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Clinical Reasoning: An unusual cause of indeterminate spells

2016-12-05T12:45:30-08:00

A 38-year-old, right-handed woman presented to the epilepsy clinic for evaluation of recurrent spells. These spells are characterized by an aura of a "rushing" cephalic sensation and a sense of "spaciness" or "dizziness" followed by loss of awareness with subsequent amnesia for the event. During these events, the patient is observed by family to sit down and slump forward or fall, followed by hyperventilation and occasionally staring, for up to 3 minutes. There is no head turn, eye deviation, or abnormal body movements. Postictally, she reports generalized weakness without focality and confusion. The spells occurred sporadically for 8 years, but recently increased in frequency to 5 to 20 times per day. Triggers included lack of sleep, stress, and various food products. The patient reported some improvement with levetiracetam therapy at 1,500 mg twice daily.




Teaching NeuroImages: Cytomegalovirus infection mimicking a brain tumor in a kidney transplant recipient

2016-12-05T12:45:30-08:00

A 62-year-old man presented with a 7-day history of progressive headache and right-sided weakness. The patient was a kidney transplant recipient, 16 years ago, because of diabetic nephropathy. Medications included prednisone and mycophenolate mofetil. Examination revealed right hemiparesis. Brain MRI showed a frontal space-occupying lesion on the left side (figure 1). Serology results were noncontributory. Biopsy was inconclusive. Surgery was performed, and pathology confirmed cytomegalovirus (CMV) infection (figure 2). The patient improved after receiving ganciclovir.




Teaching NeuroImages: Nonfluent variant primary progressive aphasia: A distinctive clinico-anatomical syndrome

2016-12-05T12:45:30-08:00

A 66-year-old woman presented with 4 years of progressive speech difficulty. She had nonfluent speech with phonemic errors but intact single-word comprehension and object knowledge. Her grammar was impaired in both speech and writing, and she exhibited orofacial apraxia. A clinico-radiologic (see figure) diagnosis of nonfluent variant primary progressive aphasia was made.




Teaching NeuroImages: Multicompartmental intracranial hemorrhage in a pediatric patient

2016-12-05T12:45:30-08:00

A previously healthy 9-year-old girl presented with sudden-onset headache followed by confusion. In the emergency department, she was hypertensive, bradycardic, and no longer responsive to any stimuli. An emergent head CT scan demonstrated a left frontal intraparenchymal hematoma with intraventricular and subarachnoid extension as well as subfalcine herniation (figure). She underwent decompressive hemicraniectomy, and digital subtraction angiography confirmed a 7-mm left middle cerebral artery aneurysm (figure).




Spotlight on the December 6 issue

2016-12-05T12:45:30-08:00




Statistics and the detection of scientific misconduct

2016-12-05T12:45:30-08:00

The paper by Bolland et al.1 in this issue had a longer "gestation" than usual at Neurology®; it was received on December 4, 2015. We usually review on a tight timeline and publish important work quickly. But this manuscript has a different focus as it presents a statistical analysis that demonstrates probable scientific misconduct (fraud) on a large scale. It is also unique in that its analysis uses complicated methods that may be beyond what most readers are willing to tackle. However, the bottom line is simple: there are statistical methods that, when properly applied, can detect fraudulent behavior by investigators. Clinical trial data can thereby be validated or called into question. In this instance, analysis of a collection of studies by a large research group suggested that at least some of the studies were likely to be fraudulent.




Predicting which NF1 optic pathway gliomas will require treatment

2016-12-05T12:45:30-08:00

Since Riccardi's1 landmark article in 1981 delineating the clinical manifestations of what we now call neurofibromatosis type 1 (NF1) and neurofibromatosis type 2, we have made great strides in our understanding of the genetic and molecular underpinnings of these distinct conditions. This knowledge has led to the emergence of plausible biologic agents that target specific points in ras-activated downstream pathways for the treatment of various complications of NF1, such as plexiform neurofibromas and optic pathway gliomas (OPGs).2 Yet, despite this progress, clinicians caring for these children continue to struggle with more basic questions, such as how best to follow these individuals and when to intervene. This is most evident in the care of children with NF1 OPGs.




Systematic review and statistical analysis of the integrity of 33 randomized controlled trials

2016-12-05T12:45:30-08:00

Background:

Statistical techniques can investigate data integrity in randomized controlled trials (RCTs). We systematically reviewed and analyzed all human RCTs undertaken by a group of researchers, about which concerns have been raised.

Methods:

We compared observed distributions of p values for between-groups differences in baseline variables, for standardized sample means for continuous baseline variables, and for differences in treatment group participant numbers with the expected distributions. We assessed productivity, recruitment rates, outcome data, textual consistency, and ethical oversight.

Results:

The researchers were remarkably productive, publishing 33 RCTs over 15 years involving large numbers of older patients with substantial comorbidity, recruited over very short periods. Treatment groups were improbably similar. The distribution of p values for differences in baseline characteristics differed markedly from the expected uniform distribution (p = 5.2 x 10–82). The distribution of standardized sample means for baseline continuous variables and the differences between participant numbers in randomized groups also differed markedly from the expected distributions (p = 4.3 x 10–4, p = 1.5 x 10–5, respectively). Outcomes were remarkably positive, with very low mortality and study withdrawals despite substantial comorbidity. There were very large reductions in hip fracture incidence, regardless of intervention (relative risk 0.22, 95% confidence interval 0.15–0.31, p < 0.0001, range of relative risk 0.10–0.33), that greatly exceed those reported in meta-analyses of other trials. There were multiple examples of inconsistencies between and within trials, errors in reported data, misleading text, duplicated data and text, and uncertainties about ethical oversight.

Conclusions:

A systematic approach using statistical techniques to assess randomization outcomes can evaluate data integrity, in this case suggesting these RCT results may be unreliable.




Optic pathway glioma volume predicts retinal axon degeneration in neurofibromatosis type 1

2016-12-05T12:45:30-08:00

Objective:

To determine whether tumor size is associated with retinal nerve fiber layer (RNFL) thickness, a measure of axonal degeneration and an established biomarker of visual impairment in children with optic pathway gliomas (OPGs) secondary to neurofibromatosis type 1 (NF1).

Methods:

Children with NF1-OPGs involving the optic nerve (extension into the chiasm and tracts permitted) who underwent both volumetric MRI analysis and optical coherence tomography (OCT) within 2 weeks of each other were included. Volumetric measurement of the entire anterior visual pathway (AVP; optic nerve, chiasm, and tract) was performed using high-resolution T1-weighted MRI. OCT measured the average RNFL thickness around the optic nerve. Linear regression models evaluated the relationship between RNFL thickness and AVP dimensions and volume.

Results:

Thirty-eight participants contributed 55 study eyes. The mean age was 5.78 years. Twenty-two participants (58%) were female. RNFL thickness had a significant negative relationship to total AVP volume and total brain volume (p < 0.05, all comparisons). For every 1 mL increase in AVP volume, RNFL thickness declined by approximately 5 microns. A greater AVP volume of OPGs involving the optic nerve and chiasm, but not the tracts, was independently associated with a lower RNFL thickness (p < 0.05). All participants with an optic chiasm volume >1.3 mL demonstrated axonal damage (i.e., RNFL thickness <80 microns).

