DANGEROUS DELAY—THE MISDIAGNOSIS OF SPONTANEOUS INTRACRANIAL HYPOTENSION

Spontaneous intracranial hypotension—an important cause of “new daily persistent headaches”—is not a well-recognized clinical entity. Misdiagnosis of spontaneous intracranial hypotension is frequent, and these misdiagnoses can have serious consequences for patients, according to Wouter I. Schievink, MD. “The typical patient with spontaneous intracranial hypotension has a headache that occurs or worsens soon after assuming an upright position and disappears or improves after resuming a recumbent position,” said Dr. Schievink, of the Maxine Dunitz Neurosurgical Institute at Cedars-Sinai Medical Center in Los Angeles. The onset is usually gradual but may be acute; severity varies from mild to incapacitating. Nausea, vomiting, photophobia, and posterior neck pain or stiffness are commonly associated symptoms, he added. “Effective treatment is available,” he noted, “and the risks of treatment for the variety of conditions that may mimic spontaneous intracranial hypotension are significant.” Dr. Schievink therefore investigated diagnostic delay in a cohort of patients with spontaneous intracranial hypotension. The results were reported in the December 2003 Archives of Neurology.

During the 18-month study period, 18 patients (15 women; mean age, 38) were identified as having a spontaneous spinal cerebrospinal fluid (CSF) leak documented by computed tomography. Treatment consisted of surgical repair of the CSF leak in 13 patients and nonsurgical management in five patients. All patients had a positional headache at initial examination, Dr. Schievink reported; however, only one patient was diagnosed as having spontaneous intracranial hypotension at the first physician encounter.

Of the other 17 patients, initially incorrect diagnoses included migraine, meningitis, various other headache types, posterior cervical strain, subarachnoid hemorrhage, transient ischemic attack, subdural hematoma, and psychogenic effects. These patients sought attention from one to six physicians before the correct diagnosis was made. A total of 33 working diagnoses were made; these included chiari malformation, ocular myasthenia gravis, and cervical radiculopathy.

The delay to correct diagnosis ranged from four days to 13 years, Dr. Schievink said. During this period, diagnostic procedures associated with risk that were performed on these patients included cerebral autobiography, craniotomy with meningeal biopsy, and transesophageal echocardiography. Erroneous diagnoses also resulted in craniotomies for decompression of cerebella tonsillar descent and evacuation of subdural fluid collection.

“These data clearly show that for most patients with spontaneous intracranial hypotension, the diagnosis is missed initially and the diagnostic delay is significant,” said Dr. Schievink. “This exposes patients to risks associated with treatment for the disorders that can mimic intracranial hypotension.” While he acknowledged that spontaneous intracranial hypotension “is rare among patients with headache complaints,” Dr. Schievink concluded that it is “an important diagnostic consideration for patients with ‘new daily persistent headaches’ ” and that “increasing the awareness of this spontaneous form of positional headache will likely result in fewer patients in whom the diagnosis is missed.”

Schievink WI. Misdiagnosis of spontaneous intracranial hypotension. Arch Neurol. 2003;60:1713-1718.

THE GENETICS AND ENVIRONMENT OF ISCHEMIC STROKE

“In certain combinations, pairing of common unfavorable genetic factors, which alone confer only minor or non-significant risk, with clinical risk factors can greatly increase the susceptibility to ischemic stroke,” concluded the authors of a report on the interaction of genotype and “classical clinical risk factors for ischemic stroke” in the December 2003 Journal of Neurology, Neurosurgery, and Psychiatry.

The investigators analyzed the data on 867 consecutive Caucasian Hungarian patients with acutely developing ischemic stroke and no history of stroke events. These data were compared to those of 743 randomly selected, age- and sex-matched healthy Hungarian controls. All subjects in the stroke group underwent detailed clinical scrutiny, including medical history, family anamnesis, an evaluation of vascular risk factors, general physical and neurologic examination, and other testing and examinations. Smoking and drinking habits and the presence of hypertension or diabetes mellitus were recorded for all participants, as were serum cholesterol level, serum triglyceride level, platelet count, and hematocrit. The Factor V Leiden G1691A (Leiden V), the prothrombin G20210A, the methylenetetrahydrofolate reductase C677T (MTHFR C677T) mutations, the angiotensin-converting enzyme I/D (ACE I/D), and apolipoprotein E epsilon4 (APOE epsilon4) genotypes were examined by polymerase chain reaction technique.

The investigators found that mean body mass index, serum cholesterol level, and serum triglyceride level were all significantly higher in the stroke group than the control group. Hypertension, diabetes, ischemic heart disease, smoking, and drinking also occurred more frequently among stroke patients than controls, they reported. The frequency of APOE epsilon4 was significantly higher in the stroke patients than in the controls; no other genotype was associated with a significant increase in risk of ischemic stroke.

