Determination of Syncope Etiology Can Be Costly--What Is Necessary?

Yield of Diagnostic Tests in Evaluating Syncopal Episodes in Older Patients. Mendu ML, McAvay G, et al:

Arch Intern Med 2009; 169 (July 27): 1299-1305

Despite extensive evaluation, the cause of syncope remains unknown in approximately 50% of older patients.

Background: Syncope is common, accounting for 1% to 3% of emergency department visits and <6% of hospital admissions with estimated costs of $6 billion per year in the United States. Patients typically undergo extensive cardiac and neurological testing. Objective: To determine the frequency, yield, and costs of tests to evaluate syncope in older adults. Design: Retrospective review of patients' medical records. Participants: 1,920 patients (mean age, 79 years; 53% female) with 2,106 admissions were included. Only 6% had neurological deficits on examination. Results: The most frequently ordered tests were electrocardiogram (99% of admissions), telemetry (95%), and cardiac enzymes (95%), and head CT (63% of admissions). Only 2% of echocardiograms revealed findings reported to contribute to the etiology of syncope. Telemetry helped define the etiology in 5% of cases. Overall, results from cardiac enzymes, head CT, echocardiography, carotid ultrasonography, and electroencephalography all affected the diagnosis or management in <5% of cases and helped determine syncope etiology <2% of the time. The single test with the highest yield in determining the etiology of syncope (15% to 21%) was measurement of postural blood pressure (BP) changes. However, this was performed in only 38% of cases, with only 24% of patients having their blood pressure recorded while lying and then standing. The most commonly reported etiologies for syncope were vasovagal and orthostatic hypotension. For 47% of syncopal episodes, no etiology could be determined. Arrhythmia and other cardiac causes accounted for a total of 16% of cases. Applying the San Francisco Syncope Rule (congestive heart failure, shortness of breath, abnormal electrocardiogram, hematocrit <30%, or systolic BP <90 at presentation) selected outpatients were more likely to have a serious cause for syncope and a worse prognosis. The investigators examined the cost of various tests used to help establish the etiology of syncope. Overall, the cost of head CT to determine the etiology of 1 case of syncope was estimated at >$99,000, and the overall cost of electroencephalography to determine the etiology of 1 case of syncope was almost $66,000. In contrast, the overall cost of postural BP recording to help determine the etiology of 1 case of syncope was estimated at $23 to $33. Conclusions: Many unnecessary tests are obtained to evaluate syncope; selecting tests based on history and physical examination (including postural BP recording) could result in a more cost-effective approach to evaluating older patients with syncope. Reviewer's Comments: An editorial accompanies this article in which a cardiologist points out that many unnecessary tests are ordered because of patient expectations and the practice of defensive medicine. The American Heart Association and the American College of Cardiology have published guidelines that all patients with syncope should have a history and physical examination and an electrocardiogram. If cardiac disease is suggested, further cardiac testing is indicated. Clearly, electroencephalography and neuroimaging should be reserved for patients for whom a neurological disorder is suspected clinically. (Reviewer-W. Steven Metzer, MD).

Keywords: Syncope, Diagnosis, Diagnostic Tests, Postural Blood Pressure, Orthostasis

Print Tag: Refer to original journal article Stroke Before or During First 4 Weeks in GCA Patients in VB Circulation

Strokes at Time of Disease Diagnosis in a Series of 287 Patients With Biopsy-Proven Giant Cell Arteritis. Gonzalez-Gay MA, Vazquez-Rodriguez TR, et al:

Medicine 2009; 88 (July): 227-235

Most strokes in giant cell arteritis are in the vertebrobasilar circulation.

Objective: To ascertain, in a population served by a single referral center, the incidence of strokes in giant cell arteritis (GCA) at the time of diagnosis, and to explore factors that may predict the occurrence of stroke. Design: Population-based, retrospective review. Participants: 287 patients with biopsy-proven GCA seen at a regional referral center were included in the study. Methods: Biopsies were done for all patients with clinical manifestations of GCA or with isolated polymyalgia rheumatica (PMR) plus constitutional symptoms, and/or an erythrocyte sedimentation rate >80 mL/1st hour. The study focused on strokes as "presenting symptoms" of GCA, defined as occurring any time before, and up to 4 weeks after, biopsy, diagnosis, and commencement of glucocorticoid (GLC) therapy. Demographic information and risk factors, clinical findings (particularly those relevant to GCA), laboratory data, imaging, and treatment information were obtained. Both GLC and antithrombotic therapy were noted. Strokes were assigned to the vertebrobasilar (VB) or internal carotid artery (ICA) circulations based on neurological syndrome and imaging. Transient ischemic attacks were excluded. Statistical analysis was by stepwise logistic regression. Results: 8 of the 287 patients (2.8%) had strokes during the relevant time period, 7 in the VB circulation. Surprisingly, in 5 of these 8 patients, the stroke occurred after the initiation of GLC, usually in the first 10 days. The only factor more common in GCA stroke patients versus patients without stroke was smoking. Delay before diagnosis, age and gender, other stroke risk factors, atrial fibrillation, and antithrombotic therapy were not associated with altered stroke risk. No GCA disease manifestation predicted higher risk of stroke. The only laboratory abnormality differentiating stroke from nonstroke patients was a slightly lower hemoglobin in patients without stroke. In the multivariable analysis, hypertension and permanent visual loss increased the odds ratio of stroke, while female gender and lower hematocrit lowered the odds ratio. Conclusions: The incidence of stroke before and during the first 4 weeks after diagnosis of GCA is low (2.8%). In general, this follows what has been reported recently in other studies. Most strokes occurring in this time frame in GCA patients were in the VB circulation. Reviewer's Comments: This confirms the severe involvement of the VB circulation in strokes associated with GCA, which is in turn explained by the frequent involvement of the extracranial vertebral arteries, as observed in autopsy cases of GCA. This skewed distribution supports the idea that it is the vasculitic process (rather than other risk factors commonly contributing to stroke risk) that is the mechanism for stroke in these elderly patients with GCA. The observation that most of the strokes occurred in those who had already started GLC therapy underlines the fact that the arterial damage inflicted by the vasculitides may not rapidly or completely resolve with therapy, even though the inflammatory component is blunted. (Reviewer-James W. Schmidley, MD).