Conclusions:

Greater OPG and AVP volume predicts axonal degeneration, a biomarker of vision loss, in children with NF1-OPGs. MRI volumetric measures may help stratify the risk of visual loss from NF1-OPGs.




Long-term treatment of epilepsy with everolimus in tuberous sclerosis

2016-12-05T12:45:30-08:00

Objective:

To evaluate the long-term benefit and safety of everolimus for the treatment of medically refractory epilepsy in patients with tuberous sclerosis complex (TSC).

Methods:

Everolimus was titrated over 4 weeks and continued an additional 8 weeks in a prospective, open-label, phase I/II clinical trial design. Participants demonstrating initial benefit continued treatment until study completion (48 months). The primary endpoint was percentage of patients with a ≥50% reduction in seizure frequency compared to baseline. Secondary endpoints assessed absolute seizure frequency, adverse events (AEs), behavior, and quality of life.

Results:

Of the 20 participants who completed the initial study phase, 18 continued extended treatment. Fourteen of 18 (78%) participants completed the study, all but 1 of whom reported ≥50% reduction in seizure frequency at 48 months. All participants reported at least 1 AE, the vast majority (94%) of which were graded mild or moderate severity. Improvements in behavior and quality of life were also observed, but failed to achieve statistical significance at 48 months.

Conclusions:

Improved seizure control was maintained for 4 years in the majority of patients with TSC with medically refractory epilepsy treated with everolimus. Long-term treatment with everolimus is safe and well-tolerated in this population. Everolimus may be a therapeutic option for refractory epilepsy in TSC.

Classification of evidence:

This study provides Class IV evidence that for patients with TSC with medically refractory epilepsy everolimus improves seizure control.




Proportion of single-chain recombinant tissue plasminogen activator and outcome after stroke

2016-12-05T12:45:30-08:00

Objective:

To determine whether the ratio single chain (sc)/(sc + 2 chain [tc]) recombinant tissue plasminogen activator (rtPA) influences outcomes in patients with cerebral ischemia.

Methods:

We prospectively included consecutive patients treated with IV rtPA for cerebral ischemia in 13 stroke centers and determined the sc/(sc + tc) ratio in the treatment administered to each patient. We evaluated the outcome with the modified Rankin Scale (mRS) at 3 months (prespecified analysis) and occurrence of epileptic seizures (post hoc analysis). We registered Outcome of Patients Treated by IV Rt-PA for Cerebral Ischaemia According to the Ratio Sc-tPA/Tc-tPA (OPHELIE) under ClinicalTrials.gov identifier no. NCT01614080.

Results:

We recruited 1,004 patients (515 men, median age 75 years, median onset-to-needle time 170 minutes, median NIH Stroke Scale score 10). We found no statistical association between sc/(sc + tc) ratios and handicap (mRS > 1), dependency (mRS > 2), or death at 3 months. Patients with symptomatic intracerebral hemorrhages had lower ratios (median 69% vs 72%, adjusted p = 0.003). The sc/(sc + tc) rtPA ratio did not differ between patients with and without seizures, but patients with early seizures were more likely to have received a sc/(sc + tc) rtPA ratio >80.5% (odds ratio 3.61; 95% confidence interval 1.26–10.34).

Conclusions:

The sc/(sc + tc) rtPA ratio does not influence outcomes in patients with cerebral ischemia. The capacity of rtPA to modulate NMDA receptor signaling might be associated with early seizures, but we observed this effect only in patients with a ratio of sc/(sc + tc) rtPA >80.5% in a post hoc analysis.




A human brain network derived from coma-causing brainstem lesions

2016-12-05T12:45:30-08:00

Objective:

To characterize a brainstem location specific to coma-causing lesions, and its functional connectivity network.

Methods:

We compared 12 coma-causing brainstem lesions to 24 control brainstem lesions using voxel-based lesion-symptom mapping in a case-control design to identify a site significantly associated with coma. We next used resting-state functional connectivity from a healthy cohort to identify a network of regions functionally connected to this brainstem site. We further investigated the cortical regions of this network by comparing their spatial topography to that of known networks and by evaluating their functional connectivity in patients with disorders of consciousness.

Results:

A small region in the rostral dorsolateral pontine tegmentum was significantly associated with coma-causing lesions. In healthy adults, this brainstem site was functionally connected to the ventral anterior insula (AI) and pregenual anterior cingulate cortex (pACC). These cortical areas aligned poorly with previously defined resting-state networks, better matching the distribution of von Economo neurons. Finally, connectivity between the AI and pACC was disrupted in patients with disorders of consciousness, and to a greater degree than other brain networks.

Conclusions:

Injury to a small region in the pontine tegmentum is significantly associated with coma. This brainstem site is functionally connected to 2 cortical regions, the AI and pACC, which become disconnected in disorders of consciousness. This network of brain regions may have a role in the maintenance of human consciousness.




Comment: Coma-causing brainstem lesions

2016-12-05T12:45:30-08:00

Arousal, or wakefulness, is an integral component of consciousness and prerequisite for other brain functions, yet its neuroanatomy in humans is poorly understood. Classically, the brainstem "reticular formation" has been considered important for wakefulness.1 Experiments in rodents suggest this brainstem area can be subdivided into functionally discrete regions, and that injury to one region in the pontine tegmentum reliably disrupts arousal and produces coma.2 A homologous brainstem region is likely present in humans, based on analysis of coma-causing lesions.3 However, it remains unclear whether there is a human brainstem site significantly more associated with coma-causing lesions than with non–coma-causing lesions, and exactly where this site is located. Such a brainstem site would likely maintain arousal through ascending projections to other brain regions (originally termed the ascending reticular activating system, or ARAS),1,4 but this network of brain regions in humans is also unclear.




Feasibility of the collection of patient-reported outcomes in an ambulatory neurology clinic

2016-12-05T12:45:30-08:00

Objective:

To determine whether patients could self-report physical and mental health assessments in the waiting room and whether these assessments would be associated with modified Rankin Scale (mRS) and Quality of Life in Epilepsy (QOLIE-10) scores.

Methods:

We offered iPad-based surveys to consecutive adult neurology patients at check-in to collect patient-reported outcome measures (PROMs). We collected demographic and clinical data on 6,075 patients through survey or administrative claims and PROMs from participating patients. We compared demographic characteristics of participants and nonparticipants and tested associations between physical and mental health scores and mRS and QOLIE-10.