In combination with hypertension or diabetes, the Leiden V mutation increased the relative risk of ischemic stroke. The ACE D/D and homozygous MTHFR 677TT mutations “exerted synergistic effects in combination with drinking or smoking in the development of ischemic stroke.” APOE epsilon4 increased the unfavorable influences of hypertension, diabetes, smoking, and drinking on the incidence of ischemic stroke, the investigators reported.

The findings “suggest some general rules for the interactions of the examined common genetic mutations and common clinical risk factors at the phenotype level,” the researchers said. “Genetic factors that are minor or insignificant when present alone can not only exert an additive effect, but also facilitate the effects of other common clinical risk factors at a clinical phenotype level. Their co-occurrence in the same subject can, therefore, give rise to a highly significant relative risk of an ischemic stroke.”

Szolnoki Z, Somogyvári F, Kondacs A, et al. Evaluation of the modifying effects of unfavorable genotypes on classical clinical risk factors for ischemic stroke. J Neurol Neurosurg Psychiatry. 2003;74:1615-1620.

BIOMARKERS FOR ALZHEIMER’S DISEASE CORRELATE WITH AUTOPSY CONFIRMED DIAGNOSES

Cerebrospinal fluid (CSF) tau and ß-amyloid were shown to be associated with Alzheimer’s disease pathology and can help discriminate Alzheimer’s disease from other dementing disorders, according to a report in the December 2003 Archives of Neurology. However, the researchers from the University of Pennsylvania in Philadelphia noted, the biomarkers were “less helpful in identifying patients with Alzheimer’s disease with concomitant Lewy bodies or in differentiating Alzheimer’s disease from prion diseases.”

The investigators examined a cohort of 107 patients undergoing a clinical evaluation for dementia, four pathologically confirmed normal elderly subjects, and 69 cognitively normal elderly subjects with two to eight years follow-up since lumbar puncture. All participants received a standard neurologic evaluation, including cognitive testing. Additional clinical and laboratory tests were performed at the discretion of the evaluating physician. CSF was obtained by standard clinical procedures and assayed for tau and ß-amyloid peptides. Seventy-four patients were diagnosed with Alzheimer’s disease; of these, 10 had Lewy body variant Alzheimer’s disease, three had an amyloid precursor protein mutation, and one had a presenilin 2 mutation. Eight patients had prion disease. Eleven patients had clinical signs and symptoms of dementia categorized as “other.”

Mean tau level was 612 pg/mL for the 74 patients with Alzheimer’s disease, 272 pg/mL for 10 patients with frontal dementia, 282 pg/mL for three patients with Lewy body dementia, and 140 pg/mL for 73 cognitively normal control subjects. The definitive diagnosis regarding the efficacy of tau and ß-amyloid as biomarkers for Alzheimer’s disease was based on the findings at autopsy, the researchers said. When using a cutoff value of 234 pg/mL, CSF tau had a sensitivity of 85%, specificity of 84%, positive predictive value of 87%, and positive likelihood ratio of 5.3 to correctly distinguish patients with Alzheimer’s disease from cognitively normal control subjects, they noted.

The investigators also reported that ß-amyloid was reduced in patients with Alzheimer’s disease (61 fmol/mL) compared with patients with frontal dementia (133 fmol/mL) and control subjects (109 fmol/mL), but not compared with patients with Lewy body dementia (14 fmol/mL) or prion disease (60 fmol/mL). “While we found the expected reduced ß-amyloid in the Alzheimer’s disease cohort compared with cognitively normal subjects, the addition of this information did not add to the diagnostic value of tau,” they stated.

The study “confirmed an association between elevated CSF tau levels premortem and the pathological hallmarks of Alzheimer’s disease, indicating that high CSF tau levels, in the appropriate clinical setting, strongly supports a diagnosis of Alzheimer’s disease,” they concluded, adding that “CSF tau level may be helpful in distinguishing Alzheimer’s disease from other forms of dementia, including neurodegenerative disorders such as frontal dementia and Lewy body dementia.”

Clark CM, Xie S, Chittams J, et al. Cerebrospinal fluid tau and ß-amyloid: how well do these biomarkers reflect autopsy-confirmed dementia diagnoses? Arch Neurol. 2003;60:1696-1702.