Keywords: Giant Cell Arteritis, Cerebral Infarction

Print Tag: Refer to original journal article IV Levetiracetam Is Effective as Acute Tx in Children

Role of Intravenous Levetiracetam in Acute Seizure Management of Children. Kirmani BF, Crisp ED, et al:

Pediatr Neurol 2009; 41 (July): 37-39

An IV loading dose of LEV at 50 mg/kg is quite effective in the treatment of acute seizure emergencies in children, including refractory SE.

Background: IV levetiracetam (LEV) is not approved by the Food and Drug Administration for the emergent treatment of seizures. It is typically given as a loading dose to initiate therapy or to replace oral doses, but it is also being used in the treatment of refractory status epilepticus (SE). If LEV is effective in the treatment of refractory SE or for repetitive seizures, it would be logical to evaluate it as potential primary therapy. Objective: To evaluate the safety and efficacy of IV LEV for the treatment of refractory SE and acute seizure exacerbations in children. Methods: An electronic medical record review at a single institution identified children who ranged in age from 2 months to 18 years of age who had received an IV loading dose of LEV. Documentation included patient demographics, reason for IV LEV administration, seizure type and characteristics, underlying diagnosis, loading and maintenance LEV dose, other antiepileptic drugs used, response to treatment, adverse effects, and ongoing maintenance therapy. Results: A total of 32 children (17 boys and 15 girls) were identified, who had received an IV loading dose of LEV. The indication for treatment was SE in 16 patients, acute exacerbation of seizures in 15, and increased intensity of infantile spasms in 1 patient. New onset seizures were present in 9 patients. LEV was given after unsuccessful initial therapy with IV lorazepam and a loading dose of fosphenytoin in approximately 60% of cases. The LEV loading dose ranged from 25 to 70 mg/kg, but the most commonly used dose was 50 mg/kg. The dose was typically infused over 15 minutes. The response to LEV was considered favorable and included cessation of SE in all patients. Clinical and electrographic improvement was typically seen within 30 minutes following IV LEV administration. An IV maintenance dose of LEV was then continued at 25 mg/kg every 12 hours. IV LEV was well tolerated, with no noted immediate adverse effects. One patient subsequently developed a rash, and 1 developed increased behavioral issues that improved in response to vitamin B6 administration. Oral LEV was continued at discharge in 90% of patients and was used as monotherapy in approximately 50%. Reviewer's Comments: The standard protocol for the acute treatment of seizure emergencies including SE typically includes an initial dose of a benzodiazepine followed by a loading dose of fosphenytoin. In this review of patients, when this therapy failed, a loading dose of LEV was quite effective. Studies should be considered that would evaluate emergent use of LEV prior to fosphenytoin. A fosphenytoin loading dose typically produces dramatic ataxia. In that regard, LEV is better tolerated. (Reviewer-Gregory B. Sharp, MD).

Keywords: Acute Seizures, Children, IV Levetiracetam, Refractory SE

Print Tag: Refer to original journal article Levetiracetam Toxicity Can Cause Neurological Side Effects.

Levetiracetam Accumulation in Renal Failure Causing Myoclonic Encephalopathy With Triphasic Waves. Vulliemoz S, Iwanowski P, et al:

Seizure 2009; 18 (June): 376-378

Levetiracetam dosages must be adjusted downward in the presence of renal failure.

Background: Triphasic waves on the electroencephalogram are often found in conjunction with acute confusional states and myoclonus/asterixis. Etiologies, in addition to hepatic encephalopathy, include renal failure, hypoxia, valproate-induced hyperammonemia, cephalosporins, and penicillin in the face of renal failure and several drugs such as levodopa, lithium, and naproxen. Objective: The authors report another, potentially common cause of these findings. Results: An 80-year-old female was admitted with generalized myoclonic jerks and a confusional state. In 2001, she had been admitted with similar symptoms resulting in a generalized tonic clonic seizure felt secondary to an old stroke and she was discharged on valproic acid. Drug-induced hyperammonemic encephalopathy a year later led to a change from valproic acid to levetiracetam, 1000 mg twice daily. Past medical history was significant for hypertension, type II diabetes mellitus, chronic renal failure, and vascular Parkinsonism. Other medications included levodopa benserazide 25/100 3 times daily, verapamil, propranolol, metformin, oxazepam, and escitalopram, with no recent dose changes. Neurological examination was significant for an acute confusional state as well as generalized action and rest myoclonus. Myoclonus stopped spontaneously a few days after admission. Blood work showed an increased creatinine level at 148 μmol/L (norm, 35 to 88) and creatinine clearance of 29 mL/min (norm, 40 to 75 mL/min) with normal electrolytes, CBC, liver functions, serum ammonium, thyroid functions, lumbar puncture, and absent antithyroid antibodies. MRI showed severe vascular white matter changes and a right prefrontal infarct. Electroencephalography (EEG) after the myoclonus subsided showed generalized slowing. The patient was discharged with no change in medications. Two months later, she was readmitted with moderate confusional state and status myoclonicus. EEG showed diffuse theta/delta slowing and prominent multifocal triphasic waves. There was no EEG correlate to the generalized myoclonus. Laboratory tests were stable including renal function. Levetiracetam was lowered to 250 mg twice daily and myoclonus and mental confusion disappeared 3 days later. Levetiracetam level was 184 μmol/L on admission and 53 μmol/L after decrease in dose (therapeutic level, 35 to 120 μmol/L). Levetiracetam was then stopped. Two days later, myoclonus recurred with no change in renal function and normal metabolic parameters otherwise. An EEG showed a focus of spikes and polyspikes over the frontal midline. Levetiracetam was restarted at 250 mg twice daily along with a 3-day course of low-dose clonazepam. The last level of levetiracetam was 90 μmol/L and there was no recurrence of myoclonus after 6 months. Conclusions: The authors conclude that this is the first case of metabolic encephalopathy with myoclonus and triphasic waves associated with levetiracetam toxicity in the setting of chronic renal failure. Reviewer's Comments: Levetiracetam is an excellent anticonvulsant for the treatment of focal onset and generalized seizures. Caution must be exercised with its use in patients with renal failure. (Reviewer-John Schwankhaus, MD).

