Online newspaper of professor Yasser Metwally

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

September 20, 2008 — Levodopa combined with carbidopa remains the most effective approach to the symptomatic relief of idiopathic parkinson disease. Over time, however, an increasing number of parkinsonian patients evidence motor complications, notably motor response fluctuation (end of dose failure, on/off phenomenon… etc) and abnormal involuntary movement.. Dopaminergic treatment of parkinsonian patients is composed of two main stages, an initial honeymoon stage in which the patient’s response is typically good, to be followed after the lapse of a few years by anther stage in which the clinical response is plagued by response fluctuation and involuntary movement. The progression from one stage to the other stage is almost invariable in every single patient. Motor complications of dopaminergic treatment is mainly due to striatal, mainly putaminal, degeneration ( as a part of the natural progression of the disease ) following degeneration of the nigral dopaminergic projections. In addition, pathological modification of striatal receptors, partially related to the nonphysiological delivery of levodopa in a continuous pulsatile mode, might be responsible for the various types of dyskinesias observed in the second stage

As a point of departure, a quick overview of the peripheral and central Pharmacokinetics of levodopa will be presented. Levodopa is mainly absorbed from the duodenum and the proximal small intestine and factors which enhance gastric emptying enhance levodopa absorption and vice versa. The half life time of the circulating L-dopa is very short (about 90 minutes) and this half life time is almost doubled if a peripheral decarboxylase inhibitor (carbidopa) is used., L-dopa is decarboxylated in the dopaminergic neurons of the substantia nigra into dopamine. The dopamine is stored in the presynaptic terminals in the corpus striatum (mainly the putamen). Dopamine is normally stored in presynaptic vesicles termed chromaffin granules and is released into the synaptic cleft by a calcium dependant process, however dopamine formed by decarboxylation of exogenous L-dopa is not incorporated into the normal storage pool in the chromaffin granules but rather is accumulated in the cytosol of the presynaptic terminals until delivered into the synaptic cleft .

Dopamine in the synaptic cleft is driven (by continuous release) from the presynaptic store and subsequently its concentration remains constant so long as the striatal storage capacity remains within reasonable limits. In this way striatal dopamine availability does not depend on the plasma levodopa level and the concentration of striatal dopamine remains fairly constant in the face of the wild fluctuations and swings of plasma levodopa level that normally occur due to the short half life time of levodopa. Early in the disease the striatal storage capacity of dopamine will buffer the peripheral oscillations of L-dopa level and will transform the intermittent pulsatile delivery of L-dopa into a sustained clinical response (by maintaining a constant concentration of dopamine in the synaptic cleft) . In this way the clinical response is not directly related to, or dependant on, the peripheral plasma concentration of L-dopa.

However with progressive denervation / degeneration of the corpus striatum, the storage capacity of the brain to dopamine is reduced to a critical level and the brain is no longer capable of buffering the peripheral oscillations of L-dopa level by continuously releasing dopamine into the synaptic cleft to maintain a constant concentration of it . The concentration of dopamine in the synaptic cleft will fluctuate with fluctuation of the plasma level of L-dopa and peripheral kinetics of L-dopa become of paramount importance. Under such circumstances the duration of the antiparkinsonian action of L-dopa diminishes, ultimately to the point where clinical fluctuations become a direct reflection of the variations of the plasma concentration of L-dopa.

The initial stage of good response to -L-dopa probably coincide with the stage where pathological changes are confined to the substantia nigra with a reasonable striatal storage capacity, however when pathological changes extend to involve the putamen ( progressive putaminal denervation and degeneration) with the resultant of reduction of the storage capacity of the brain to dopamine, the initial good sustained response to L-dopa is replaced by an unexpectedly fluctuant response that oscillates with oscillation of the plasma concentration of L-dopa .

References

1. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 9.4a October 2008 [Click to have a look at the home page]

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

September 19, 2008 — DBS was first used in the 1970s for the treatment of chronic pain. Mixed results and poor electrode design caused a cessation of significant activity in this field in the 1980s, but over the last 10 years, DBS has reemerged as a treatment for movement disorders.

Mechanism of action: Currently, no clear explanation of the mechanism of action of DBS exists, although several hypotheses have been formulated. High-frequency stimulation may create a global hyperpolarization of the cell membrane, resulting in a loss of excitability. Alternatively, stimulation may jam signal flow out of an abnormally functioning structure. Finally, antedromic and orthodromic depolarization currents may modulate neuronal activity at sites distant from the stimulation target.

Advantages: The main advantages of DBS are reversibility and adjustability. Because the DBS lead is left in place, physicians have ongoing access to the target site, allowing them to adjust stimulation parameters in response to changes in the patient’s condition. If stimulation induces unwanted adverse effects, the stimulator can be turned off, adjusted, or removed. In the event that DBS proves clinically ineffective, the patient has not suffered an irreversible lesion to the brain. Additional advantages include the ability to intervene at targets that cannot or should not be lesioned and the provision of a unique opportunity to study human basal ganglia physiology.

Disadvantages: The main disadvantage of DBS is the cost. Currently, the cost of the device is approximately $10,000 per unit. Additional disadvantages include an increased risk of infection due to the presence of implanted hardware and the cost of maintenance (ie, repair/replacement of fractured wires, repeated office visits for stimulation adjustments). Currently, battery exhaustion necessitates replacement of the entire pulse generator, the most expensive component of the system (cost is approximately $8,000) every few years.

Procedure: DBS implantation is performed in 2 stages. During the first stage, the DBS lead is implanted stereotactically into the target nucleus. During the second stage, the DBS lead is connected subcutaneously to an implantable pulse generator (IPG), which is inserted into a pocket beneath the skin of the chest wall, like a pacemaker. As with most stereotactic movement disorder procedures, the first stage is performed with the patient awake to allow monitoring of neurologic status. The stereotactic headframe is applied on the morning of surgery and a targeting MRI is performed. A combination of MER and macroelectrode stimulation is used to refine the desired target physiologically. The DBS lead is implanted and anchored to the skull with a burr hole cap.

A brain MRI is obtained immediately postoperatively to confirm proper electrode placement and to make sure that no hemorrhage has occurred. If the MRI is acceptable, the patient is returned to the operating room, where the remainder of the device is implanted under general anesthesia.

The electrode is thin (approximately 1.3 mm in diameter) and flexible, so that it atraumatically moves with the brain. The device can be programmed to deliver stimulation in monopolar or bipolar fashion, employing any of the 4 electrode contacts, alone or in combination. Thus, a great deal of therapeutic flexibility is provided, permitting customized stimulation for each patient. Stimulation parameters can be adjusted at any time using a transcutaneous programmer.

• Thalamic DBS

Thalamic DBS initially was used contralateral to previous thalamotomies to reduce the risk associated with bilateral thalamotomy. The results were so encouraging that thalamic DBS progressively substituted thalamotomy as the treatment of choice for medically refractory tremor. A decade of experience in Europe and the United States indicates that thalamic DBS is equivalent to thalamotomy for tremor suppression. As with thalamotomy, patients must be assessed carefully regarding the disability caused by tremor rather than bradykinesia and rigidity. Because the lesion is eliminated, hemorrhage rates and cognitive adverse effects may be less frequent than with thalamotomy.

Because of the promising results achieved in the thalamus, DBS has been applied to other key targets for the treatment of PD.