Results:

Of 6,075 patients seen by neurologists during the study period, 2,992 (49.3%) participated in the survey. Compared to nonparticipating patients, participating patients more often were privately insured (53.5% vs 42.7%, p < 0.01), married (51.5% vs 47.9%, p < 0.01), and seen in general neurology (nonsubspecialty) clinics (53.1% vs 46.6%, p < 0.01) and more likely to report English as their preferred language (50.1% vs 38.4%, p < 0.01). Participating patients had a mean physical health T score of 28.7 (SD 15) and mental health T score of 33 (SD 15), which were 3 and 2 SD worse than the average for the US general population, respectively. Mean T scores in every category of the mRS were different from every other category (n = 232, p < 0.01). Patient Reported Outcomes Measurement Information System-10 T scores were linearly associated with QOLIE-10 scores (n = 202, p < 0.01)

Conclusions:

Systematic digital collection of PROMs is feasible. Differences among survey participants and nonparticipants highlight the need to develop multilingual measurement tools that may improve collection from vulnerable populations.




Asymptomatic Alzheimer disease: Defining resilience

2016-12-05T12:45:30-08:00

Objective:

To define robust resilience metrics by leveraging CSF biomarkers of Alzheimer disease (AD) pathology within a latent variable framework and to demonstrate the ability of such metrics to predict slower rates of cognitive decline and protection against diagnostic conversion.

Methods:

Participants with normal cognition (n = 297) and mild cognitive impairment (n = 432) were drawn from the Alzheimer’s Disease Neuroimaging Initiative. Resilience metrics were defined at baseline by examining the residuals when regressing brain aging outcomes (hippocampal volume and cognition) on CSF biomarkers. A positive residual reflected better outcomes than expected for a given level of pathology (high resilience). Residuals were integrated into a latent variable model of resilience and validated by testing their ability to independently predict diagnostic conversion, cognitive decline, and the rate of ventricular dilation.

Results:

Latent variables of resilience predicted a decreased risk of conversion (hazard ratio < 0.54, p < 0.0001), slower cognitive decline (β > 0.02, p < 0.001), and slower rates of ventricular dilation (β < –4.7, p < 2 x 10–15). These results were significant even when analyses were restricted to clinically normal individuals. Furthermore, resilience metrics interacted with biomarker status such that biomarker-positive individuals with low resilience showed the greatest risk of subsequent decline.

Conclusions:

Robust phenotypes of resilience calculated by leveraging AD biomarkers and baseline brain aging outcomes provide insight into which individuals are at greatest risk of short-term decline. Such comprehensive definitions of resilience are needed to further our understanding of the mechanisms that protect individuals from the clinical manifestation of AD dementia, especially among biomarker-positive individuals.




Sleep problems and hypothalamic dopamine D3 receptor availability in Parkinson disease

2016-12-05T12:45:30-08:00

Objective:

To investigate the relationship between hypothalamic D3 dopamine receptor availability and severity of sleep problems in Parkinson disease (PD).

Methods:

Twelve patients were assessed with PET and the high-affinity dopamine D3 receptor radioligand [11C]-propyl-hexahydro-naphtho-oxazin ([11C]-PHNO). Severity of sleep problems was rated with appropriate subitems of the Unified Parkinson's Disease Rating Scale part I (patient questionnaire) and the Epworth Sleepiness Scale.

Results:

We found that lower dopamine D3 receptor availability measured with [11C]-PHNO PET was associated with greater severity of excessive daytime sleepiness but not with problems of falling asleep or insomnia.

Conclusion:

In our cohort of patients with PD, the occurrence of excessive daytime sleepiness was linked to reductions in hypothalamic dopamine D3 receptor availability. If these preliminary findings are confirmed in larger cohorts of patients with polysomnographic characterization, selective pharmacologic modulation of the dopaminergic D3 system could be used to increase daytime alertness in patients with PD.




Clinical spectrum of Castleman disease-associated neuropathy

2016-12-05T12:45:30-08:00

Objective:

To define the peripheral neuropathy phenotypes associated with Castleman disease.

Methods:

We conducted a retrospective chart review for patients with biopsy-proven Castleman disease evaluated between January 2003 and December 2014. Patients with associated peripheral neuropathy were identified and divided into 2 groups: those with Castleman disease without POEMS syndrome (CD-PN) and those with Castleman disease with POEMS syndrome (CD-POEMS). We used a cohort of patients with POEMS as controls. Clinical, electrodiagnostic, and laboratory characteristics were collected and compared among patient subgroups.

Results:

There were 7 patients with CD-PN, 20 with CD-POEMS, and 122 with POEMS. Patients with CD-PN had the mildest neuropathy characterized by predominant sensory symptoms with no pain and mild distal sensory deficits (median Neuropathy Impairment Score of 7 points). Although both patients with CD-POEMS and patients with POEMS had a severe sensory and motor neuropathy, patients with CD-POEMS were less affected (median Neuropathy Impairment Score of 33 and 66 points, respectively). The degree of severity was also reflected on electrodiagnostic testing in which patients with CD-PN demonstrated a mild degree of axonal loss, followed by patients with CD-POEMS and then those with POEMS. Demyelinating features, defined by European Federation of Neurologic Societies/Peripheral Nerve Society criteria, were present in 43% of the CD-PN, 78% of the CD-POEMS, and 86% of the POEMS group.

Conclusion:

There is a spectrum of demyelinating peripheral neuropathies associated with Castleman disease. CD-PN is sensory predominant and is the mildest phenotype, whereas CD-POEMS is a more severe sensory and motor neuropathy. Compared to the POEMS cohort, those with CD-POEMS neuropathy have a similar but less severe phenotype. Whether these patients respond differently to treatment deserves further study.




Gray matter MRI differentiates neuromyelitis optica from multiple sclerosis using random forest

2016-12-05T12:45:30-08:00

Objective:

We tested whether brain gray matter (GM) imaging measures can differentiate between multiple sclerosis (MS) and neuromyelitis optica (NMO) using random-forest classification.

Methods:

Ninety participants (25 patients with MS, 30 patients with NMO, and 35 healthy controls [HCs]) were studied in Tehran, Iran, and 54 (24 patients with MS, 20 patients with NMO, and 10 HCs) in Padua, Italy. Participants underwent brain T1 and T2/fluid-attenuated inversion recovery MRI. Volume, thickness, and surface of 50 cortical GM regions and volumes of the deep GM nuclei were calculated and used to construct 3 random-forest models to classify patients as either NMO or MS, and separate each patient group from HCs. Clinical diagnosis was the gold standard against which the accuracy was calculated.

Results:

The classifier distinguished patients with MS, who showed greater atrophy especially in deep GM, from those with NMO with an average accuracy of 74% (sensitivity/specificity: 77/72; p < 0.01). When we used thalamic volume (the most discriminating GM measure) together with the white matter lesion volume, the accuracy of the classification of MS vs NMO was 80%. The classifications of MS vs HCs and NMO vs HCs achieved higher accuracies (92% and 88%).

Conclusions:

GM imaging biomarkers, automatically obtained from clinical scans, can be used to distinguish NMO from MS, even in a 2-center setting, and may facilitate the differential diagnosis in clinical practice.

Classification of evidence:

This study provides Class II evidence that GM imaging biomarkers can distinguish patients with NMO from those with MS.




