• Are Patients Satisfied With Pallidotomy?
• Early Risk After Lobar Hemorrhage—A Clue From Molecular Genetics
• Cholinesterase Inhibitors as Psychotropic Agents
• Sports Concussion—Getting Back in the Game

From the patients' standpoint, unilateral and bilateral pallidotomy can reduce the key symptoms of Parkinson's disease (ie, akinesia, tremor, and rigidity), according to a study published in the February Neurosurgery. However speech deterioration and visual disturbances were reported, especially in patients who underwent simultaneous bilateral pallidotomy.

Researchers followed a group of patients who underwent either unilateral or bilateral pallidotomy to assess satisfaction with surgical outcomes. Among 56 consecutive patients, 44 (79%) completed the evaluation a median of seven months after surgery. The remaining 12 patients could not complete the forms independently or did not return for follow-up. Prior to surgery, all the patients had experienced unacceptable side effects from medication, such as levodopa-induced dyskinesias or severe on-off fluctuations, or had no benefit from treatment. Dyskinesias, dystonia, and rigidity were considered the best indications for the procedure, whereas freezing, gait disturbances, and akinesia were considered relative indications. Patients with dementia or "Parkinson's plus" syndromes were excluded.

The result of surgery was rated excellent or good by 14 of the patients (64%) who received unilateral procedures and 13 of the patients (76%) who received simultaneous bilateral procedures. Most of the patients (34) said they would have opted for the surgery again and would recommend the surgery to other patients (33). Not surprisingly, less than one third of the patients who rated the outcome as poor or fair would have the surgery again or recommend it to others.

According to visual analog scale, akinesia and walking scores improved, particularly after bilateral pallidotomy. Tremor usually improved after surgery, but to a limited extent. Thalamotomy or thalamic stimulation remains the preferred surgical option for relieving tremor, the authors noted. Rigidity improved immediately in 65% of the patients in the unilateral group and in 80% of patients in the bilateral group. Lessening rigidity may have had a role in pain reduction and better sleep.

Of the 13 patients who rated their outcomes as fair or poor, 11 reported a worsening of voice volume and nine a worsening of articulation. Worsened swallowing ability was also reported by about one third of patients; worsened drooling was reported by 80% of the bilateral group and 45% of the unilateral group. The authors recommended that surgical intervention should be targeted "lateral enough to avoid the internal capsule, with a small safety margin of 1 to 2 mm to accommodate postoperative edema."

Nearly 40% of patients reported subjective visual deterioration. Yet on objective testing, only one patient had a confirmed visual field defect. One third of the patients reported worse concentration. Decreased memory was reported by 46% of the unilateral and 12% of the bilateral group, and one third of patients reported increased depression.

Since the questionnaires and tests were subjective, it would have been interesting to correlate them to objective pre- and postoperative measures, wrote Roy A. E. Bakay, MD, in an accompanying commentary. The sample sizes were small, he added.

Patient assessments can be biased, echoed Andres M. Lozano, MD, PhD. "Understandably, patients want to get better, they expect to get better, they want to please the physician, and they can be afraid of reporting adverse effects." However, he wrote, also in an accompanying commentary, "it is usually enlightening to note the incongruence between the physician's and the patient's perspectives regarding the relative merits or shortcomings of surgical interventions."

Favre J, Burchiel KJ, Taha JM, Hammerstad J. Outcome of unilateral and bilateral pallidotomy for Parkinson's disease: patient assessment. Neurosurgery. 2000;46:344-355.

Apolipoprotein E (APOE) genotype can identify patients with lobar intracerebral hemorrhage who are at high risk for early recurrence, according to a report in the January 27 New England Journal of Medicine. Patients with either or both epsilon2 and epsilon4 alleles were found to have a higher risk of recurrence than patients with the epsilon3 allele, suggesting that genotyping can be clinically useful in assessing prognosis.

Researchers determined the APOE genotype of 71 elderly patients (mean age, 75 years) who presented with primary lobar hemorrhage. As expected, the frequency of the epsilon2 and epsilon4 alleles was higher in this cohort than in control elderly populations. About half of the patients carried one or both alleles. Study exclusion criteria were any hemorrhagic focus outside the lobar brain regions and the presence of another definite cause of hemorrhage such as trauma, excessive warfarin therapy, vasculitis, cerebral tumor, coagulopathy, or vascular malformation. In the patient group, 49 met criteria for probable cerebral amyloid angiopathy-related hemorrhage on the basis of pathologic demonstration of amyloid angiopathy or gradient-echo MRI evidence of hemorrhage lesions. Patients were followed for a mean of two years after initial hemorrhage.