• Pallidal DBS

Siegfrid and Lippitz introduced bilateral pallidal (ie, GPi) stimulation in 1994, reporting improvements in rigidity, akinesia, and LID in 4 patients.

Stimulator programming in the pallidum is more challenging than in the thalamus. Higher stimulation voltages may exacerbate freezing, nullifying the therapeutic effects of L-DOPA. Moreover, stimulation in different regions of the pallidum may have strikingly different effects. Dorsal GPi stimulation has been reported to improve akinesia and rigidity but may result in abnormal involuntary movements (ie, dyskinesias). In contrast, ventral GPi stimulation can exacerbate akinesia and gait abnormalities but improves rigidity and LID.

• Subthalamic DBS

While select patients with PD derive significant benefit from neuroablation or stimulation at VIM and/or GPi, in most instances akinesia (ie, freezing) and gait abnormalities are not improved significantly. Unfortunately, these symptoms are commonly the most disabling features of advancing PD. Consequently, a great deal of attention has been paid to a new procedure—bilateral electrostimulation of the subthalamic nucleus.

Rationale: Hyperactivity of the excitatory pathway from STN to GPi is considered a key pathophysiological hallmark of PD, a fact that is supported by the observation that lesioning the STN in primates with MPTP reverses their parkinsonism.

Indications: Preliminary results of surgery suggest that bilateral STN stimulation is indicated in patients with advancing idiopathic PD who are still responsive to levodopa but who suffer from fluctuations in medication response, tremor, rigidity, and/or akinesia in the off state (ie, when medications are not working) and LID in the on state.

Results: To date, the most extensive analysis of STN stimulation was published by Limousin et al in 1998. They reported on their first 24 patients to undergo STN-DBS, 20 of whom had been monitored for 1 year or more. They reported that bilateral STN stimulation relieved rigidity and tremor. Off-state scores on the Unified Parkinson Disease Rating Scale (UPDRS; a widely accepted rating scale of PD signs) improved by more than 60% on average, while on-state scores improved by 10%. Tremor and gait subscores also were improved. Patients suffered less pronounced motor fluctuations and experienced an average medication dose reduction of 50%. As a result of the reduction of medication dose, the amount and severity of LID also was reduced.

Complications: Adverse events reported in the Limousin study included transient confusion, hallucinations, temporospatial disorientation, and abulia. These symptoms tended to resolve within 2 weeks. One patient who exhibited symptoms of early dementia preoperatively suffered a more significant and permanent cognitive decline, reinforcing the importance of preoperative neuropsychological testing. Eyelid apraxia, hypophonia, and worsened postural instability also have been reported. Hemiballismus can occur with higher stimulation voltages, but it is controlled successfully by reducing the voltage and/or decreasing the dose of L-DOPA. Intracerebral hemorrhage, the most significant operative risk, can result in permanent neurologic sequelae, including aphasia, hemiparesis, coma, and death.

• Is subthalamic nucleus stimulation neuroprotective?

STN stimulation has been hypothesized to be neuroprotective, slowing down the progression of PD. The STN provides excitatory (glutamatergic) output to the GPi, the substantia nigra pars reticulata (SNr), the pedunculopontine nucleus, and the dopaminergic neurons in the SNc. Therefore, STN hyperactivity caused by loss of dopaminergic input to the striatum (see Pathophysiology) may, in turn, produce excitotoxic damage to the dopaminergic neurons to which they project, resulting in further neuronal loss in the SNc. Thus, pharmacologic or surgical therapies that reduce STN neuronal hyperactivity may be neuroprotective to the dopaminergic neurons of the SNc, possibly slowing or halting the progression of PD. Further studies are required to evaluate this hypothesis.

References

1. Alterman RL, Sterio D, Beric A: Microelectrode recording during posteroventral pallidotomy: impact on target selection and complications. Neurosurgery 1999 Feb; 44(2): 315-21; discussion 321-3.

2. Bejjani B, Damier P, Arnulf I: Pallidal stimulation for Parkinson’s disease. Two targets? Neurology 1997 Dec; 49(6): 1564-9.
3. Freed CR, Greene PE, Breeze RE: Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med 2001 Mar 8; 344(10): 710-9.
4. Laitinen LV, Bergenheim AT, Hariz MI: Leksell’s posteroventral pallidotomy in the treatment of Parkinson’s disease. J Neurosurg 1992 Jan; 76(1): 53-61.
5. Lang AE, Lozano AM: Parkinson’s disease. Second of two parts. N Engl J Med 1998 Oct 15; 339(16): 1130-43.
6. Limousin P, Krack P, Pollak P: Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 1998 Oct 15; 339(16): 1105-11.
7. Obeso JA, Linazasoro G, Gorospe A, et al.: Complications associated with chronic levodopa therapy in Parkinson’s disease. Complications associated with chronic levodopa therapy in Parkinson’s disease. In: CW Olanow and JA Obeso, eds. Beyond the decade of the brain 1997; 2: 11-31.
8. Rodriguez MC, Obeso JA, Olanow CW: Subthalamic nucleus-mediated excitotoxicity in Parkinson’s disease: a target for neuroprotection. Ann Neurol 1998 Sep; 44(3 Suppl 1): S175-88.
9. Siegfrid J, Lippitz B: Bilateral chronic electrostimulation of ventroposterolateral pallidum: a new therapeutic approach for alleviating all parkinsonian symptoms. Neurosurgery 1994; 35: 1126-1129.
10. Svennilson E, Torvik A, Lowe R, et al.: Treatment of parkinsonism by stereotactic thermolesions in the pallidal region. Acta Psychiatr Neurol Scand 1960; 35: 358.
11. Tasker RR: Thalamotomy. Neurosurg Clin N Am 1990; 1: 841-64.

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

September 18, 2008 — Stereotactic surgery has made a resurgence in the treatment of PD. This is mainly because many patients with advanced PD experience significant disability or adverse effects despite optimal medical management.

Our understanding of basal ganglia physiology and circuitry are improving dramatically. Both the globus pallidus (GP) and the subthalamic nucleus (STN) are hyperactive in PD. Advances in surgical techniques, neuroimaging, and electrophysiologic recordings allow stereotaxic maneuvers to be done more accurately and with lower morbidity than ever before.

• Thalamotomy and chronic thalamic stimulation are effective in reducing medically refractory tremor.

  • The mechanisms of action of thalamotomy are not known; its effects may be due to destruction of autonomous neural activity (synchronous bursts) at the same frequency as limb tremor.

  • Basal ganglia stereotactic surgery initially targeted the GP and the ansa lenticularis until Hassler and Reichert selected the ventral nucleus of the thalamus as the favored site for tremor reduction.

  • More than 90% of patients with PD who undergo this procedure have improvement in tremor and rigidity of the limbs contralateral to the side of the lesion.

  • Assessments in early studies were often qualitative rather than quantitative, but experience indicated that unilateral thalamotomies were effective for the treatment for parkinsonian tremor.

  • Long-term follow-up studies have been uncontrolled and unblinded, but thalamotomy appears to have a lasting beneficial effect.

  • Kelly and Gillingham reported that 57% of patients with PD were free of tremor 10 years after the operation. Kelly et al reported improvement of tremor in 86% of 36 patients with a mean follow-up of 33 months in whom modern surgical techniques including microelectrode recording were used. Jankovic reported no recurrence of tremor in 36 patients followed for a mean of 60 months. Other parkinsonian symptoms such as bradykinesia and tremor ipsilateral to the surgery progressed over time.