NMDA receptor encephalitis and other antibody-mediated disorders of the synapse: The 2016 Cotzias Lecture

2016-12-05T12:45:30-08:00

Investigations during the last 10 years have revealed a group of disorders mediated by antibodies against ion channels and synaptic receptors, which cause both neurologic and psychiatric symptoms. In this review, I discuss the process of discovery and immunologic triggers of these disorders, and use anti-NMDA receptor encephalitis to emphasize the importance of understanding the underlying physiopathologic mechanisms in those diseases. A better knowledge of these mechanisms reveals points of convergence with other disorders (e.g., schizophrenia), suggests treatment strategies beyond immunotherapy, and is helping us understand how memories are formed and retrieved.




What can we do for people with drug-resistant epilepsy?: The 2016 Wartenberg Lecture

2016-12-05T12:45:30-08:00

Treatment goals for epilepsy are no seizures, no side effects, as soon as possible, but these goals are too often unmet. Approximately 1 million people in the United States continue to have seizures despite adequate treatment with antiseizure drugs, representing 40% of those with epilepsy, and 80% of the cost of epilepsy. Drug-resistant epilepsy (DRE) can be associated with developmental delay in infants and young children, and severe disability and morbidity in older children and adults, as well as a mortality rate 5–10 times that of the general population. While diagnosis and treatment at a full-service (levels 3 and 4) epilepsy center are demonstrated to improve seizure control, fewer than 1% of people with DRE are referred, and those who are, are referred an average of over 20 years after onset of habitual seizures. A possible reason for this is the misconception that all these epilepsy centers offer is surgery. Specialized multidisciplinary teams, consisting of neurologists, clinical neurophysiologists, neurosurgeons, neuroradiologists, psychologists, psychiatrists, social workers, and counselors, which constitute full-service epilepsy centers, can recognize and address pseudopharmacoresistance due to nonadherence, seizures that are not epilepsy, treatable underlying conditions, misdiagnosis of epilepsy syndromes, treatment with the wrong drug or wrong dosage, and lifestyle issues that are remediable. A variety of alternative treatment approaches are offered in addition to surgery, and for patients who continue to have seizures, full-service epilepsy centers have psychologists, psychiatrists, social workers, and counselors specialized in recognizing, and addressing, the psychological and social challenges experienced by people with epilepsy. Surgery for epilepsy remains, arguably, the most underutilized of all acceptable medical interventions, and the reasons for this are unclear. Often, excellent surgical candidates are not recognized as such by general neurologists, but if more patients with DRE were referred to full-service epilepsy centers, more surgical candidates would be identified by epilepsy specialists. All patients with medication-resistant epilepsy, defined as failure of 2 appropriate trials of antiseizure drugs due to inefficacy and not intolerance, who continue to be compromised by seizures deserve a timely consultation at a full-service epilepsy center. Early referral provides the best opportunity to avoid irreversible psychological and social problems, a lifetime of disability, and premature death.




Changes of optic nerve head induced by eye movement

2016-12-05T12:45:30-08:00

Flashes of light or phosphenes are the sensation of light without light actually entering the eye. This phenomenon can be evoked by stimulation of the retina or the visual cortex of the brain and can appear unilaterally or bilaterally. From an ophthalmologic perspective, phosphenes can arise from photoreceptor induction by mechanical,1,2 inflammatory,3 or vascular4 stimuli. Therefore, it is necessary to determine the origin of phosphenes for further management. We encountered a patient who reported having phosphenes while moving his eyes laterally. We performed various ophthalmologic imaging studies to identify the origin of these phosphenes.




CD62L test at 2 years of natalizumab predicts progressive multifocal leukoencephalopathy

2016-12-05T12:45:30-08:00

Flashes of light or phosphenes are the sensation of light without light actually entering the eye. This phenomenon can be evoked by stimulation of the retina or the visual cortex of the brain and can appear unilaterally or bilaterally. From an ophthalmologic perspective, phosphenes can arise from photoreceptor induction by mechanical,1,2 inflammatory,3 or vascular4 stimuli. Therefore, it is necessary to determine the origin of phosphenes for further management. We encountered a patient who reported having phosphenes while moving his eyes laterally. We performed various ophthalmologic imaging studies to identify the origin of these phosphenes.




A giant dumbbell-shaped primitive neuroectodermal tumor in the brain

2016-12-05T12:45:30-08:00

A 5-year-old girl presented with an 8 x 10-cm dumbbell-shaped mass in her left occipitoparietal region (figure 1). A preoperative CT angiogram demonstrated a large subcutaneous mass with abundant blood vessels (figure 2A). MRI revealed a giant extracranial–intracranial space-occupying lesion (figure 2, B–D). After endovascular embolization, we resected the tumor (figure 2E). The postoperative pathologic diagnosis was primitive neuroectodermal tumor (figure 2F). Primitive neuroectodermal tumor extension to the brain is rare; imaging is not pathognomonic and requires confirmation by pathology. Early intervention is preferable.




Multidisciplinary treatment of a giant scalp nevus with intracranial extension

2016-12-05T12:45:30-08:00

A 46-year-old man presented with a 4-year history of headache and visual field defect. Physical examination revealed a large patch of pigmented skin with alopecia areata measuring 10 x 12 cm in the right occipitotemporal region (figure 1A). Imaging showed a large intracranial space-occupying mass (figure 1, B–D). Pitch-black, chocolate-like substance was found during the surgery (figure 2A). The wound was repaired using split-skin graft (figure 2B). Pathologic examination confirmed the diagnosis of pigmented nevus. Giant pigmented nevus is a congenital melanocytic lesion originating from the neural crest.1 Intracranial spread is extremely rare2 and may represent a malignant transformation.













Mystery Case: CSF-1R mutation is a cause of intracranial cerebral calcifications, cysts, and leukoencephalopathy

2016-11-28T12:45:42-08:00

A 37-year-old man was referred for a 1-year history of word naming difficulties and progressive executive dysfunction along with anxiety. Clinical examination showed generalized hyperreflexia and bilateral Babinski sign but was otherwise normal. His brain MRI (figure, A and B) showed extensive leukoencephalopathy with multiple small cysts within the white matter changes and no gadolinium enhancement. CT identified punctate calcifications with deep frontal and juxtacortical distribution (figure, C and D). His mother died at 63 years after a 10-year history of progressive cognitive impairment of frontal type, walking difficulties, and urinary incontinence. Her brain imaging was strikingly similar to her son's (figure, E–H).




Clinical Reasoning: A 70-year-old woman with acute-onset weakness and progressive hemiataxia

2016-11-28T12:45:42-08:00

A 70-year-old woman with a history of insulin-dependent type 2 diabetes mellitus (IDDM), breast cancer treated with lumpectomy in 2012, hyperlipidemia, hypertension, coronary artery disease, and congestive heart failure with pacemaker presented with acute-onset difficulty using her right arm and leg. She was in her usual state of health until 3 weeks before admission, when she tripped over her grandson's toy on the floor, falling on her right side. Prior to falling, neither she nor her family had noted any weakness or difficulty with walking. Because her symptoms failed to improve over 3 weeks, she eventually presented to an emergency department.