Keywords: Levetiracetam, Triphasic Waves, Myoclonus, Renal Failure

Print Tag: Refer to original journal article Rapid IV Loading Dose of Levetiracetam Is Safe in Children and Young Adults

Rapid Infusion of a Loading Dose of Intravenous Levetiracetam With Minimal Dilution: A Safety Study. Wheless JW, Clarke D, et al:

J Child Neurol 2009; 24 (August): 946-951

A loading dose of levetiracetam at 40 mg/kg can be mixed 1:1 with normal saline and infused over 5 minutes in children and young adults to rapidly achieve a maximum serum concentration.

Background: IV administration of antiepileptic drugs (AEDs) is needed for urgent therapy and when patients are unable to take oral medication. The safety of IV administration of levetiracetam (LEV) has been established in adults, and is approved by the Food and Drug Administration as adjunctive therapy for partial-onset seizures and juvenile myoclonic epilepsy in patients who are ≥16 years of age. In order to consider IV LEV as primary therapy for acute seizure emergencies, including status epilepticus, safety with rapid infusion needs to be established. Objective: To evaluate the safety of a single, rapid, IV loading dose of LEV in children and young adults. Design/Participants: In this open-label, prospective, single-center study, participants ranged from 4 to 32 years of age and had a confirmed diagnosis of either partial-onset or generalized epilepsy. Methods: The loading dose of LEV was considered as a rational component of therapy. All patients were alert, had normal renal function, and were on a regular diet. Most were on a single AED when the LEV loading dose was given, but some were not on AED therapy. Subjects were assigned to receive a single loading dose of 20, 40 or 60 mg/kg, or a maximal dose of 1000, 2000 or 3000 mg, respectively. Each dose was assigned to a group of 15 patients. The commercially available IV formulation of LEV at 100 mg/mL was diluted 1:1 with either normal saline or D5W. The infusion was given using a flow control pump. The 20- and 40-mg/kg doses were infused over 5 minutes, and the 60-mg/kg dose was given over 6 minutes. Vital signs and electrocardiogram were monitored. A peak serum concentration was measured immediately following completion of administration. The volume of distribution was calculated. Results: The mean age of participants was 14 years, and most were Caucasian and male. Adverse events were uncommon and minor. One patient developed a mild rash that was likely unrelated to LEV administration. Two patients complained of pain at the infusion site, 1 of which discontinued participation as a result. No changes were noted in cardiac rhythm or blood pressure. The mean serum concentration following the 20- mg/kg dose was 40 μg/mL and was equivalent in the 40-mg/kg and 60-mg/kg groups at just over 100 μg/mL. The volume of distribution was essentially equivalent in all groups at approximately 0.4 L/kg. Reviewer's Comments: In this study, a single loading dose of LEV was administered rapidly over 5 to 6 minutes without significantly associated risk. It appears that a dose of 40 mg/kg will rapidly achieve a maximal serum concentration. This supports the more detailed studies to evaluate IV LEV as a component of primary therapy for status epilepticus and other seizure emergencies. (Reviewer-Gregory B. Sharp, MD).

Keywords: IV Levetiracetam, Rapid Infusion, Loading Dose, Safety

Print Tag: Refer to original journal article PET May Predict Early Conversion of MCI to Alzheimer's Dz

Conversion of Amyloid Positive and Negative MCI to AD Over 3 Years. An 11C-PIB PET Study. Okello A, Koivunen J, et al:

Neurology 2009; (July 22): epub ahead of print

Rapid conversion from MCI to AD is associated with significantly higher amyloid in anterior cingulate and frontal cortex, and APOE ε4 genotype.

Background: Amnestic mild cognitive impairment (MCI) is defined as subjective and objective memory impairment with relatively normal performance and other cognitive domains, intact activities of daily living, and failure to meet diagnostic criteria for dementia. It appears that 10% to 15% of patients with MCI progress to Alzheimer's disease (AD) each year. There is currently great interest in using surrogate markers to identify those individuals who are more likely to progress to AD. Objective: To investigate the utility of 11C-Pittsburgh compound B (PIB) PET to predict conversion of MCI to AD. Design: Prospective, case-controlled study. Participants: 31 subjects meeting diagnostic criteria for amnestic MCI were included; 14 of these were from the UK (mean age, 66.6 years); the remaining 17 subjects were recruited from Finland (mean age, 71.7 years). These MCI subjects were compared to a control group of 26 age-matched healthy volunteers with no neurologic or psychiatric disease. Methods: All subjects underwent baseline PIB PET and were followed clinically for up to 3 years. The 17 subjects from Finland also underwent APOE ε4 genotyping. Results: Compared to controls, the MCI subjects overall had a significantly higher increase in PIB retention on PET scanning in the anterior cingulate, posterior cingulate, frontal, temporal, parietal, and occipital cortex, with the greatest increase being noted in the anterior and posterior cingulate cortex (approximately 40%). Of the 31 MCI subjects, 17 (55%) had increased PIB retention on PET at baseline, and 14 of these 17 subjects (82%) converted to AD during follow-up. In contrast, only 1 of the 14 MCI subjects who did not have increased PIB retention on PET converted to AD over the 3-year follow-up period. Forty-seven percent of the PIB-positive subjects with MCI converted to AD within 1 year of the baseline study. These faster converters were noted to have significantly higher PIB retention on PET in the anterior cingulate and frontal cortex than the slower converters. The presence of the APOE ε4 allele was also significantly associated with faster conversion rates in PIB-positive MCI subjects. Conclusions: MCI subjects with increased PIB retention on PET are significantly more likely to convert to AD than MCI subjects without increased PIB retention on PET, and faster converters have significantly higher PIB retention levels at baseline than slower converters. Reviewer's Comments: This interesting article provides evidence that PIB PET could prove to be a useful marker for determining which patients with amnestic MCI are more likely to convert to AD. The role of this technology in clinical practice is yet to be defined. PIB PET will probably assume an increasingly important role in studies of new therapeutic agents that might delay progression of patients with amnestic MCI to dementia. (Reviewer-W. Steven Metzer, MD).

