it reduces the cancer risk. Milk should not be added in this tea as it reduces the value of the antioxidants.
4. Green tea lowers the risk of Parkinson's and Alzheimer's. Thereby, protecting the brain in old age. Alzheimer's is a neurodegenerative disease, which causes dementia. Parkinson's being the second common neurodegenerative disease also involves death of dopamine, produced by the neurons of the brain. The bioactive compounds of the green tea have multiple protective effects and reduce the risk of these disorders.
5. The dental health can be given a boost by drinking green tea. The catechins found in green tea stop the growth of certain virus and bacteria. This helps to lower the risk of infections and in turn improves the dental health, halitosis and caries.
6. The risk of type 2 diabetes, which is considered to be an epidemic disease can be lowered by having green tea. In diabetes there is an increased blood sugar level and green tea improves this insulin sensitivity.
7. Green tea lowers the LDL and total cholesterol. It also protects against the LDL particles from oxidation. This is turn is believed to lower the risk of cardiovascular disease.