Teaching NeuroImages: Orbital infarction syndrome from giant cell arteritis

2016-11-28T12:45:42-08:00

A 76-year-old man with a 3-month history of headaches, scalp pain, and jaw claudication presented with unilateral right eye complete ptosis, near-complete ophthalmoplegia, a fixed mid-dilated pupil, corneal edema with stromal thickening, and hypoesthesia in the right trigeminal V1 distribution. Temporal artery biopsy confirmed giant cell arteritis. CT angiography showed absent filling of the right ophthalmic artery and luminal narrowing affecting the right superficial temporal artery. MRI showed T2 diffusion-weighted imaging hyperintensity along the right optic nerve in the optic canal and bulbus oculi (figure). His clinicoradiographic presentation was consistent with orbital infarction syndrome.1




Teaching NeuroImages: Idiopathic hypertrophic pachymeningitis

2016-11-28T12:45:42-08:00

A 39-year-old woman presented with acute, painless left monocular vision loss in the context of 6 months of right peripheral facial weakness and prior right optic neuropathy. MRI showed asymmetric, bilateral smooth pachymeningeal enhancement with involvement of the optic canals (figure 1). Autoimmune, inflammatory, and neoplastic testing including CSF and serum immunoglobulin G4 levels were unremarkable. Dural biopsy revealed chronic lymphohistiocytic pachymeningitis without granulomatous inflammation (figure 2), consistent with idiopathic hypertrophic pachymeningitis (IHP). Clinical and radiographic responses were achieved with steroids and methotrexate. IHP is a diagnosis of exclusion characterized by headache and cranial neuropathies.1 MRI T1-contrasted images show smooth, thickened, enhancing pachymeninges.2







Spotlight on the November 29 Issue

2016-11-28T12:45:42-08:00




The swinging pendulum of biomarkers in mitochondrial disease: The role of FGF21

2016-11-28T12:45:42-08:00

Mitochondrial diseases are clinically and genetically heterogeneous metabolic disorders that often present a substantial diagnostic challenge even for experienced clinicians.1 Although diagnostic clues are sought using widely available clinical chemistry tests (e.g., elevated serum lactate, pyruvate, or creatine kinase levels), patients are frequently subjected to invasive investigations including a muscle biopsy. Even then, a definitive diagnosis may not be forthcoming and consequently the identification of noninvasive diagnostic biomarkers has the potential to streamline the diagnostic process for both clinicians and patients.




The eternal promise of EEG-based biomarkers: Getting closer?

2016-11-28T12:45:42-08:00

Several years ago, a colleague in the developmental clinic asked me to tell him what I thought about a brain mapping EEG report brought in by a parent. The report made a number of bold pronouncements about the child's brain function, such as, "Decreased current in the fusiform gyrus indicates face-processing difficulties." From my research using EEG to study the pathophysiology of developmental disabilities, I knew that making even a single conclusion about group data took years of painstaking development of cognitive experiments and obsessive analysis of the data using a variety of signal-processing techniques. The notion that automatic software could validly produce several conclusions from a few minutes' worth of spontaneous EEG data seemed far-fetched.




FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders

2016-11-28T12:45:42-08:00

Objective:

To validate new mitochondrial myopathy serum biomarkers for diagnostic use.

Methods:

We analyzed serum FGF21 (S-FGF21) and GDF15 from patients with (1) mitochondrial diseases and (2) nonmitochondrial disorders partially overlapping with mitochondrial disorder phenotypes. We (3) did a meta-analysis of S-FGF21 in mitochondrial disease and (4) analyzed S-Fgf21 and skeletal muscle Fgf21 expression in 6 mouse models with different muscle-manifesting mitochondrial dysfunctions.

Results:

We report that S-FGF21 consistently increases in primary mitochondrial myopathy, especially in patients with mitochondrial translation defects or mitochondrial DNA (mtDNA) deletions (675 and 347 pg/mL, respectively; controls: 66 pg/mL, p < 0.0001 for both). This is corroborated in mice (mtDNA deletions 1,163 vs 379 pg/mL, p < 0.0001). However, patients and mice with structural respiratory chain subunit or assembly factor defects showed low induction (human 335 pg/mL, p < 0.05; mice 335 pg/mL, not significant). Overall specificities of FGF21 and GDF15 to find patients with mitochondrial myopathy were 89.3% vs 86.4%, and sensitivities 67.3% and 76.0%, respectively. However, GDF15 was increased also in a wide range of nonmitochondrial conditions.

Conclusions:

S-FGF21 is a specific biomarker for muscle-manifesting defects of mitochondrial translation, including mitochondrial transfer-RNA mutations and primary and secondary mtDNA deletions, the most common causes of mitochondrial disease. However, normal S-FGF21 does not exclude structural respiratory chain complex or assembly factor defects, important to acknowledge in diagnostics.

Classification of evidence:

This study provides Class III evidence that elevated S-FGF21 accurately distinguishes patients with mitochondrial myopathies from patients with other conditions, and FGF21 and GDF15 mitochondrial myopathy from other myopathies.




Race/ethnicity, socioeconomic status, and ALS mortality in the United States

2016-11-28T12:45:42-08:00

Objective:

To determine whether race/ethnicity and socioeconomic status are associated with amyotrophic lateral sclerosis (ALS) mortality in the United States.

Methods:

The National Longitudinal Mortality Study (NLMS), a United States–representative, multistage sample, collected race/ethnicity and socioeconomic data prospectively. Mortality information was obtained by matching NLMS records to the National Death Index (1979–2011). More than 2 million persons (n = 1,145,368 women, n = 1,011,172 men) were included, with 33,024,881 person-years of follow-up (1,299 ALS deaths , response rate 96%). Race/ethnicity was by self-report in 4 categories. Hazard ratios (HRs) for ALS mortality were calculated for race/ethnicity and socioeconomic status separately and in mutually adjusted models.

Results:

Minority vs white race/ethnicity predicted lower ALS mortality in models adjusted for socioeconomic status, type of health insurance, and birthplace (non-Hispanic black, HR 0.61, 95% confidence interval [CI] 0.48–0.78; Hispanic, HR 0.64, 95% CI 0.46–0.88; other races, non-Hispanic, HR 0.52, 95% CI 0.31–0.86). Higher educational attainment compared with < high school was in general associated with higher rate of ALS (high school, HR 1.23, 95% CI 1.07–1.42; some college, HR 1.24, 95% CI 1.04–1.48; college, HR 1.10, 95% CI 0.90–1.36; postgraduate, HR 1.31, 95% CI 1.06–1.62). Income, household poverty, and home ownership were not associated with ALS after adjustment for race/ethnicity. Rates did not differ by sex.

Conclusion:

Higher rate of ALS among whites vs non-Hispanic blacks, Hispanics, and non-Hispanic other races was not accounted for by multiple measures of socioeconomic status, birthplace, or type of health insurance. Higher rate of ALS among whites likely reflects actual higher risk of ALS rather than ascertainment bias or effects of socioeconomic status on ALS risk.