Keywords: Dementia, Alzheimer's Disease, MCI, Pittsburgh Compound B, PET, Amyloid

Print Tag: Refer to original journal article Ultra-High Field MRI Quantifies Cortical MS Pathology

In Vivo Imaging of Cortical Pathology in Multiple Sclerosis Using Ultra-High Field MRI. Mainero C, Benner T, et al:

Neurology 2009; (July 29): epub ahead of print

Cortical MS plaques seen previously only with histology can be imaged with ultra-high field MRI.

Background: Pathological studies of multiple sclerosis (MS) show that cortical plaques comprise a substantial portion of the total lesion load in MS. These plaques are not detectable by standard MRI. Ultra-high field MRI (7 to 9.4 T) increases the signal-to-noise ratio 2- to 3-fold over 3T MRI and potentially could visualize these cortical lesions. Objective: To image MS cortical lesions previously detected only by histopathology, find the best imaging techniques, and study cortical lesion types, white matter lesion load, and clinical disability. Participants/Methods: 9 patients with relapsing-remitting MS (RRMS), 7 patients with secondary progressive MS (SPMS), and 8 normal controls were studied with a 7T MRI. Patients were relapse-free at least 3 months before study entry and had not received corticosteroids in the previous month. All but 1 patient had received disease-modifying therapy for ≥3 months. Disability was measured using the Expanded Disability Status Scale (EDSS). The median EDSS score was 3.0 (range, 1.0 to 6.5). Controls consisted of age-matched healthy men and women. MRI sequences included 2-dimensional fast low-angle shot (FLASH)-T2*-weighted spoiled gradient-echo, T2-weighted turbo spin-echo (TSE), and a 3-dimensional magnetization-prepared rapid gradient echo. Results: Ultra-high field MRI detected 199 cortical lesions and permitted their characterization based on established histopathological criteria. Type I plaques (leukocortical) extended from white matter partly into the cortex. Type II plaques were intracortical but did not span the cortical width. Type III and IV involved the subpial cortex and extended partly or completely through the cortical width, respectively. Among 16 patients, types III-IV accounted for 50% of all cortical plaques. Of the remaining plaques, 36% were type I and 14% were type II. This closely resembled the distribution of plaque types found in recent pathological studies. Cortical plaque distribution was uneven with 106 frontal, 47 parietal, 29 temporal, and 17 occipital plaques. Among 72 type I (leukocortical) plaques, 15 displayed a hypointense "susceptibility ring" believed to be due to invasion of iron rich macrophages that reflected active inflammation. SPMS patients harbored almost twice the number of cortical plaques compared to RRMS patients. The greater number of type III to IV lesions was associated with greater disability and older age. No relationship was found between white matter lesion load and the number or type of cortical plaques. T2*-weighted images produced the highest contrast-to-noise ratio for all plaque types. Controls showed no lesions. Conclusions: 7T MRI differentiated cortical lesion types previously detected only by histology. If confirmed with larger studies, ultra-high field MRI could be used to quantify cortical MS pathology over time and in response to therapy. Reviewer's Comments: Ultra-high field MRI is starting to achieve in vivo resolution of disease processes previously possible only with the aid of a microscope. (Reviewer-Michael Jacewicz, MD).

Keywords: Cortical Pathology, Ultra-High Field MRI

Print Tag: Refer to original journal article Predicting Dz Severity and Medication Complications of MS

Patterns of Motor and Non-Motor Features in Parkinson's Disease. van Rooden SM, Visser M, et al:

J Neurol Neurosurg Psychiatry 2009; 80 (August): 846-850

Psychotic and autonomic symptoms, along with daytime sleepiness and axial symptoms are associated with a more severe disease state.

Objective: To evaluate the presence and nature of patterns of coherency among the motor and non-motor domains in Parkinson's disease (PD) and to examine which clinical parameters are related to the potential patterns. Methods: This study is part of the PROfiling PARKinson's disease (PROPARK) study, which looks at phenotype, genotype, disability, and global outcomes of health in PD patients. Recruited patients had to fulfill the U.K. Parkinson's Disease Society Brain Bank criteria for idiopathic PD. Information was obtained on all patients, including age, age at onset, disease duration, disease severity (Hahn & Yahr scale), and medication (levodopa dose equivalent units). Domains assessed were motor signs (tremor, bradykinesia, rigidity, axial symptoms, and second axial factor of freezing, swallowing and speech), and motor complications, cognitive impairment (memory, attention, executive functioning, and visuospatial function, psychotic symptoms, autonomic dysfunction (constipation, urinary dysfunction, and cardiovascular dysfunction), depressive symptoms, nighttime sleep problems, and daytime sleepiness. Patients were assessed while they benefited from their anti-Parkinsonian medications. The total group was randomly subdivided into 2 groups, with the first group subjected to an exploratory factor analysis (EFA) with oblique rotation to allow for correlation of factors. Results of EFA were then used to construct a model that was tested in the second sample using confirmatory factor analysis. Model measures testing the lack of fit were then used to see how well the data fit. Multiple forward linear regression analysis with 2 blocks was then used to explore the relationship between the different factors and the disease process and medical therapy while removing variation due to demographic characteristics. Results: 397 patients were included in the analysis after removal of 18 who had undergone stereotactic surgery. The 2 subsamples did not differ significantly for any characteristics. After EFA, 4 factors were identified. Factor 1 included psychotic and autonomic symptoms, daytime sleepiness, and axial symptoms. Factor 2 included nighttime sleep problems and motor fluctuations. Factor 3 had axial symptoms, motor fluctuations, and dyskinesias, and factor 4 had tremor, bradykinesia, and rigidity. Factor 1 was the strongest factor and was related to advancing disease. Factor 3 encompassed motor fluctuations and was related to dopaminergic medications. The other 2 factors were only marginally related to disease severity or medications. Conclusions: Factor 1, comprising non-motor and axial symptoms, may help monitor disease progression. Reviewer's Comments: As PD disease severity is linked to several non-motor symptoms, new disease severity scales should include these to better monitor disease progression. (Reviewer-John Schwankhaus, MD).