  • The mortality rate for thalamotomy in PD is estimated to be less than 0.3%. Death usually is the result of basal ganglia hemorrhage or indirect postoperative complications such as pulmonary embolism or infection. Persistent morbidity is uncommon, consisting mainly of dysarthria, dysphagia, or mild paresis.

  • Complications from bilateral thalamotomy are common; more than 25% of patients experience speech impairment. Mental changes also can persist after bilateral surgery. Therefore, bilateral thalamotomies generally are avoided.

• Thalamic deep brain stimulation (DBS): High-frequency stimulation (>100 Hz) during thalamotomy of the target site, usually the VIM nucleus of the thalamus, had the same effect as destruction.

  • Benabid et al implanted electrodes in the ventral intermediate (VIM) nucleus to evaluate the effect of chronic stimulation, with promising results.

  • In 1997, the FDA approved the Activa Tremor Control therapy, which uses a DBS lead, an extension that connects the DBS lead to an implantable pulse generator (IPG), and the Itrel II IPG. The intracranial end of the DBS lead has 4 platinum-iridium contacts, which are 1.5 mm in length and separated by 1.5 mm. The DBS lead is connected to the IPG device by means of an extension that is tunneled under the skin. The IPG is implanted subcutaneously in the infraclavicular area.

  • Any of the stimulating contacts can be used for monopolar stimulation or any 2 or more can be used in combination for bipolar stimulation. Stimulation usually is initiated on postoperative day 1 and is adjusted by using an external programming device.

  • Adjustable parameters include pulse width, amplitude, stimulation frequency, and choice of active contacts. The patient can turn the stimulator on or off using a handheld magnet. The usual stimulation parameters are frequency of 135-185 Hz, pulse width of 60-120 microseconds, and amplitude of 1-3 V.

  • Thalamic stimulation has marked efficacy similar to that of thalamotomy in reducing contralateral tremor. Approximately 90% of patients have tremor reduction. Some patients show a microthalamotomy effect, or reduction of tremor after implantation of the electrode, even when the stimulator is not on. This is presumably due to a small lesion created by placement of the electrode.

  • The morbidity and mortality rates of thalamic stimulation are low.

  • Complications of surgery include intracerebral hemorrhage, seizures, and confusion. Complications related to the device include wire erosion, IPG infection, malfunction of the IPG, electrical shocking, and lead migration.

  • Adverse effects related to stimulation are reversible with reduction in stimulation and usually are well tolerated. Other adverse effects due to stimulation that may occur include dysarthria, disequilibrium, paresis, and gait disorder.

  • The advantages of DBS include reversibility, ability to change stimulus parameters to increase efficacy or reduce adverse effects, and ability to perform bilateral operations with reduced risk of permanent dysarthria.

  • Disadvantages include the cost of the system, presence of an implanted foreign body, future need to replace the battery, and possibility of mechanical problems.

  • The mechanism of action of DBS is unknown. Persistent depolarization, stimulation of inhibitory systems, and neuronal jamming have been proposed as possible mechanisms of action.

• Thalamotomy vs thalamic stimulation: A randomized trial comparing thalamotomy and thalamic stimulation currently is being conducted in Denmark. Studies to date suggest that the 2 procedures have equal efficacy, but DBS may be associated with fewer adverse effects.

• Pallidotomy: This procedure is effective in reducing contralateral dyskinesia.

  • Although pallidotomy was used in the 1950s, the results were inconsistent; this has been attributed to inappropriate target selection. Thalamotomy was the preferred procedure because it more reliably reduced tremor.

  • With the introduction of stereotactic frames, target localization improved, but the results of pallidotomy remained inconsistent. After the discovery of levodopa in the 1960s, the use of pallidotomy for PD waned. However, Laitinen et al reexamined posteroventral pallidotomy in 38 patients with PD and reported significant improvement in bradykinesia, rigidity, tremor, ambulation, speech, and drug-induced dyskinesias.

  • Other studies using standardized clinical rating scales also have reported significant improvement in parkinsonian symptoms after unilateral pallidotomy in PD. Baron reported results of GPi pallidotomy in 15 patients with advanced PD. The mean total Unified Parkinson Disease Rating Scale (UPDRS) score improved by 30%, mean activities of daily living (ADL) off score improved by 34%, and the motor examination off score improved by 25%. The motor on score improved by 13% at 3 months and 6 months, but worsened at 1-year follow-up. Improvement in contralateral drug-induced dyskinesias and tremor was dramatic. The results of neuropsychological assessments revealed no significant changes. Two of the patients in this study developed dementia and did not improve, suggesting that patients with moderate to severe dementia may have a poor surgical outcome. Persistent complications included superior quadrantanopia in 1 patient.

  • Lang performed a 2-year prospective study of 40 patients with PD who underwent GPi pallidotomy. At 6 months follow-up, overall improvement in off period motor scores was 28%, improvement in off period ADLs was 29%, improvement in contralateral dyskinesia scores was 82%, and improvement in ipsilateral dyskinesias was 44%. Persistent complications included contralateral facial weakness (2), dysarthria (3), dysphagia (2), impaired concentration (3), changes in personality or behavior (2), worsening of handwriting (4), worsening of balance (2), word finding difficulty (1), and worsening of dementia (1).

  • Bilateral pallidotomy rarely is recommended. Although bilateral pallidotomy causes a striking reduction in levodopa-induced dyskinesias, complications are relatively common and include speech difficulties, dysphagia, and cognitive impairment. Indications for a staged second side pallidotomy are limited and may include an excellent response to the first operation without any persistent complications, unchanged neuropsychological testing, and persistent disabling dyskinesias on the contralateral side.

  • Most centers performing pallidotomy use anatomical imaging (stereotactic CT scan or MRI) and electrical stimulation. Some also use microelectrode recordings. Although good results have been reported in some patients who underwent targeting only with imaging and macrostimulation, the authors strongly recommend the use of microelectrode recording for this procedure.

• Pallidal stimulation

  • Based on the success of thalamic DBS for tremor, Siegfried and Lippitz assessed DBS of the ventroposterolateral pallidum. They implanted bilateral GPi electrodes in 3 patients with PD. The investigators reported improvement in the Webster Rating Scale scores and on-off motor fluctuations.

  • Pahwa et al reported their experience with 5 patients who underwent pallidal stimulation. ADL subscores of the UPDRS improved by 19% in the off state and by 42% in the on state. Patient diaries demonstrated an increase in on time with a decrease in off time and on time with dyskinesias. One patient had an asymptomatic intracranial bleed. Another patient had facial dystonia and paresthesias that required surgical repositioning of the lead.

  • Kumar et al studied 8 patients with PD who underwent GPi stimulation (4 unilateral and 4 bilateral). At 3-month follow-up, UPDRS total motor score while off medication with the stimulator on was 27% better than at baseline. In the off state, the ADL subscores improved by 26%, and the on ADL subscores improved by 40%. Levodopa-induced dyskinesias were improved by 60%.

• Pallidotomy vs pallidal stimulation

  • Kumar et al compared the effects of pallidotomy and GPi stimulation. They reported similar objective improvements with the 2 procedures. However, the risk of complications was higher in the pallidotomy group.