In vivo visualization of tau deposits in corticobasal syndrome by 18F-THK5351 PET

2016-11-28T12:45:42-08:00

Objective:

To determine whether 18F-THK5351 PET can be used to visualize tau deposits in brain lesions in live patients with corticobasal syndrome (CBS).

Methods:

We evaluated the in vitro binding of 3H-THK5351 in postmortem brain tissues from a patient with corticobasal degeneration (CBD). In clinical PET studies, 18F-THK5351 retention in 5 patients with CBS was compared to that in 8 age-matched normal controls and 8 patients with Alzheimer disease (AD).

Results:

3H-THK5351 was able to bind to tau deposits in the postmortem brain with CBD. In clinical PET studies, the 5 patients with CBS showed significantly higher 18F-THK5351 retention in the frontal, parietal, and globus pallidus than the 8 age-matched normal controls and patients with AD. Higher 18F-THK5351 retention was observed contralaterally to the side associated with greater cortical dysfunction and parkinsonism.

Conclusions:

18F-THK5351 PET demonstrated high tracer signal in sites susceptible to tau deposition in patients with CBS. 18F-THK5351 should be considered as a promising candidate radiotracer for the in vivo imaging of tau deposits in CBS.




Hippocampal volumes predict risk of dementia with Lewy bodies in mild cognitive impairment

2016-11-28T12:45:42-08:00

Objective:

To predict the risk of probable dementia with Lewy bodies (DLB) competing with Alzheimer disease (AD) dementia by hippocampal volume (HV) in patients with mild cognitive impairment (MCI) with impairments in amnestic or nonamnestic cognitive domains.

Methods:

Patients with MCI (n = 160) from the Mayo Clinic Alzheimer's Disease Research Center, who participated in an MRI study at baseline from 2005 to 2014, were followed with approximately annual clinical evaluations. HVs were analyzed from 3T MRIs using FreeSurfer (5.3). Hippocampal atrophy was determined from the most normal 10th percentile of the measurement distributions in a separate cohort of clinically diagnosed patients with AD dementia. The subdistribution hazard ratios for progression to probable DLB and AD dementia were estimated by taking into account the competing risks.

Results:

During a median (range) follow-up of 2.0 (0.7–8.1) years, 20 (13%) patients with MCI progressed to probable DLB, and 61 (38%) progressed to AD dementia. The estimated subdistribution hazard ratio (95% confidence interval) for normal HV relative to hippocampal atrophy for progression to AD dementia was 0.56 (0.34–0.91; p = 0.02) after taking into account the competing risks. The estimated hazard ratio for normal HV relative to hippocampal atrophy for progression to probable DLB was 4.22 (1.42–12.6; p = 0.01) after adjusting for age and after including the MCI subtype in the model.

Conclusions:

Preserved hippocampal volumes are associated with increased risk of probable DLB competing with AD dementia in patients with MCI. Preservation of HV may support prodromal DLB over AD, particularly in patients with MCI with nonamnestic features.




Gram-negative bacterial molecules associate with Alzheimer disease pathology

2016-11-28T12:45:42-08:00

Objective:

We determined whether Gram-negative bacterial molecules are associated with Alzheimer disease (AD) neuropathology given that previous studies demonstrate Gram-negative Escherichia coli bacteria can form extracellular amyloid and Gram-negative bacteria have been reported as the predominant bacteria found in normal human brains.

Methods:

Brain samples from gray and white matter were studied from patients with AD (n = 24) and age-matched controls (n = 18). Lipopolysaccharide (LPS) and E coli K99 pili protein were evaluated by Western blots and immunocytochemistry. Human brain samples were assessed for E coli DNA followed by DNA sequencing.

Results:

LPS and E coli K99 were detected immunocytochemically in brain parenchyma and vessels in all AD and control brains. K99 levels measured using Western blots were greater in AD compared to control brains (p < 0.01) and K99 was localized to neuron-like cells in AD but not control brains. LPS levels were also greater in AD compared to control brain. LPS colocalized with Aβ1-40/42 in amyloid plaques and with Aβ1-40/42 around vessels in AD brains. DNA sequencing confirmed E coli DNA in human control and AD brains.

Conclusions:

E coli K99 and LPS levels were greater in AD compared to control brains. LPS colocalized with Aβ1-40/42 in amyloid plaques and around vessels in AD brain. The data show that Gram-negative bacterial molecules are associated with AD neuropathology. They are consistent with our LPS-ischemia-hypoxia rat model that produces myelin aggregates that colocalize with Aβ and resemble amyloid-like plaques.




Cerebrovascular reactivity and white matter integrity

2016-11-28T12:45:42-08:00

Objective:

To compare the diffusion and perfusion MRI metrics of normal-appearing white matter (NAWM) with and without impaired cerebrovascular reactivity (CVR).

Methods:

Seventy-five participants with moderate to severe leukoaraiosis underwent blood oxygen level–dependent CVR mapping using a 3T MRI system with precise carbon dioxide stimulus manipulation. Several MRI metrics were statistically compared between areas of NAWM with positive and negative CVR using one-way analysis of variance with Bonferroni correction for multiple comparisons.

Results:

Areas of NAWM with negative CVR showed a significant reduction in fractional anisotropy by a mean (SD) of 3.7% (2.4), cerebral blood flow by 22.1% (8.2), regional cerebral blood volume by 22.2% (7.0), and a significant increase in mean diffusivity by 3.9% (3.1) and time to maximum by 10.9% (13.2) (p < 0.01), compared to areas with positive CVR.

Conclusions:

Impaired CVR is associated with subtle changes in the tissue integrity of NAWM, as evaluated using several quantitative diffusion and perfusion MRI metrics. These findings suggest that impaired CVR may contribute to the progression of white matter disease.




Neighborhood socioeconomic index and stroke incidence in a national cohort of blacks and whites

2016-11-28T12:45:42-08:00

Objective:

To assess the relationship between neighborhood socioeconomic characteristics and incident stroke in a national cohort of black and white participants.

Methods:

The study comprised black (n = 10,274, 41%) and white (n = 14,601) stroke-free participants, aged 45 and older, enrolled in 2003–2007 in Reasons for Geographic and Racial Differences in Stroke (REGARDS), a national population-based cohort. A neighborhood socioeconomic score (nSES) was constructed using 6 neighborhood variables. Incident stroke was defined as first occurrence of stroke over an average 7.5 (SD 3.0) years of follow-up. Proportional hazards models were used to estimate associations between nSES score and incident stroke, adjusted for demographics (age, race, sex, region), individual socioeconomic status (SES) (education, household income), and other risk factors for stroke.

Results:

After adjustment for demographics, compared to the highest nSES quartile, stroke incidence increased with each decreasing nSES quartile. The hazard ratio (95% confidence interval) ranged from 1.28 (1.05–1.56) in quartile 3 to 1.38 (1.13–1.68) in quartile 2 to 1.56 (1.26–1.92) in quartile 1 (p < 0.0001 for linear trend). After adjustment for individual SES, the trend remained marginally significant (p = 0.085). Although there was no evidence of a differential effect by race or sex, adjustment for stroke risk factors attenuated the association between nSES and stroke in both black and white participants, with greater attenuation in black participants.