Keywords: Parkinson's Dz, Dz Severity, Medication Complications, Predictive Symptoms

Print Tag: Refer to original journal article Administrative Databases Can Be Seriously Misleading

Inaccuracy of the Administrative Database: Comparative Analysis of Two Databases for the Diagnosis and Treatment of Intracranial Aneurysms. Woodworth GF, Baird CJ, et al:

Neurosurgery 2009; 65 (August): 251-257

ADBs are relatively easy to access and provide investigators with large sample sizes, which usually translate into high statistical power.

Background: Many studies on healthcare utilization, delivery, and outcomes rely on administrative databases (ADB). ADBs are relatively easy to access and provide investigators with large sample sizes, which usually translate into high statistical power. In almost all cases, they are digital and therefore easily acquired and probed statistically. This is especially true in countries with nationalized health service, such as the European democracies, and in the U.S. for the Medicare population. Unfortunately, ADBs are usually not validated or at best only incompletely so. Objective: To compare an ADB with a database maintained at a university hospital. The condition addressed was intracranial aneurysm and the question addressed was the accuracy of diagnosis and procedure codes. Methods: The ADB in this study was that of the Maryland Health Services Review Commission. The Department of Neurosurgery aneurysm database at the Johns Hopkins University is referred to as the departmental database (DDB). The DDB was prospectively collected by 1 of the authors, and included radiologically proven intracranial aneurysms in patients admitted to the hospital and treated. ICD-9 codes for subarachnoid hemorrhage from ruptured aneurysm and for unruptured aneurysm were used. Procedural codes included those for clipping and other therapy (endovascular). The study compared the accuracy of recorded diagnoses and procedures in the 2 databases with hospital records, and looked for trends in their accuracy over time. Results: The ADB was much less accurate. Overall, the DDB missed 1.3% of aneurysm cases, the ADB missed 16%. The ADB incorrectly included 1.2% of cases, and the DDB incorrectly included none. The ADB was significantly less accurate in classifying aneurysms as ruptured versus unruptured, and in identifying the type of treatment employed (endovascular vs surgical clipping). Unfortunately, there were no trends toward improved accuracy in the ADB over the 17-year course of the study. The authors also examined the number of publications relying on data from ADBs, using a PubMed search. This number grew from 34 in the first year of the study (1991) to 467 (a greater than 10- fold increase) in 2007. Conclusions: The authors concluded that the accuracy of the Maryland Administrative Database was significantly lower than that of the departmental database. They discuss in detail the implications of these inaccuracies. Reviewer's Comments: In the current political climate, the impact of decisions made on the basis of inaccurate data derived from administrative databases may be far reaching and potentially deleterious to the public health. (Reviewer-James W. Schmidley, MD).

Keywords: Subarachnoid Hemorrhage, Intracranial Aneurysm, Administrative Health Care Data

Print Tag: Refer to original journal article Retinal Microvascular Abnormalities More Common in Lacunar Strokes

Retinal Microvasculature in Acute Lacunar Stroke: A Cross-Sectional Study. Lindley RI, Wang JJ, et al:

Lancet Neurol 2009; 8 (July): 628-634

Acute lacunar stroke is more likely to be secondary to nonatherothrombotic causes.

Background: While lacunar strokes constitute 25% of all ischemic strokes, the pathology is not well understood. The proposed mechanisms include lipo hyalinosis, hyaline arteriosclerosis, microatheromas, and small vessel damage from breakdown of the blood-brain barrier. It has been difficult to study lacunar strokes due to low fatality rates resulting in few pathological specimens and an inability of brain imaging techniques to produce high enough resolution of the small arteries involved in lacunar strokes. Interestingly, the retinal and cerebral small vessels share similar embryological origins, sizes (40 to 200 μm) and structure (end arteries with no anastomosis); further, the blood-brain and blood-retinal barriers are structurally and functionally similar. Retinal vessels can be imaged directly and can be quantitatively assessed by computerized techniques. Recently an association between retinal vascular abnormalities and white matter lesions on MRI has been described. Objective: To assess whether changes in the retinal microvasculature are associated with acute ischemic stroke. Participants/Methods: The patients were recruited prospectively within 7 days of acute stroke from 3 centers in Australia and Singapore as a part of The Multi-Centre Retina and Stroke Study (MCRS). Each patient had clinical assessment, retinal photography, and imaging of the brain. Lacunar stroke was diagnosed by Treatment of Acute Stroke Trial (TOAST) or Oxfordshire Community Stroke Project (OCSP) criteria and MRI findings. Results: Of the 1321 patients recruited, 410 (31%) had lacunar stroke. Hypertension, diabetes mellitus, and dyslipidemia were equally likely in both lacunar and non-lacunar ischemic strokes, although there were more smokers in former group. The patients with lacunar strokes were more likely to have retinal microvascular changes, even after adjusting for age, sex, smoking history, hypertension, and diabetes. The odds ratios were 3.55 for focal arteriolar narrowing, 1.96 for arteriovenous nipping, 2.32 for enhanced light reflex of the arteriolar wall, 1.33 for generalized retinal arteriolar narrowing, 1.45 for small arteriole:venule ratio, and 1.35 for retinal venular narrowing. Conclusions: The findings from this study suggest that lacunar stroke is a manifestation of nonatherothrombotic occlusive small vessel disease. Reviewer's Comments: This is a landmark study providing data supporting nonatherothrombotic basis for causation of lacunar strokes. These findings also explain why intensive antiplatelet treatment is not as effective as expected in secondary stroke prevention trials, including the MATCH study in which 53% had lacunar strokes. This study together with another recent paper demonstrating subtle, diffuse blood-brain barrier dysfunction in lacunar strokes (Wardlaw JM, Annals of Neurology 2009; 65:194-202) suggests an etiological role for endothelial dysfunction. The retinal imaging may provide a powerful surrogate marker for treatment efficacy in the future stroke trials. (Reviewer-James W. Schmidley, MD).