  • A prospective randomized study of unilateral surgery compared these 2 procedures in 13 patients with PD. The procedures provided a comparable effect on UPDRS and ADLs, and the complications were similar in the 2 groups. These results are preliminary, and further investigations are required.

• Subthalamotomy

  • In PD, the STN is hyperactive, suggesting that modulation of its activity may have therapeutic benefit.

  • Surgery aimed at the STN only recently has been investigated. The procedure was performed in unilateral STN lesions (3 left and 2 right) in 5 patients whose PD was characterized by severe gait freezing and axial akinesia.

  • Cardinal PD symptoms were improved at 3 months after surgery. One patient had a large subthalamic infarct.

  • Due to the risk of surgical complications, subthalamic stimulation currently is preferred over subthalamotomy.

• Subthalamic stimulation

  • Experience with subthalamic stimulation is preliminary, but this approach appears to have considerable potential.

  • Early studies indicate that off motor scores are improved approximately 60% and ADL scores 30-58%.

  • Bradykinesia, tremor, and rigidity are improved significantly.

  • Dyskinesias are decreased because of the marked reduction of levodopa dosage (40-50%) following surgery.

  • Complications include intracerebral hemorrhages and transient mental status changes.

• Subthalamic vs pallidal stimulation

  • Krack et al compared GPi and STN stimulation in 8 patients who had onset of PD while relatively young.

  • In the off state, the mean motor score improved by 71% with STN stimulation and by 39% with GPi stimulation. In the on state, dyskinesias were decreased markedly in the GPi group and decreased somewhat in the STN group. However, due to a marked reduction in the maintenance levodopa dose in the STN group, the severity of everyday dyskinesias was similar to that of the GPi group.

  • This preliminary study favored the STN target over GPi in young-onset PD patients.

• Transplantation

  • Neural transplantation is a potential treatment for PD because the neuronal degeneration is site and type specific (ie, dopaminergic), the target area is well defined (ie, striatum), postsynaptic receptors are relatively intact, and the neurons provide tonic stimulation of the receptors and appear to serve a modulatory function.

  • Multiple sources of dopamine-producing cells, including fetal nigral cells, sympathetic ganglia, carotid body glomus cells, PC-12 cells, and neuroblastoma cells, have been studied.

  • Although the transplantation of autologous adrenal medullary cells into the human putamen in patients with PD initially was reported to provide significant clinical benefit, other investigators using similar techniques failed to replicate these dramatic effects. General consensus is now that the benefits of adrenal tissue implant do not justify the risks. The procedure has been abandoned.

  • In animal PD models, fetal nigral dopaminergic cells have been shown to survive transplantation into the striatum, form synaptic connections, develop extensive striatal reinnervation, exhibit relatively normal electrical firing patterns, and improve motor function. The results of fetal tissue implantation in patients with PD have been inconsistent. This may be due to differences in transplant variables and evaluations performed.

  • Recently, Hauser et al reported 2-year follow-up for 6 patients with PD who underwent bilateral fetal nigral transplantation. Immunosuppression was provided for 6 months. Complications related to surgery were mild and transient. Mean total UPDRS scores improved by 32%, and mean percentage of on time without dyskinesias improved from 22-60%. Mean putaminal fluorodopa on PET scan improved significantly in comparison to baseline. Robust survival of transplanted cells was demonstrated in 2 patients who died at 18 months of causes unrelated to the transplant procedure. Prospective, blinded, randomized studies are being performed to evaluate the long-term safety and efficacy of fetal nigral transplantation in patients with PD.

  • Transplantation of fetal porcine cells in patients with advanced PD is now under study.

  • In the laboratory, genetic engineering of cells and the use of stem cells are being investigated.

References

1. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 9.4a October 2008 [Click to have a look at the home page]

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

December 17, 2008 — The goal of medical management of PD is to provide control of signs and symptoms for as long as possible while minimizing adverse effects. Medications usually provide good symptomatic control for 4-6 years. After this, disability progresses despite best medical management, and many patients develop long-term motor complications including fluctuations and dyskinesia. Additional causes of disability in late disease include postural instability (balance difficulty) and dementia.

Figure 1. Drugs in Parkinson’s disease: a nigrostriatal neurone and striatal dopamine receptors. Levodopa crosses the blood-brain barrier, enters a neurone and is converted to dopamine. (Click to magnify figure)

1. Carbidopa and benserazide reduce peripheral conversion of levodopa to dopamine by AAAD, thus reducing side-effects of excess circulating dopamine.

2. Dietary amino acids from a high-protein meal may inhibit active transport into brain by competing with levodopa.
3. Levodopa is converted (AAAD) to dopamine in nigrostriatal neurones.
4. At the nerve terminal, amantadine enhances dopamine release.
5. Dopamine agonist drugs react with dopamine receptors.
6. Selegeline, the MAO-B inhibitor, blocks dopamine breakdown.
7. Entacapone, a COMT inhibitor, prolongs dopamine activity by blocking breakdown. 

AAAD, aromatic amino acid decarboxylase; COMT, catechol-O-methyl transferase.

• Putative neuroprotective therapy: Neuroprotective therapies are defined as those that slow the underlying loss of dopamine neurons.

  • If a neuroprotective therapy were available for PD, it would be administered from the time of diagnosis onward.

  • Selegiline is the medication that has garnered the most interest as a possible neuroprotective agent.

  • Laboratory investigations continue to provide evidence that selegiline affords a neuroprotective effect for dopamine neurons independent of MAO-B inhibition.

  • Selegiline has been demonstrated to protect cultured dopamine neurons from MPP+ toxicity, an effect that cannot be attributed to MAO-B inhibition. Tatton and Greenwood demonstrated that selegiline protects dopamine cells in mice from MPTP toxicity even when administered after a delay sufficient to allow the oxidation of MPTP to MPP+.

  • In cell-culture systems, selegiline’s neuroprotective effect is mediated by new protein synthesis. Selegiline induces transcriptional events that result in increased synthesis of antioxidant and anti-apoptotic proteins. Recent evidence indicates that one of selegiline’s metabolites, desmethylselegiline, is the active agent for neuroprotection.

  • In the clinical study called deprenyl (selegiline) and tocopherol (vitamin E) antioxidative therapy of parkinsonism (DATATOP), the Parkinson Study Group evaluated the ability of these 2 medications to delay progression of clinical disability in early PD. Eight hundred patients were randomized to receive selegiline (10 mg/d) or placebo and tocopherol (2000 IU/d) or placebo. Patients assigned to receive selegiline, with placebo or with tocopherol, experienced a significant delay in the need for levodopa therapy (hazard ratio = 0.50, P <0.001). Patients assigned to receive placebo required levodopa at a projected median of 15 months from enrollment, while those who received selegiline required levodopa at a projected median of 24 months after enrollment. Tocopherol had no effect on progression of disability.

  • The study conclusively demonstrated that selegiline delays the need for levodopa therapy in early PD; this result is consistent with the hypothesis that selegiline may slow disease progression. However, the study also found that selegiline provided a small symptom-relieving effect, and whether the delay in the need for levodopa was due entirely or in part to this modest effect is not clear.