Conclusions:

Risk of incident stroke increased with decreasing nSES but the effect of nSES is attenuated through individual SES and stroke risk factors. The effect of neighborhood socioeconomic characteristics that contribute to increased stroke risk is similar in black and white participants.




Effect of aphasia on acute stroke outcomes

2016-11-28T12:45:42-08:00

Objective:

To determine the independent effects of aphasia on outcomes during acute stroke admission, controlling for total NIH Stroke Scale (NIHSS) scores and loss of consciousness.

Methods:

Data from the Tulane Stroke Registry were used from July 2008 to December 2014 for patient demographics, NIHSS scores, length of stay (LOS), complications (sepsis, deep vein thrombosis), and discharge modified Rankin Scale (mRS) score. Aphasia was defined as a score >1 on question 9 on the NIHSS on admission and hemiparesis as >1 on questions 5 or 6.

Results:

Among 1,847 patients, 866 (46%) had aphasia on admission. Adjusting for NIHSS score and inpatient complications, those with aphasia had a 1.22 day longer LOS than those without aphasia, whereas those with hemiparesis (n = 1,225) did not have any increased LOS compared to those without hemiparesis. Those with aphasia had greater odds of having a complication (odds ratio [OR] 1.44, confidence interval [CI] 1.07–1.93, p = 0.0174) than those without aphasia, which was equivalent to those having hemiparesis (OR 1.47, CI 1.09–1.99, p = 0.0137). Controlling for NIHSS scores, aphasia patients had higher odds of discharge mRS 3–6 (OR 1.42 vs 1.15).

Conclusion:

Aphasia is independently associated with increased LOS and complications during the acute stroke admission, adding $2.16 billion annually to US acute stroke care. The presence of aphasia was more likely to produce a poor functional outcome than hemiparesis. These data suggest that further research is necessary to determine whether establishing adaptive communication skills can mitigate its consequences in the acute stroke setting.




Safety of lumbar puncture in comatose children with clinical features of cerebral malaria

2016-11-28T12:45:42-08:00

Objective:

We assessed the independent association of lumbar puncture (LP) and death in Malawian children admitted to the hospital with the clinical features of cerebral malaria (CM).

Methods:

This was a retrospective cohort study in Malawian children with clinical features of CM. Allocation to LP was nonrandom and was associated with severity of illness. Propensity score–based analyses were used to adjust for this bias and assess the independent association between LP and mortality.

Results:

Data were available for 1,075 children: 866 (80.6%) underwent LP and 209 (19.4%) did not. Unadjusted mortality rates were lower in children who underwent LP (15.3% vs 26.7% in the no-LP group) but differences in covariates between the 2 groups suggested bias in LP allocation. After propensity score matching, all covariates were balanced. Propensity score–based analyses showed no change in mortality rate associated with LP: by inverse probability weighting, the average risk reduction was 2.0% at 12 hours (95% confidence interval –1.5% to 5.5%, p = 0.27) and 1.7% during hospital admission (95% confidence interval –4.5% to 7.9%, p = 0.60). Undergoing LP did not change the risk of mortality in subanalyses of children with severe brain swelling on MRI or in those with papilledema.

Conclusion:

In comatose children with suspected CM who were clinically stable, we found no evidence that LP increases mortality, even in children with objective signs of raised intracranial pressure.




Estimating risk of word-finding problems in adults undergoing epilepsy surgery

2016-11-28T12:45:42-08:00

Objective:

This retrospective, observational study examined the frequency and magnitude of change in naming ability as a function of side/site of epilepsy surgery and identified predictive factors to assist clinicians in identifying patients at low, moderate, or high risk of postoperative naming decline.

Methods:

A total of 875 adults with pharmacoresistant epilepsy (454 left/421 right; 763 temporal/87 frontal/25 posterior quadrant) met inclusion criteria and completed the Boston Naming Test before and after surgery. Clinically meaningful change in naming ability was assessed using reliable change indices for epilepsy. Demographic, cognitive, and seizure variables were examined to determine factors most predictive of naming decline and to develop a decision tree to assist with clinical decision-making.

Results:

Naming decline was rare in right-sided resections and did not exceed the level expected by chance (5% overall; 90% confidence interval [CI] ± 2%). Naming decline occurred in 41% (CI ± 5%) of patients after left temporal resection (TLR) compared to 10%–12% (CI ± 10%–19%) in other left-sided surgical groups. A sizable proportion of left TLR patients (17%; CI ± 4%) showed substantial declines in naming (>11 points). Decline following left TLR was related to later age at seizure onset, older age at surgery, and higher preoperative naming ability. These factors correctly predicted naming decline in 68% of patients and were associated with degree of decline following left TLR. A decision tree is provided to assist clinicians in identifying patients at low, moderate, or high risk for postoperative naming declines.

Conclusions:

In addition to discussions regarding risk for memory decline following left TLR, patients should be counseled about potential decline in word-finding ability.




Prevalence of lifetime depression in a large hemiplegic migraine cohort

2016-11-28T12:45:42-08:00

Objective:

To determine the prevalence of depression and determinants associated with depression in a large population of hemiplegic migraine (HM) patients.

Methods:

We conducted a cross-sectional, validated questionnaire study among 89 well-defined HM patients and 235 headache-free controls. The prevalence of lifetime depression and its relation to migraine characteristics was assessed.

Results:

HM patients had increased odds for lifetime depression (odds ratio 3.73, 95% confidence interval 2.18–6.38) compared with controls. Use of acute antimigraine medication was associated with lifetime depression.

Conclusions:

Depression is part of the monogenic hemiplegic migraine phenotype. Further studies are needed to elucidate the pathophysiologic role of HM genes in comorbid depression. For now, clinicians should take comorbid depression into consideration when starting prophylactic treatment of HM.




Practice advisory: The utility of EEG theta/beta power ratio in ADHD diagnosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology

2016-11-28T12:45:42-08:00

Objective:

To evaluate the evidence for EEG theta/beta power ratio for diagnosing, or helping to diagnose, attention-deficit/hyperactivity disorder (ADHD).

Methods:

We identified relevant studies and classified them using American Academy of Neurology criteria.

Results:

Two Class I studies assessing the ability of EEG theta/beta power ratio and EEG frontal beta power to identify patients with ADHD correctly identified 166 of 185 participants. Both studies evaluated theta/beta power ratio and frontal beta power in suspected ADHD or in syndromes typically included in an ADHD differential diagnosis. A bivariate model combining the diagnostic studies shows that the combination of EEG frontal beta power and theta/beta power ratio has relatively high sensitivity and specificity but is insufficiently accurate.

Conclusions:

It is unknown whether a combination of standard clinical examination and EEG theta/beta power ratio increases diagnostic certainty of ADHD compared with clinical examination alone.