Keywords: Lacunar Stroke, Retinal Microvascular Changes, MRI, Atherothrombosis

Print Tag: Refer to original journal article Possible Therapy for Spinal Muscular Atrophy

Oral Administration of the Thyrotropin-Releasing Hormone (TRH) Analogue, Taltireline Hydrate, in Spinal Muscular Atrophy. Kato Z, Okuda M, et al:

J Child Neurol 2009; 24 (August): 1010-1012

A trial of oral therapy with taltireline hydrate, a TRH analogue, at a daily dose of 0.2 mg/kg resulted in improved strength in a single patient with spinal muscular atrophy type 3.

Background: Spinal muscular atrophy (SMA) disorders are classified as type 1, 2, or 3 depending on the age of onset and clinical course. Degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem accounts for the progressive motor deterioration. Type 1, the most common and severe form, is also known as infantile spinal muscular atrophy or Werdnig-Hoffmann disease. Type 2 (intermediate form) and type 3 (Kugelberg-Welander disease) have a later onset and less severe course. SMA disorders are inherited in an autosomal recessive pattern, and are due to deletions or mutations in the survival motor neuron 1 (SMN1) gene on chromosome 5q13. SMN protein appears to play a role in mRNA synthesis in motor neurons and also may inhibit apoptosis. The degree of abnormality in SMN protein correlates with severity of disease. The differences in SMN protein and phenotypic expression appear to be related in part to the modifying gene SMN2, which lies close to the SMN1 gene. SMN2 is largely deleted in most cases of SMA type 1. There is no definitive treatment for these disorders. Recent reports have noted potential efficacy of therapy with intravenous injection of thyrotropin-releasing hormone (TRH) in patients with SMA. Objective: To document a positive effect on a patient with SMA type III treated with oral administration of taltireline hydrate, a TRH analogue. Case Report: An 18-year-old young man with SMA type III was initially treated with IV TRH at 17 years of age. He experienced flushing, nausea, and abdominal discomfort during the infusions. There was transient improvement in motor strength and function, but these had returned to baseline within 5 months. He was then treated with taltireline hydrate with an initial oral test dose of 0.1 mg/kg or 5 mg for 1 day. This was followed with 0.2 mg/kg per day or 10 mg/day for 24 days. Muscle strength was objectively measured before and after the course of therapy with testing of several proximal muscles by handheld dynamometer. Results: Strength improved, following therapy, in all muscles tested. Functionally, his ability to walk improved, and he was able to rise and stand from a seated position, which he could not do prior to the therapy. There were no clinical or laboratory identified adverse effects including thyroid stimulating hormone suppression. Reviewer's Comments: Although this experience as reported is limited to one patient, the results do offer promise. A long-term, prospective trial of oral therapy with taltireline hydrate in patients with all three forms of SMA should be considered. (Reviewer-Gregory B. Sharp, MD).

Keywords: Spinal Muscular Atrophy, Taltireline Hydrate

Print Tag: Refer to original journal article Do Concurrent Anticonvulsants Affect Ketogenic Diet?

The Influence of Concurrent Anticonvulsants on the Efficacy of the Ketogenic Diet. Morrison PF, Pyzik PL, et al:

Epilepsia 2009; 50 (8): 1999-2001

Phenobarbital may have a negative impact on ketogenic diet efficacy, and zonisamide may have a positive effect.

Background: The ketogenic diet (KD) is used as therapy for medically refractory epilepsy in children. It is not known if specific antiepileptic drugs (AEDs) used concurrently with the KD have a positive or negative effect on KD efficacy. Objective: To examine the relationship between specific AEDs and KD in the treatment of children with epilepsy. Design/Methods: A retrospective study was performed at Johns Hopkins Hospital. The study included 217 consecutive children who were started on the KD between 2000 and 2007. Patients who had AED dosage adjustments during the first 3 months on the KD or who had incomplete available data were excluded, resulting in 115 remaining patients. Attention was paid to demographic data, seizure type and frequency, epilepsy syndrome, age at seizure onset, age at KD initiation, number of AEDs used prior to KD, and AEDs used during KD. A standard KD protocol employed at Johns Hopkins was utilized. Efficacy was analyzed after 3 months on the KD with respect to the 5 most common concurrently used AEDs in this group of patients. Positive responders were those with >50% reduction in seizure frequency. Results: The mean age at KD initiation was just under 5 years. A median of 4 AEDs had been tried before the KD, and patients were on a median of 2 AEDs (range, 1 to 5) when the KD was started. The most common AEDs used during the diet were valproic acid in 38 patients, topiramate in 31, levetiracetam in 27, lamotrigine in 25, zonisamide in 21, and phenobarbital in 14. Approximately one-half of the patients had either Lennox- Gastaut syndrome or mixed multiple seizure types. Just over 70% of patients were positive responders with a >50% reduction in seizures. The best response rate was seen in patients on zonisamide, at 90%. The worst response rate occurred in patients on phenobarbital, at just over 40%. Concurrent therapy with levetiracetam, lamotrigine, topiramate, and valproic acid did not appear to have a relative impact. The difference in response relative to individual AEDs did not appear to be affected by seizure type, epilepsy syndrome, baseline seizure frequency, or other features. Reviewer's Comments: This study indicates that phenobarbital may have a negative impact on KD efficacy, and zonisamide may have a positive effect. (Reviewer-Gregory B. Sharp, MD).

Keywords: Ketogenic Diet, Anticonvulsants, Epilepsy, Children

Print Tag: Refer to original journal article Don't Be Misled by Monomelic Amyotrophy

Bilaterally Symmetric Form of Hirayama Disease. Pradhan S:

Neurology 2009; 72 (June 16): 2083-2089

Although Hirayama disease is unilateral, it may also be bilateral asymmetrical or bilateral symmetrical.