  • In one study, selegiline was associated with increased mortality rate in patients with PD. The Parkinson’s Disease Research Group of the United Kingdom reported a 57% higher mortality rate in patients assigned to receive selegiline plus levodopa than in those who received levodopa alone (mortality ratio = 1.57, 95% confidence interval 1.09-2.30, P = 0.015). The difference in mortality rate emerged between the third and fifth years of treatment, and no obvious explanation regarding its cause was identified.

  • Many questions have been raised regarding the results and methodology of this study. Mortality rates were not significantly different between groups when the analysis was based on what patients actually were taking and not on intention to treat. In addition, the mortality rate was unusually high in both groups (28% in patients receiving selegiline, 18% in those not receiving selegiline).

  • Currently, when selegiline is employed as monotherapy in early PD, it is with the hope that the rate of dopamine neuronal degeneration may be slowed or that a delay in the introduction of levodopa may be associated with long-term clinical benefit.

• Symptomatic therapy

  • Levodopa, coupled with a peripheral decarboxylase inhibitor (PDI), remains the criterion standard of symptomatic treatment for PD. It provides the greatest antiparkinsonian benefit with the fewest adverse effects.

  • Dopamine agonists provide symptomatic benefit comparable to levodopa/PDI in early disease but lack sufficient efficacy to control signs and symptoms by themselves in later disease.

  • Concerns exist that levodopa/PDI might accelerate disease progression or contribute to the development of motor fluctuations and dyskinesia.

  • Interest exists regarding whether dopamine agonists should be used as initial symptomatic therapy in early disease, rather than levodopa/PDI, to reduce long-term disability and delay the onset of motor fluctuations and dyskinesia.

• Is levodopa toxic?

  • Levodopa administration increases dopamine turnover and may increase free radical production. Many studies have demonstrated that high concentrations of levodopa increase oxidative stress and are toxic to isolated dopamine neurons in culture. This toxicity is reduced in the presence of glial cells.

  • In animal models, levodopa has been demonstrated to induce neuronal loss in rodents with severe nigral lesions but not in healthy animals or those with moderate lesions. One study found that levodopa provided protective effects for dopamine neurons in rats with moderate nigral lesions.

  • As with other toxins, low-level exposure to a system that can withstand the insult may result in upregulation of protective mechanisms. Exposure of susceptible or overwhelmed systems to relatively high concentrations of the toxin may lead to cell death.

  • Whether levodopa has a toxic or protective effect in the brain with PD is unknown. Assessment of levodopa’s effect on the underlying rate of clinical progression and on the rate of neuronal loss is needed using markers, such as those used in PET and SPECT scanning.

• Levodopa and long-term sequelae

  • As PD progresses, fewer dopamine neurons are available to store and release levodopa-derived dopamine. The patient’s clinical status begins to fluctuate more and more closely in concert with plasma levodopa levels. Exposing striatal dopamine receptors to fluctuating dopamine concentrations may cause a hypersensitivity that is expressed clinically as peak-dose dyskinesia. Fluctuating levodopa-derived dopamine concentrations in association with advancing disease therefore may be responsible for development of motor fluctuations and dyskinesia.

  • In contrast to levodopa, the long-acting dopamine agonists (ie, bromocriptine, pergolide, pramipexole, ropinirole, cabergoline) provide relatively smooth and sustained receptor stimulation. In marmosets with MPTP lesions, levodopa administration causes significantly more dyskinesia than bromocriptine or ropinirole.

  • Montastruc et al randomized 60 previously untreated patients to receive initial therapy with bromocriptine followed by levodopa/PDI when required or with levodopa/PDI alone. After 5 years, motor complications were significantly fewer and appeared significantly later in the patients who received bromocriptine and levodopa/PDI than in those who received levodopa/PDI alone.

• Early disease treatment strategies

  • The younger the patient, the more emphasis the authors place on long-term considerations to guide early treatment. Young patients have a longer life expectancy and are more likely to develop motor fluctuations and dyskinesia. Because definitive information is not yet available regarding the effect of early treatment strategies on long-term outcome, the authors currently rely on theoretical considerations and results of laboratory animal and open-label studies in human patients.

  • For older patients, less emphasis is placed on long-term considerations; the focus is on providing adequate symptomatic benefit in the near term with as few adverse effects as possible.

  • At the time of diagnosis, a discussion is initiated to review current information regarding selegiline and evidence of its possible neuroprotective effects.

  • The younger the patient, the more critical the need for neuroprotection, and the more likely the authors are to initiate selegiline.

  • Symptomatic therapy is introduced when the patient experiences functional disability. The selection of medication depends in part on the nature and cause of the disability.

  • If disability is due solely to tremor, a tremor-specific medication, such as an anticholinergic agent, can be used. Anticholinergic medications provide good tremor relief in approximately 50% of patients but do not improve bradykinesia or rigidity. Because tremor may respond to one anticholinergic medication and not another, a second anticholinergic usually is tried if the first is not successful. These medications should be introduced at a low dose and escalated slowly to minimize adverse effects, which include memory difficulty, confusion, and hallucinations. Adverse cognitive effects are relatively common, especially in the elderly.

  • If disability is due to a dopamine-responsive symptom such as bradykinesia, rigidity, decreased dexterity, slow speech, or shuffling gait, a dopaminergic medication (dopamine agonist or levodopa/PDI) should be introduced. Symptomatic medications are started at a low dose, escalated slowly, and titrated to control symptoms. Most patients require symptomatic dopaminergic therapy to ameliorate bradykinesia and rigidity within 1-2 years after diagnosis.

  • For patients younger than 65 years, the authors initiate symptomatic therapy with a dopamine agonist and then add levodopa/PDI when the dopamine agonist alone no longer controls symptoms adequately. Dopamine agonists provide antiparkinsonian efficacy comparable to levodopa/PDI for 6-18 months or longer and may control symptoms adequately for several years.

  • When the dopamine agonist no longer provides adequate symptomatic control despite titration to the usual maximum or highest tolerated dose, add levodopa/PDI. The relatively sustained dopamine receptor stimulation provided by the dopamine agonist may buffer receptors from fluctuating levodopa-derived dopamine concentrations and afford a lower incidence of motor fluctuations and dyskinesia.

  • For patients who are demented or those older than 70 years, who may be prone to adverse effects from dopamine agonists, and for those likely to require treatment for only a few years, the authors may elect not to use a dopamine agonist and depend on levodopa/PDI as primary symptomatic therapy.

  • For patients aged 65-70 years, the authors make a judgment based on general health and cognitive status. The more robust and cognitively intact the patient, the more likely the authors are to start symptomatic treatment with a dopamine agonist and add levodopa/PDI when necessary.

  • When introducing a dopamine agonist, starting at a low dose and escalating slowly is important. The dose should be titrated upward until symptoms are controlled, the maximum dose is reached, or adverse effects become intolerable. The most common adverse effects of dopamine agonists are nausea, orthostatic hypotension, hallucinations, and somnolence. Nausea usually can be reduced by having the patient take the medication after meals. Domperidone, a peripheral dopamine agonist available outside the US, is very helpful in relieving refractory nausea.

  • Levodopa/PDI is introduced at a low dose and escalated slowly. It usually is introduced using the controlled release (CR) formulation, which may allow fewer daily intakes than immediate release levodopa/PDI, thereby affording greater convenience. A prospective, blinded study demonstrated that levodopa/carbidopa CR provided significantly greater long-term improvement in activities of daily living (ADLs) than immediate release levodopa/carbidopa.