Nineteen patients (21%) had recurrent symptomatic hemorrhages during follow-up, yielding an incidence of 14.3 per 100 person-years. Although all the recurrent hemorrhages were in a different site from the index hemorrhage, 18 remained in the lobar region. Eight patients did not survive to discharge; another four died within six months of recurrence. Cerebral amyloid angiopathy was found in all cases. Patients with no recurrence, conversely, had a relatively good clinical course, with survival rates of 88% at one year and 78% at three years.

The presence of the epsilon2 or epsilon4 allele was a predictor of recurrence (risk ratio, 3.8). Among the 18 patients who had a recurrent hemorrhage, 14 were carriers of either or both epsilon2 and epsilon4. Only four patients with the common epsilon3/epsilon3 genotype had a recurrence.

The small group of patients with the epsilon2/epsilon4 genotype appeared to have the highest risk of early recurrence. Among the eight patients who had recurrences within the first six months, four had this uncommon genotype, the authors reported. There were no differences in time to recurrence between the patients who were heterozygous for epsilon2 or epsilon4 and the small group who were homozygous for epsilon2 (one patient) or epsilon4 (four).

The time to recurrence did not vary significantly with age, sex, dementia, or diabetes mellitus. Hypertension was also unassociated with recurrence; however, it was not consistently monitored during follow-up. "From a practical standpoint, attentive control of hypertension remains the prudent course in patients with suspected amyloid angiopathy," the authors wrote.

A history of hemorrhagic stroke prior to study entry was associated with a high risk of recurrence (risk ratio, 6.4). However, previous hemorrhage is unlikely to play a causal role in recurrence, the authors suggested. "Previous hemorrhage instead probably acts as a marker of other genetic or environmental risk factors for aggressive disease," they wrote.

Previously implicated as a risk factor for dyslipidemia and Alzheimer's disease, APOE genotype also appears to play an important role in amyloid angiopathy-related hemorrhage. The epsilon4 allele has been associated with increased vascular deposition of the ß-amyloid peptide whereas the epsilon2 allele has been associated with degenerative changes in the amyloid-laden vessel wall. "Both effects are specific to the vasculopathy of cerebral amyloid angiopathy, since neither allele is associated with other types of intracranial hemorrhage, such as hypertensive hemorrhage," the authors wrote. It should be noted, they continued, that despite its association with epsilon2 and epsilon4, amyloid angiopathy-related hemorrhage is not uncommon in patients with the epsilon3 genotype. Taken together, this study raises the possibility that APOE genotyping may be useful in assessing a patient's risk of recurrent lobar hemorrhage, the study authors concluded.

"Data from studies that identify high-risk cases, such as the study reported by O'Donnell et al, can be used to refine the inclusion criteria for smaller, randomized trials involving patients at high risk for recurrent hemorrhage," commented Ralph Sacco, MD, in an accompanying editorial. "All this preparatory work will lead to the design of better, more cost-effective treatment trials with a greater chance of success," he wrote.

O'Donnell HC, Rosand J, Knudsen KA, et al. Apolipoprotein E genotype and the risk of recurrent lobar intracerebral hemorrhage. N Engl J Med. 2000;342:240-245.
Sacco RL. Lobar intracerebral hemorrhage. N Engl J Med. 2000;342:276-279.

Acetylcholinesterase inhibitors have psychotropic effects and may play an important role in controlling psychiatric and behavioral disturbances in patients with Alzheimer's disease, according to a report in the January American Journal of Psychiatry.

Based on a review of the English-language literature pertinent to the response of neuropsychiatric symptoms to cholinergic agents in Alzheimer's disease and related conditions, Jeffrey L. Cummings, MD, reported that acetylcholinesterase inhibitors reduce neuropsychiatric symptoms, ameliorate behavioral disturbances, and enhance cognition.

Acetylcholinesterase inhibitors exert their beneficial effect on cognition by blocking acetylcholinesterase and enhancing cholinergic function. Acetylcholinesterase is located in the synaptic space and synaptic membrane of the neurons of the cholinergic system. Cholinergic neurons manufacture choline acetyltransferase, which catalyzes the synthesis of acetylcholine. While all cerebral cortical layers receive cholinergic innervation, the amount varies by region. Limbic areas have the highest density; paralimbic regions, the next highest density; unimodal and heteromodal association cortices have intermediate densities; and the primary visual cortex has the lowest. It is the limbic structure that determines the emotional valence of stimuli, influences the impact of emotionally relevant information on cortical function, and plays a major role in emotionally relevant brain function. Thus, therapy that regulates limbic function also regulates emotion and behavior; limbic cholinergic structures likely mediate the beneficial response to acetylcholinesterase inhibitors.

Cholinergic abnormalities have been linked to psychiatric disturbances, said Dr. Cummings; evidence includes similarities between anticholinergic toxicity and neuropsychiatric symptoms of Alzheimer's disease, response of psychiatric symptoms to cholinesterase inhibitors in conditions with cholinergic deficits, and the anatomic distribution of the cholinergic deficits. In Alzheimer's disease, cholinesterase inhibitors are thought to restore function in brain regions critical to emotion. Hallucinations, apathy, anxiety, disinhibition, agitation, depression, delusions, and aberrant motor behavior are reduced.