Background: Hirayama disease (also known as brachial monomelic amyotrophy, Sobue disease, and benign juvenile muscular atrophy of the distal upper extremity) is a focal motor neuron disease of the hand and forearm. Although the disorder occurs worldwide, most large series have been reported from Japan and India. In most cases, the weakness/atrophy is unilateral; when bilateral, it is distinctively asymmetrical. Objective: To describe patients with Hirayama disease with bilateral and symmetrical weakness/atrophy. Methods: The records of patients with Hirayama disease seen at 2 large academic medical centers in India between 1992 and 2008 were reviewed. Patients included had the following: (1) onset between the teenage years and early 20s; (2) muscle atrophy, chronic denervation, and reinnervation with or without active denervation in C7, C8, and T1 distribution; (3) relative sparing of brachioradialis (giving an oblique atrophy appearance to the forearm); (4) no sensory loss and normal sensory nerve action potentials; and (5) initial worsening over 1 to 3 years followed by stabilization. Patients with bilateral weakness were considered symmetrical if there was <20% side-to-side difference between the median, ulnar, and radial compound muscle action potentials. Results: Of 106 patients with Hirayama disease, 11 had bilateral symmetrical weakness confirmed by electrodiagnostic studies. In 9 of 11 patients, the weakness and atrophy started unilaterally and spread to the contralateral limb during the next 1 to 3 years, resulting in bilateral and symmetrical appearance. As with many patients with Hirayama disease, cervical MRI changes were common: 7 of 11 patients had T2 signal abnormalities in the lower cervical cord, 9 of 11 patients had symmetric cervical cord atrophy, and all 11 patients had band-like cord flattening and crescent-shaped enhancing epidural space extending from C4 to T2 spine level. Conclusions: Bilateral symmetric weakness occurs in approximately 10% of patients with Hirayama disease, although, in most cases, the onset is unilateral. The term monomelic amyotrophy is misleading, and Hirayama disease is a preferred term. Reviewer's Comments: Although many patients with Hirayama disease have clinical and/or EMG evidence of bilateral involvement, this study confirms that bilateral and symmetric weakness of the hands and forearms may occur, although most patients have a unilateral onset. Along with the author, I prefer using the term Hirayama disease, and this study confirms that monomelic amyotrophy is a misleading name. (Reviewer- Bashar Katirji, MD).

Keywords: Focal Motor Neuron Disease, Hirayama Disease

Print Tag: Refer to original journal article CIDP Incidence Equal to Guillain-Barré Syndrome

Incidence and Prevalence of CIDP and the Association of Diabetes Mellitus. Laughlin RS, Dyck PJ, et al:

Neurology 2009; 73 (July 7): 39-45

The incidence of CIDP is 1.6/100,000/year and is similar to that of the Guillain-Barré syndrome. There is no association between CIDP and diabetes mellitus.

Background: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a treatable autoimmune neuropathy. Its diagnosis depends on clinical, electrophysiological, and pathological criteria. The incidence and prevalence of CIDP has not been well established, with estimates of prevalence ranging between 1.9 and 7.7 per 100,000. In addition, several reports during the last 2 decades suggested that diabetes mellitus (DM) may be a risk factor for CIDP. Objective: To determine the prevalence and incidence of CIDP in a northern U.S. population (Olmsted County, Minnesota), and to validate a possible association between DM and CIDP. Methods: Patients diagnosed with CIDP who resided in Olmsted County and who were seen over a 20-year period (January 1982 through December 2001) were identified using the Mayo Clinic records and the Rochester Epidemiology Project. All patients fulfilled 3 clinical criteria: (1) progressive symptoms for a period ≥8 weeks; (2) involvement of large compared with small nerve fibers; and (3) fairly symmetrical distal and proximal weakness with areflexia/hyporeflexia. Electrodiagnostic criteria included the following in at least 2 motor nerves: significant conduction velocity slowing (<70% of lower limit of normal [LLN] if amplitude is >50% of LLN or <50% of LLN if amplitude is <50% of LLN), distal latency slowing (>150% of LLN), conduction block (>50% drop in amplitudes), or F-wave slowing. Definite CIDP was defined as fulfillment of all the clinical and electrodiagnostic criteria; probable CIDP was defined as fulfillment of all clinical and partial electrodiagnostic (or pathologic, laboratory, or treatment response) criteria; and possible CIDP was defined as fulfillment of only the clinical criteria. Results: 23 patients (10 female and 13 male; 22 adults and 1 child) met CIDP criteria (19 definite, 4 probable). The median age was 58 years (range, 4 to 83 years). Two patients had monoclonal gammopathy of undetermined significance (MGUS). The annual incidence was 1.6 per 100,000 or 1.4 per 100,000 if the 2 MGUS patients were excluded. This incidence did not change significantly within the 20-year period. The prevalence was 8.9 per 100,000 persons on January 1, 2000. Only 1 of 23 patients with CIDP had DM (4%) compared to 14 of 115 age-matched controls (12%). Conclusions: The incidence of CIDP was 1.6 per 100,000/year in Olmsted County, Minnesota, while the prevalence was 8.9 per 100,000 persons. There is no definite association between CIDP and DM. Reviewer's Comments: This study is important for 2 reasons. First, it showed that the incidence of CIDP is equal to that of the Guillain-Barré syndrome (not lower as previously perceived). The latter incidence was analyzed in the same population as well as nationally (Neurology 2008; 70: 1608-1613). Second, it revealed that DM is not a risk factor for developing CIDP. Previous reports of such an association were most likely caused by using soft clinical criteria, and particularly soft electrodiagnostic criteria for demyelination, to misdiagnose diabetic polyneuropathies or amyotrophy as CIDP. (Reviewer-Bashar Katirji, MD).

Keywords: CIDP, Diabetes

Print Tag: Refer to original journal article Distinguishing SN From Distal Axonopathy

The Pattern and Diagnostic Criteria of Sensory Neuronopathy: A Case-Control Study. Camdessanché J-P, Jousserand G, et al:

Brain 2009; 132 (July): 1723-1733

A combination of certain clinical and nerve conduction study data can reliably distinguish sensory neuronopathy from distal axonopathy.