  • The levodopa dose is titrated to control clinical symptoms; most patients experience a good response on a daily dose of 400-600 mg/d for 3-5 years or more. Doses higher than those necessary to control symptoms adequately should be avoided.

  • If nausea occurs, the dose may be taken following a meal. Additional measures to alleviate nausea include adding extra carbidopa or introducing domperidone.

• Advanced disease treatment strategies

  • Patients initially experience stable, sustained benefit through the day in response to dopaminergic medications. However, after 4-6 years, many patients notice that the benefit from immediate release levodopa/carbidopa wears off after 4-5 hours. Over time, this shortened duration of response becomes more fleeting, and clinical status fluctuates more and more closely in concert with peripheral levodopa concentration. Ultimately, benefit lasts only 1-2 hours. The time when medication is providing benefit for bradykinesia, rigidity, and tremor is called on time, and the time when medication is not providing benefit is called off time.

  • By 5-6 years after diagnosis, many patients develop peak-dose dyskinesia consisting of choreiform, twisting/turning movements that occur when levodopa-derived dopamine levels are peaking. At this point, increasing dopamine stimulation is likely to worsen peak-dose dyskinesias. Over time, the therapeutic window narrows because of a progressive decrease in the threshold for peak-dose dyskinesia. The therapeutic window lies above the threshold required to improve symptoms (on threshold) and below the threshold for peak-dose dyskinesia (dyskinesia threshold).

  • Although many patients prefer dyskinesia to off time, the clinician should recognize that dyskinesia can be sufficiently severe to be troublesome to the patient, either by interfering with activities or because of discomfort. Asking patients how they feel during both off time and time with dyskinesia is important in titrating medication optimally. Having patients fill out a diary may be helpful; the diary should be divided into half-hour time periods on which patients denote whether they are off, on without dyskinesia, on with nontroublesome dyskinesia, or on with troublesome dyskinesia. The goal of medical management is to minimize off time and time on with troublesome dyskinesia.

  • Treating motor fluctuations in the absence of peak-dose dyskinesia is relatively easy. Several different strategies, either alone or in combination, can be used to provide more sustained dopaminergic therapy. Possible strategies include adding a dopamine agonist, cathechol-O-methyltransferase (COMT) inhibitor, or selegiline; dosing levodopa more frequently; increasing the levodopa dose; or switching from immediate release to CR levodopa preparation. Unless limited by the emergence of peak-dose symptoms such as dyskinesia or hallucinations, dopaminergic therapy should be increased until off time is eliminated.

  • The treatment of patients with both motor fluctuations and troublesome peak-dose dyskinesia can be difficult. The goal of treatment in this situation is to provide as much good functional time through the day as possible. This is accomplished by maximizing on time with no or nontroublesome dyskinesia. An attempt is made to reduce both off time and time with troublesome or disabling dyskinesia. Unfortunately, a decrease in dopaminergic therapy may increase off time and an increase in dopaminergic therapy may worsen peak-dose dyskinesia.

  • For patients with severe fluctuations and dyskinesia, the best balance between off time and troublesome dyskinesia is sought. The patient’s relative preference for off time versus dyskinesia needs to be taken into account.

  • For patients with motor fluctuations and dyskinesia on levodopa/PDI, the addition of a dopamine agonist, COMT inhibitor, or selegiline may be helpful. Dyskinesia may increase when these medications are added, necessitating the downward titration of levodopa.

  • For patients on CR levodopa, switching to immediate release levodopa/carbidopa often provides a more consistent and predictable dosing cycle and allows finer titration. In general, smaller levodopa doses are administered more frequently. A dose should be sought that is sufficient to provide benefit without causing troublesome dyskinesia. The time to wearing-off then determines the appropriate interdose interval. The extreme of this strategy is using liquid levodopa, a solution with which the dose can be titrated finely and administered every hour. Propranolol or amantadine may be of some benefit to reduce dyskinesia.

  • Tolcapone is the first COMT inhibitor available for clinical use. It inhibits the peripheral metabolism of levodopa to 3-O-methyldopa (3-OMD), thereby prolonging levodopa half-life and making more levodopa available for transport across the blood-brain barrier over a longer time. In the US, tolcapone is indicated for use in patients with PD who are on levodopa/carbidopa and are experiencing motor fluctuations that are not controlled readily with further manipulations of levodopa or the addition of other adjunctive therapies.

  • If dyskinesia emerges, the levodopa dose should be reduced. In patients who already have dyskinesia, the levodopa dose often is reduced by 30-50% at the time tolcapone is introduced.

  • Because of the potential risk of hepatotoxicity, tolcapone should not be initiated in any patient who exhibits clinical evidence of liver disease or if alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values have been greater than the upper limit of normal on 2 separate occasions in the past.

  • Entacapone is a newer COMT inhibitor that does not cause hepatotoxicity; liver function tests are not required with this medication.

  • Levodopa/PDI, dopamine agonists, and anticholinergics each provide good benefit for tremor in approximately 50% of patients. If a patient is experiencing troublesome tremor and symptoms are not controlled adequately with one medication, another should be tried. Clozapine (in very low doses) may be of benefit in otherwise refractory tremor. If the tremor is not controlled adequately with medication, thalamotomy or thalamic stimulation surgery may be considered at any time during the disease.

Figure 2. The site of action of common drugs for parkinson disease (Click to magnify figure)

References

1. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 9.4a October 2008 [Click to have a look at the home page]

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

September 17, 2008 — Individuals who had higher vitamin B12 levels were 6 times less likely to experience brain-volume loss, a new study shows. The results are published in the September 9 issue of Neurology.

Researchers say the findings should encourage further investigation of low vitamin B12 status as a modifiable cause of brain atrophy and subsequent cognitive impairment in the elderly.

“Clinicians should rethink what they consider normal vitamin B12 levels,” said senior author A. David Smith, DPhil, from the University of Oxford. “They may want to reconsider the current cutoffs that we use, because they may be too low.”

Dr. Smith points out that according to the Institute of Medicine, in healthy individuals, no adverse effects have been associated with excess vitamin B12 intake from supplements or foods such as meat, fish, fortified cereals, milk, and others.

• Vitamin B12 Deficiency a Public Health Problem

In the August issue of the American Journal of Clinical Nutrition, experts debated whether the mandatory fortification of foods with vitamin B12 would be beneficial (Refsum H, Smith AD. Am J Clin Nutr. 2008;88:253-254). Dr. Smith weighed in on the issue and in an editorial concluded that much work remains to be done.

“We must remember that evidence of benefit and of lack of harm is always needed before introducing mandatory population-level exposures to nutrients,” he wrote.

Dr. Smith pointed to a number of concerns, including a lack of data, issues pertaining to potential malabsorption in the elderly, and observational studies suggesting a link between vitamin B12 and an increased risk for cancer.

During an interview, Dr. Smith pointed out that many unknowns remain about what adverse effects may be associated with excessive amounts of vitamin B12. But, he noted, “We know that an oral dose of 1 mg of vitamin B12 will likely result in just 1% of absorption.”

Vitamin B12 deficiency is a public health problem, especially among the elderly, who tend to have lower rates of absorption, so more vitamin B12 intake could help reverse this problem, Dr. Smith said.