The observed psychotropic effects of cholinesterase inhibitors have therapeutic implications, Dr. Cummings continued. However, variations in treatment efficacy have been noted, possibly explained by varying cholinergic deficits associated with age, the severity of disease, or genotype. Norepinephrine, dopamine, serotonin, gamma-aminobutyric acid, opioid peptides, galanin, substance P, and angiotensin II may also alter responses to the cholinesterase inhibitors.

Although Alzheimer's disease was the initial target of cholinesterase inhibitor therapy, indications could expand to other disorders involving the cholinergic system. Cholinergic agonists, Dr. Cummings noted, have also been reported to have a beneficial impact on psychiatric symptoms. However, responses have generally been "less consistent" than those reported with cholinesterase inhibitors.

Reducing behavioral disturbances in Alzheimer's disease is an important treatment goal, Dr. Cummings noted. Modifying disturbed behavior relieves stress for the caregiver and increases the likelihood of the patient remaining at home.

Cummings J. Cholinesterase inhibitors: a new class of psychotropic compounds. Am J Psychiatry. 2000;157:4-15.

"One of the most challenging problems faced by medical personnel responsible for the health care of athletes is the recognition and management of concussions," wrote the American Orthopaedic Society for Sports Medicine Concussion Workshop Group in the September/October 1999 issue of the American Journal of Sports Medicine. Based on the proceedings of their workshop, the group issued guidelines on the initial evaluation and management of an athlete who has sustained a potential concussion. The workshop outlined symptoms of concussion as well as its management during preseason preparation, on-the-field evaluation, and on-the-bench evaluation.

Preseason preparation, according to the new guidelines, should include ensuring that relevant personnel are adequately trained, assembling the appropriate equipment, establishing an emergency back-up plan, and asking the athletes to complete neuropsychological evaluations. The data from preseason tests should be readily available for comparison with the data from tests completed upon suspicion of concussion, as knowledge of an athlete's preseason capabilities is necessary for the interpretation of post-injury cognitive performance.

On-the-field evaluation begins with recognizing the mechanism of concussion, which may be either direct or sudden rotational or sheer force transmitted to the brain. The attendants approaching a player who may have sustained a concussion should establish respiration and be aware of the possibility of spinal injury. The athlete should then be evaluated for coma. The Glasgow Coma Scale is a standard method of assessing coma: a score of 11 or more usually indicates an excellent prognosis, while a score of seven or less usually indicates a very serious injury. The athlete's orientation can be evaluated with personal questions, such as "what did you have for dinner?"

Athletes who return to the bench under their own power should undergo on-the-bench evaluation. Many players with concussion are irritable and ask to be left alone. Evaluation should continue in a quiet place, such as the locker room. Attendants should check for dizziness, light-headedness, vertigo, blurred or double vision, photophobia, tinnitus, headache, nausea, and vomiting. Attendants should initiate a careful eye examination. Visual acuity, visual fields, extraocular motion, level of eyes, and anisocoria (3% of the population has anisocoria; the preseason exam should be consulted) should be checked.

Attendants should also evaluate nystagmus, the seventh cranial nerve (facial), the tympanic membrane, the cervical spinous processes, brachial plexus, upper extremity, and strength. The neuropsychological testing should incorporate orientation, concentration, and memory. The workshop noted that the Standardized Assessment of Concussion (SAC) was established for the immediate assessment of concussion in athletes. It is meant to provide short-term information for athletic trainers and other medical personnel; it is not meant to replace formal clinical or neuropsychological evaluation.

Players who are asymptomatic should undergo provocative testing to determine whether symptoms will occur with physical exertion. A 40-yard dash, five sit-ups, five push-ups, or five deep knee bends are usually adequate to raise intracranial pressure.

Finally, the seriousness of second-impact syndrome and postconcussion syndrome should be explained to the asymptomatic player before he or she is returned to the game.

The workshop outlined the safety of return-to-play at various times. Players who have any symptoms 15 minutes after suspected concussion should not be returned to the game. A concussion should be evaluated by a physician before the player resumes the season. Persistent symptoms may require evaluation by a neurosurgeon or a neurologist. On returning to athletic activity, the player should be carefully monitored for increased physical stress and intracranial pressure.

The workshop's report also emphasized the value of data collection. The panel promotes the establishment of databases on all athletes with concussion, wherein the use of similar neuropsychological instruments and terms facilitates longitudinal analysis of concussion. Thus, the risk of future injury and speed of recovery after concussion can be more acurately assessed.

Wojtys E, Hovda D, Landry G, et al. Concussion in sports. Am J Sports Med. 1999;27:676-687.

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