Background: It is difficult to determine if a clinically pure sensory polyneuropathy is due to a distal axonopathy or a sensory neuronopathy (SN) because nerve conduction studies (NCS) cannot distinguish between them. Objective: To devise validated diagnostic criteria for SN. Design: Retrospective study involving a referral center for neuromuscular disease. Participants: The study population consisted of 78 patients with SN. In 44 of these patients, the diagnosis was considered definite because the cause was cisplatin toxicity or paraneoplastic, which past clinicopathological studies verified as causes of SN. In the other 34 patients, the diagnosis of SN was less certain because it was based on old, unvalidated criteria: a non-length-dependent pattern of sensory loss, predominantly sensory abnormalities on NCS, and no other apparent cause. The control population consisted of 56 patients with sensory polyneuropathies known not to be SN because of a length-dependent pattern of sensory loss, a demyelinative pattern on NCS, or a known etiology. The test population consisted of 37 unselected consecutive patients referred for diagnosis of a sensory polyneuropathy. Methods: Logistic regression was used to construct a multivariate model that distinguished the SN and control groups. It was then applied to the test population, and its validity was judged by how close it came to the diagnoses of the expert clinicians at the referral center. Results: The SN patients with an uncertain and a definite diagnosis did not significantly differ from each other in regard to clinical or NCS features: mainly distal sensory loss in all limbs (>80% of patients), non-length- dependent pattern of sensory loss (>80%), paresthesias (>80%), sensory ataxia in upper or lower limbs (71%), asymmetrical sensory loss (42%), and abnormal motor-nerve conduction studies (57%). Rare variants included pure upper- or lower-limb involvement, pure small-fiber involvement, and patchy, multifocal sensory loss. Comparing the entire SN study population to the controls, logistic regression arrived at a combination of diagnostic criteria for SN that were well validated, sensitive (82%), and specific (91%): ataxia in the arms or legs + asymmetric sensory loss + sensory loss in the arms + at least 1 sensory action potential (SAP) absent or 3 SAPs <30% of lower limit of normal in the arms + <2 nerves with abnormal motor conductions in the legs. Conclusions: A combination of clinical and NCS data can reliably distinguish SN from distal axonopathy. Reviewer's Comments: The sensitivity and specificity of this scheme are not high enough to allow one to feel certain about the localizing diagnosis it provides. Distinguishing motor neuron disease from motor neuropathy (axonopathy) presents a similar problem. Because of this uncertainty, most of us take syndromes such as ataxic neuropathy and lower motor-neuron syndrome as points of departure for etiologic diagnosis, rather than a precise anatomic localization. (Reviewer-Marc D. Winkelman, MD).

Keywords: Sensory Neuronopathy, Ataxic Neuropathy, Sensory Neuropathy

Print Tag: Refer to original journal article New-Onset Seizures in HIV--Why Is It Happening?

New Onset Seizures in HIV—Seizure Semiology, CD4 Counts, and Viral Loads. Modi M, Mochan A, Modi G:

Epilepsia 2009; 50 (5): 1266-1269

In HIV patients, new-onset seizure is a nonspecific manifestation, often reflecting advanced HIV infection or AIDS.

Background: New-onset seizures (NOS) in HIV infection may be caused by focal brain lesions (FBLs), meningitis, or metabolic derangements, or there may be no identified cause (NIC). From a clinical standpoint, no clear relationship has been established between HIV and NOS. Objective: To characterize the relationship between HIV and NOS in terms of seizure type, CD4 counts, and viral loads (blood and CSF). Methods: Consecutive adult HIV-1 positive patients with NOS were recruited over a 1-year period. All patients underwent clinical exam, imaging studies, EEG, and complete blood and CSF analysis. Results: 37 HIV patients with NOS were recruited. All patients were black and heterosexual and did not use intravenous drugs. They were antiretroviral (ARV) treatment naïve, as ARV rollout in South-African public hospitals had not yet taken place at the time of the study. Twenty-one patients (57%) had FBL, 6 (16%) had meningitis, and 10 (27%) had NIC. No patients had significant metabolic derangements to account for the seizures. Of the 21 patients with FBL, 14 (66%) had tuberculomas, 3 (14%) had neurocysticercosis, 2 (10%) had cerebral infarcts, 1 (2%) had toxoplasmosis, and 1 (5%) had multifocal leukoencephalopathy. Of the 6 patients with meningitis, 3 (50%) had tuberculous meningitis, and 1 each had cryptococcal meningitis, syphilitic meningitis, and viral meningitis, respectively. Seizure semiology data were as follows: 24 (65%) generalized, 9 (24%) focal, and 4 (11%) status epilepticus. All 10 patients with NIC had generalized seizures. All 4 patients with status epilepticus had FBLs. One-half of the patients with FBLs had generalized seizures, and one-third had focal seizures. Two-thirds of meningitis patients had generalized seizures, and the rest had focal seizures. The median CD4 count was 104 cells/mL and was comparable across subgroups. The blood and CSF viral loads were also similar in all subgroups. Conclusions: New-onset seizure in HIV patients is a nonspecific manifestation of brain injury and usually reflects an advanced HIV infection or AIDS. Reviewer's Comments: The findings in this study are not really surprising, as HIV and AIDS-defining infections cause widespread, diffuse, or multifocal cerebral damage. The interesting finding, however, is the absence of focal onset of seizures in HIV patients with no identifiable cause. One possible reason for this finding is that the EEGs were performed interictally, thus reducing the overall yield. It is likely that patients with no identifiable causes may have a mild form of HIV encephalopathy; long-term outcome in these patients should be interesting, as it is possible that they may go on to develop HIV dementia. (Reviewer-Chitharanjan Rao, MD).

Keywords: HIV, AIDS, Seizures, Viral Loads, CD4 Count, Status Epilepticus, Dementia, Encephalopathy

Print Tag: Refer to original journal article