• Prospective Study

Dr. Smith’s group, led by Anna Vogiatzoglou, from the University of Oxford, conducted a prospective study of 107 community-dwelling volunteers aged 61 to 87 years without cognitive impairment at enrollment. They examined the relationship between markers of vitamin B12 status and brain-volume loss per year over a 5-year period in this elderly population.

The researchers assessed participants yearly by clinical examination, magnetic resonance imaging scans, and cognitive tests. They collected blood at baseline to measure plasma vitamin B12, transcobalamin, holotranscobalamin, methylmalonic acid, total homocysteine, and serum folate.

They found the decrease in brain volume was greater among those with lower vitamin B12 and holotranscobalamin levels. The decrease in brain volume was also greater among those with higher plasma total homocysteine and methylmalonic acid levels at baseline.

Linear regression analysis showed that associations with vitamin B12 and holotranscobalamin remained significant after adjustment for age, sex, creatinine, education, initial brain volume, cognitive test scores, systolic blood pressure, apolipoprotein E e4 status, total homocysteine, and folate.

The researchers used the upper tertile (for the vitamins) and the lower tertile (for the metabolites) as references in logistic regression analysis and adjusted for covariates.

Vitamin B12 in the bottom tertile (<308 pmol/L) was associated with increased rate of brain-volume loss. The association was similar for low levels of holotranscobalamin (<54 pmol/L).

Table 1. Risk for Brain Volume Loss Associated with Lowest vs Highest Levels of Vitamin B12 and Holotranscobalamin

Low transcobalamin saturation was also associated with brain-volume loss, but the researchers found no association with high levels of methylmalonic acid, high total homocysteine, or low levels of folate.

“The major finding of this study is that at baseline, vitamin B12 status across the normal range is associated with brain atrophy at follow-up,” write the researchers.

• Vitamin B12 Status Potential Early Marker of Brain Atrophy

Dr. Smith’s team points to a number of strengths of their study, including its prospective design with a relatively long follow-up period and its population-based setting.

The group also points to a number of limitations to the study, including the relatively small sample size and the fact that they did not investigate whether the loss in brain volume is focal or diffuse. Also, a total of 41 of the 148 participants did not have a second brain scan.

They conclude, “These findings suggest that plasma vitamin B12 status may be an early marker of brain atrophy and thus a potentially important modifiable risk factor for cognitive decline in the elderly.”

References

1. Neurology. 2008;71:826-832. Abstract

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

September 17 2008 — Results of a randomized trial show no evidence that extended-release dipyridamole, aspirin, or telmisartan  have neuroprotective effects on either disability due to a recurrent stroke or cognitive decline over time.

The results of this third factorial analysis of the Prevention Regimen for Effectively Avoiding Second Strokes (PROFESS) trial are published online August 29 in Lancet Neurology. Results of the other 2 main analyses, 1 comparing aspirin plus extended-release dipyridamole with clopidogrel for the prevention of recurrent stroke and another comparing telmisartan vs placebo in these same patients, were published online August 27 in the New England Journal of Medicine.

“PROFESS is the largest trial so far to investigate in a prespecified manner whether treatment with antiplatelet drugs or angiotensin II receptor agonists (such as telmisartan) are neuroprotective in patients who have had a recurrent stroke,” the researchers, with first author Hans-Christoph Diener, MD, from the University of Duisberg/Essen, in Essen, Germany, conclude. “The degree of functional impairment at 3 months poststroke was similar across treatment arms.”

The findings from all 3 analyses were previously presented at the 17th European Stroke Conference in Nice.

• Neuroprotective Effects?

The PROFESS trial included 20,332 patients from 695 sites in 35 countries. All had had a noncardioembolic ischemic stroke within the previous 120 days. They were randomized in a factorial design to receive aspirin (25 mg) plus extended-release dipyridamole (200 mg) twice daily or clopidogrel (75 mg) (Plavix/Iscover, Bristol-Myers Squibb/ Sanofi-Aventis) once daily. Subjects were then again randomized to receive either 80 mg per day of telmisartan or placebo.

In separate papers, the researcher have previously reported that the combination of aspirin and extended-release dipyridamole did not meet prespecified criteria for noninferiority vs clopidogrel, but rates of recurrent stroke, the primary outcome, were similar between the groups.

The trial also examined the effect of early blood-pressure lowering after a stroke using telmisartan vs placebo and found no benefit of the addition of the angiotensin-receptor blocker (ARB) in prevention of stroke recurrence, major cardiovascular events, or diabetes, at least during the 2.5 years of follow-up in this study.

This third factorial analysis investigated whether or not antiplatelet compounds such as aspirin and dipyridamole or an ARB such as telmisartan might have neuroprotective effects. Previous preclinical data had suggested neuroprotective properties for dipyridamole, aspirin (although only at very high doses), and ARBs in models of cerebral ischemia, the researchers note.

Previous neuroprotection trials have been notoriously negative, but part of the difficulty has been to have putative neuroprotectants on board at the time of stroke. With the PROFESS data, the investigators were able to look for possible neuroprotectant effects of these agents among those patients who went on to have a recurrent stroke during the study. They compared functional outcomes after recurrent strokes while on study treatment using the modified Rankin scale (mRS) and the Barthel Index 3 months after the stroke.

Recurrent strokes occurred in 9% of each treatment group, including those who received aspirin plus dipyridamole or clopidogrel and telmisartan or placebo. There was no significant difference in functional outcomes on either the mRS or the Barthel Index for the comparison of aspirin plus dipyridamole vs clopidogrel (which had not been shown previously to have any putative neuroprotective effect) or for the comparison of telmisartan vs placebo.

In addition, there was no significant difference in the median Mini-Mental State Examination (MMSE) scores, the percentage of patients with an MMSE score of 24 points or less, the percentage of patients with a drop in MMSE score of 3 points or more between 3 months and the penultimate visit, or the number of patients with dementia among the treatment groups. Further, there was no difference between groups in the proportion of patients with cognitive impairment or dementia.

“There are 2 possible explanations,” Dr. Diener told a press conference in Nice when these results were first presented. “The most likely explanation is there is no effect. The other possible explanation is that the observation at 2.5 years is not long enough. Perhaps you have to have treatment and observation times of 10 years or more to see a difference,” he speculated.

The researchers note that a planned cognitive substudy of PROFESS using more sophisticated neuropsychological assessments in a subgroup of patients will be reported later.

• Burning Clinical Questions

In a Reflection and Reaction commentary accompanying the paper, Graeme J. Hankey, MD, from Royal Perth Hospital, in Western Australia, and John W. Eikelboom, MD, from McMaster University, in Hamilton, Ontario, congratulate the researchers “for completing the largest trial of its kind in the world. The investigators addressed and answered burning clinical questions of the day, and the trial was scientifically rigorous enough to minimize bias and random error and thus ensure the internal validity of the results.”

They point out that the PROFESS investigators did not put their trust in indirect comparisons that had suggested superiority of the combination of aspirin and extended-release dipyridamole over clopidogrel but directly compared the 2, finding no evidence in the difference between these interventions in the prevention of major vascular events, including cardiac events in patients with subacute ischemic stroke.

For patients who have had a stroke and are already on 1 of these regimens, they write, “there is no need to change.” For patients just going on these medications or those who have had a recurrent stroke while on aspirin, Drs. Hankey and Eikelboom suggest the choice will be determined by several factors.