BRAIN DIFFERENCES BETWEEN DOWN SYNDROME AND ALZHEIMER’S DISEASE PRIOR TO ONSET OF DEMENTIA

The initial results of an ongoing longitudinal study of brain metabolism in Down syndrome and Alzheimer’s disease revealed that—contrary to the predictions of the researchers—there are significant differences in metabolic deterioration between the respective diseases. Investigators from the University of California, Irvine, compared imaging studies of 17 persons with Down syndrome (11 men; age range, 34 to 51) who showed an absence of dementia as determined by the Dementia Scale for Down Syndrome and the Dementia Questionnaire for Mentally Retarded Persons, to 10 persons with moderate Alzheimer’s disease (seven men; age range, 64 to 86) with Mini-Mental State Examination scores ranging from 9 to 24 (mean, 18.3) who met DSM-IV criteria for Alzheimer’s disease. The patients with Down syndrome were compared to 12 age- and sex-matched healthy controls, and the patients with Alzheimer’s disease were compared to a separate group of 12 age- and sex-matched healthy controls.

The investigators determined regional cerebral glucose metabolic rate (GMR) using [18F]fluorodeoxyglucose positron emission tomography (FDG PET). Because of the similarity of the dementia seen in Alzheimer’s disease and Down syndrome, their expectation was that “the disease process should start in similar places in the brain and progress through similar patterns of change for both groups, although the process might be accelerated in those with Down syndrome.” They found that, compared with their matched controls, GMR was lower in the Alzheimer’s disease group and in the Down syndrome group in the left fusiform gyrus/Brodmann area 37 and in the left posterior cingulated/Brodmann area 31. However, in multiple areas of the inferior temporal cortex, including the entorhinal cortex (one of the areas affected earliest by Alzheimer’s disease), GMR was significantly lower in the Alzheimer’s group compared with their controls but was significantly higher in the Down syndrome group compared with their controls.

According to the researchers, one possible explanation for this relative hypermetabolism observed in individuals with Down syndrome is that it represents “very early events in the development of Alzheimer’s disease–like neuropathology” prior to overt cell loss. “Whereas in normal brains, neurons may work efficiently, damaged neurons may have to work harder to maintain their effectiveness, as reflected as an increase in metabolic rate,” they postulated. “This may partially explain the puzzle of how people with Down syndrome maintain cognitive function, despite the presence of Alzheimer’s disease–like pathology.” Further investigation in the longitudinal study is required to determine whether this relative hypermetabolism is unique to Down syndrome or an indication of early-stage Alzheimer’s dementia, the researchers concluded in the December 23, 2003 Neurology.

Haier RJ, Alkire MT, White NS, et al. Temporal cortex hyper-metabolism in Down syndrome prior to the onset of dementia. Neurology. 2003;61:1673-1679.

THE AMYGDALA AND SEX DRIVE—INSIGHTS FROM EPILEPSY SURGERY

Patients who underwent temporal lobe resection and reported a postoperative increase in sex drive have a larger contralateral amygdalar volume than do those who reported a decrease in sex drive or no change. In addition, the mean contralateral amygdalar volume in the sexual increase group was significantly greater than that of the corresponding amygdala in controls, according to a report in the January issue of Annals of Neurology.

“We have demonstrated an association between preoperative amygdalar volume contralateral to the side of resection and postoperative sexual change in patients undergoing temporary lobe resection,” reported Amee D. Baird, of the University of Melbourne, and colleagues. “This finding provides evidence for an important role of the amygdala in regulating human sexual behavior. A larger contralateral amygdala may contribute to the expression of increased or improved sexuality after temporal lobe resection.” The researchers also pointed out that their findings occurred irrespective of side or type of temporal resection and pathology and that there was a significant positive relationship between contralateral amygdalar volume and the maximum degree of sexual change.

The researchers compared amygdalar volume in groups of patients with or without sexual changes after temporal lobe resection and in age-matched neurologically normal subjects. A total of 45 patients with intractable temporal lobe epilepsy who underwent surgical resection completed an interview and questionnaire relating to sexual outcome after surgery. Volumetric analyses of both amygdalae were conducted on the patients’ preoperative T1-weighted MRI scans and those of 46 neurologically healthy controls.

The investigators believe that their observation that a preexisting large contralateral amygdala causes predisposition to postoperative sexual increase suggests that this is a trait rather than state association. Previous studies have found enlarged amygdalar volumes in patients with a range of affective disorders.

“In our study, we found no difference in amygdalar volumes between patients with or without preoperative or postoperative psychiatric morbidity,” the authors wrote. “This suggests that our finding of larger contralateral amygdalar volumes in patients with a postoperative sexual increase cannot be accounted for by the presence of affective disorders in these patients.”

NR

Baird AD, Wilson SJ, Bladin PF, et al. The amygdala and sexual drive: insights from temporal lobe epilepsy surgery. Ann Neurol. 2004;55:87-96.

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