Clopidogrel would be the choice for those with atherothrombotic vascular disease in other vascular beds, as the combination has not been proven effective in patients with coronary artery disease, they note. Patients predisposed to bleeding or headache, for example, would likely get clopidogrel, since these were both more common with the combination. Clopidogrel costs more, although it only needs to be taken once daily, which may affect compliance, they point out. Patient preference will also play a role.

In terms of the findings of no benefit overall of telmisartan vs placebo in this study, they point out, as the researchers also did, that results of a post hoc analysis suggested some possible benefit for those treated longer than 6 months vs those treated over a shorter period. “Although the results for longer than 6 months are only hypothesis-generating, they are biologically consistent with other trials that show that the longer patients have lower blood pressure (or blood cholesterol), the lower their risk for major vascular events,” they write.

These results suggest that trials of interventions that aim to prevent the complications of high blood pressure, such as large artery stenosis, intracranial small-vessel disease, or atrial fibrillation, require follow-up longer than a few years to fully appreciate any potential effect, they conclude.

Finally, with regard to the neuroprotection hypothesis, the trial shows that aspirin and telmisartan are unlikely to have substantial neuroprotective effects, they write. But they also point out that the results may be false-negative, since the trial was not designed or powered primarily to test the neuroprotection hypothesis, and again, may have been too short to see such effects.

“The results of a substudy of PROFESS, which used more sophisticated neuropsychological instruments, will hopefully provide greater insights into this important issue,” they conclude.

• Question of Efficacy in African Americans Still Open?

Asked for comment on the PROFESS findings, Michael Sloan, MD, from the department of neurology at the University of South Florida, in Tampa, and a spokesperson for the American Heart Association/American Stroke Association said, “This is a very good study, the largest study of secondary stroke prevention and with a very novel strategy. The people who ran the study are outstanding.”

With regard to the findings comparing aspirin and extended-release dipyridamole vs clopidogrel, he pointed out that the population in this trial, where about a quarter of patients were Asian or South Asian, is very different from what is seen in the United States, where a much higher proportion are African American. “While the subgroup analysis showed no difference among ethnic groups, the fact that African Americans were underrepresented at only 3% in this trial means no conclusions can be drawn regarding the comparative efficacy of these agents in African Americans.”

His practice has been to use both strategies in different patients, he said. “The choice of therapy is based upon the patient’s overall characteristics, response to previous therapy, cost, patient preference, and side-effect profile,” he said. For example, a patient with peripheral artery disease, previous coronary artery stenting, transient ischemic attack or stroke symptoms, or those with migraine or other headaches would likely be given clopidogrel, he said. The patient without these features or who has failed aspirin therapy would be given the combination of aspirin and extended-release dipyridamole.

On the telmisartan comparison, Dr. Sloan pointed out that although there was a difference in overall blood pressure between the groups, those in the placebo group were treated with antihypertensive drugs from other classes. “I think in this study, although it’s not strictly comparable to PROGRESS or other studies, does suggest that if you have a lower blood pressure by whatever medication, you’re going to reduce your stroke risk.”

The PROFESS trial was funded by Boehringer Ingelheim. In selected countries, the telmisartan comparison was supported by Bayer Schering Pharma and GlaxoSmithKline. Dr. Diener reports that he has received honoraria and consulting and lecture fees from Abbott, AstraZeneca, Bayer Vital, Bristol-Myers Squibb, Boehringer Ingelheim, D-Pharm, Fresenius, GlaxoSmithKline, Janssen Cilag, Merck, Sharpe & Dohme, Novartis, Novo-Nordisk, Paion, Parke-Davis, Pfizer, Sanofi-Aventis, Sankyo, Servier, Solvay, Thrombogenics, Wyeth, and Yamaguchi and grant support from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Novartis, Janssen Cilag, and Sanofi-Aventis.

References

1. Lancet Neurol. 2008; Published online August 29, 2008. Abstract Abstract

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

September 16, 2008 — In a longitudinal study, low–birth-weight children had modestly increased levels of psychiatric problems such as aggression or anxiety throughout childhood.

However, those living in a disadvantaged inner-city community had a 3-fold higher risk for impulsivity and hyperactivity symptoms characteristic of attention-deficit/hyperactivity disorder (ADHD) compared with those living in a middle-class suburb.

“The differential effect of low birth weight on attention in urban children was unexpected, given that low–birth-weight effects for other outcomes such as cognitive abilities were uniform across the 2 communities,” said coauthor Naomi Breslau, PhD, from Michigan State University, in East Lansing.

“The results suggest a need for early identification of children with attention problems — even before the start of school — and a need to evaluate interventions to improve attention skills, since these contribute to children’s acquisition of academic skills and educational attainment — that is, whether they complete high school, enroll in college, and graduate,” she added.

The study, with lead author Kipling M. Bohnert, also from Michigan State University, is published in the September issue of the Archives of General Psychiatry.

• Improved Survival of Tiny Infants

Advances in neonatal medicine have increased the survival of low–birth-weight infants (2500 g or less), including very low–birth-weight infants (1500 g or less) and extremely low–birth-weight infants (1000 g or less), the authors write.

Previous studies have reported that these children have an increased risk for internalizing problems such as somatic complaints, anxiety, and depression; externalizing problems such as delinquent and aggressive behavior; and attention problems characteristic of ADHD.

The present study was based on data from low–birth-weight and normal-weight children born from 1983 through 1985 in 2 major hospitals in Detroit, Michigan. The children in the urban sample were primarily black and were more likely to have single mothers with less than a high school education.

When the children were age 6 years (n = 823) and age 11 years (n = 717), their behavior was evaluated by mothers using the Child Behavior Checklist and by teachers using the Teachers’ Report Form to determine the percentages of children with scores in the borderline or clinical assessment range.

The current study extended the previous studies to age 17 years and included 218 low–birth-weight urban children, 140 normal–birth-weight urban children, 181 low–birth-weight suburban children, and 159 normal–birth-weight suburban children.

• Attention Problems Are a “Major Concern”

Among these 17-year-olds, the adjusted odds ratios (ORs) for having externalizing and internalizing problems were slightly higher in the low–birth-weight teens than in the normal-weight teens living in the same community (adjusted OR, 1.53 and 1.28 for externalizing and internalizing problems, respectively).

Among the teens living in the disadvantaged urban community, those with a low birth weight had an approximately 3-fold greater risk of having attention problems (adjusted OR, 2.78; 95% CI, 1.77 – 4.37; P = .001). The increased risk was greatest among teens whose birth weight was 1500 g or less.

In contrast, the teens living in the middle-class suburbs had no significant increased risk for attention problems associated with low birth weight.

The increased risk of having attention problems corresponding to those of ADHD that was seen in the disadvantaged, urban, low–birth-weight children raises a “major concern,” since attention problems at the start of school predict lower academic achievement later on, the authors write.

These differences in low–birth-weight children living in advantaged vs disadvantaged communities “might reflect a beneficial influence of the enriched social environment afforded to children in suburban middle-class communities at home, at school, and in the neighborhood, [or] the urban disadvantaged environment might exacerbate the effect of prenatal adversity,” they suggest.

References

1. Arch Gen Psychiatry 2008;65:1080-1086. Abstract