Recommendations:

Level B: Clinicians should inform patients with suspected ADHD and their families that the combination of EEG theta/beta power ratio and frontal beta power should not replace a standard clinical evaluation. There is a risk for significant harm to patients from ADHD misdiagnosis because of the unacceptably high false-positive diagnostic rate of EEG theta/beta power ratio and frontal beta power. Level R: Clinicians should inform patients with suspected ADHD and their families that the EEG theta/beta power ratio should not be used to confirm an ADHD diagnosis or to support further testing after a clinical evaluation, unless such diagnostic assessments occur in a research setting.




Acute cholecystitis during treatment with alemtuzumab in 3 patients with RRMS

2016-11-28T12:45:42-08:00

Alemtuzumab is an effective therapeutic option for patients with active forms of relapsing-remitting multiple sclerosis (RRMS).1 The adverse event profile comprises an increased risk for the development of secondary autoimmune disorders as well as infusion-associated reactions. Alemtuzumab infusion is often associated with an acute cytokine release syndrome.2 Among other side effects, patients may experience headache, rash, pyrexia, and to a lesser extent hypotension, cardiac arrhythmia, and rarely anaphylactic shock. These symptoms are usually limited to the first days of infusion and do not lead to sustained impairment.1




Acute hippocampal and chronic diffuse white matter involvement in severe methanol intoxication

2016-11-28T12:45:42-08:00

A 42-year-old man presented with coma from methanol intoxication (178 mg/dL; its metabolite, formic acid, 860 μg/mL). Continuous hemodiafiltration improved his disturbance of consciousness, but he subsequently developed cognitive dysfunction and parkinsonism, which were finally alleviated by rehabilitation and amantadine therapy. Brain MRI revealed acute basal ganglionic and hippocampal lesions and chronic developmental white matter lesions (figures 1 and 2).




A case of congenital anosmia

2016-11-28T12:45:42-08:00

An 18-year-old girl presented with inability to smell from birth. She had no symptoms to suggest an endocrine disturbance. Anosmia was confirmed on bedside testing. A diagnosis of congenital anosmia was made. A 3T MRI scan (figure) of this patient revealed no olfactory bulbs but developed olfactory sulci. The rest of the brain including corpus callosum was normal. The differential diagnosis for congenital anosmia is Kallman syndrome. However, in Kallman syndrome, the olfactory sulci would also be absent.













Child Neurology: Diencephalic syndrome-like presentation of a cervicomedullary brainstem tumor

2016-11-21T12:45:31-08:00

Diencephalic syndrome is a rare clinical entity, traditionally encompassing severe failure to thrive, nystagmus, and hyperkinesis, secondary to an intracranial neoplasm that is classically located in the hypothalamic region and its vicinity. However, the presenting features can be variable, often resulting in delayed diagnosis, which may worsen prognosis. This case report describes the atypical presentation of a posterior fossa tumor with features reminiscent of diencephalic syndrome that have not previously been reported in the literature. We report a 21-month-old girl with a cervicomedullary brainstem astrocytoma, who presented with isolated gross motor developmental delay, decreased growth velocity, and stridor. The neurologic signs frequently reported in patients with diencephalic syndrome were absent; however, severe failure to thrive was present. This case broadens the etiologic differential diagnosis of diencephalic syndrome in addition to the traditional hypothalamic region tumor location. This case urges physicians to consider central neurologic processes in the differential diagnosis of children with refractory failure to thrive with or without classical features of diencephalic syndrome, in whom etiology is not identified by routine investigations, given its importance in determining prognosis and management.




Clinical Reasoning: A 64-year-old man with visual distortions

2016-11-21T12:45:31-08:00

A 64-year-old right-handed man presented to the emergency department with a 4-week history of bilateral blurred and distorted vision. He reported that objects in his central visual field appeared to change shape and were disproportionately large or small. He also reported intermittent flashes of light with altered color perception. His medical history was notable for prostate cancer treated with prostatectomy, Bell palsy at age 25, gastroesophageal reflux disease, and bilateral refractive errors. His family had also noted intermittent episodes of confusion and anger over the preceding weeks along with difficulty recognizing family members. He endorsed minimal right-sided periorbital headache but reported no diplopia, weakness, paresthesiae, numbness, speech changes, or history of similar symptoms. He had no recent history of fever, illness, or infectious exposures. He had no history of seizures or migraine. He was taking omeprazole and did not smoke or use alcohol or illicit drugs.




Journal Club: Depression before and after diagnosis with amyotrophic lateral sclerosis

2016-11-21T12:45:31-08:00

The prevalence of depression among individuals with amyotrophic lateral sclerosis (ALS) is reported to be up to 44%, depending on the assessment methodology.1 Depression negatively affects quality of life in ALS, and psychological stress is related to poorer survival among individuals with ALS.2




Teaching NeuroImages: Giant neurocysticercosis with unusual imaging manifestations

2016-11-21T12:45:31-08:00

A 6-year-old girl presented with a 3-month history of progressive left-eye strabismus and vision loss. MRI scan of the brain showed a single hypointense lesion in the left cerebral hemisphere with no perilesional edema or contrast enhancement (figure 1, A–C). At surgery, the lesion was shown to be a single large parasitic cyst measuring approximately 7.0 x 6.5 x 6.0 cm (figure 2, A–C). The patient underwent a complete resection and then was given antihelminthic therapy. This resulted in an uneventful recovery. Pathology confirmed a diagnosis of cysticercus cyst with scolex. This imaging feature of giant neurocysticercosis is very unusual.1 In the event of neurologic dysfunction or elevated intracranial pressure, emergent operative intervention should precede the administration of antihelminthic medications as the latter may weaken the cyst membrane and complicate resection. Gross total resection has advantages compared with nonsurgical treatment with antihelminthics.2




Spotlight on the November 22 issue

2016-11-21T12:45:30-08:00




IV tPA for acute ischemic stroke: Times are changing

2016-11-21T12:45:30-08:00

Based on evidence that the administration of IV tissue plasminogen activator (tPA) improved the outcomes of selected patients with acute ischemic stroke, the US Food and Drug Administration (FDA) approved its use for this purpose in 1996, leading to a revolution in stroke care.1 Following its introduction into routine clinical practice, stroke began to be viewed as a medical emergency, similar to myocardial infarction, with effective treatment dependent or early symptom recognition and patient transport to facilities capable of conducting rapid evaluations and IV tPA administration. There were, however, considerable barriers that slowed adoption; even 8 years after FDA approval, IV tPA was being given to only about 1%–2% of stroke patients.2




The AAN's Axon Registry: Mastering how we are measured

2016-11-21T12:45:30-08:00

Policymakers and payors are incentivizing the transition away from primarily fee-for-service reimbursement for the volume of services and procedures performed toward rewarding value, defined as (quality + patient experience) divided by cost. The shift from volume to value will ultimately apply to all practices, regardless of type or size.1,2




Donald H. Gilden, MD (1937-2016)

2016-11-21T12:45:30-08:00

Dr. Donald Gilden passed away on August 22, 2016, at the age of 78 years. Don was a true "renaissance man." He was an expert skier and played fast-pitch softball at the quadrennial XIth Maccabiah Games in Israel in 1981 while on an NIH Fogarty International Fellowship. He was a talented violinist whose performances on his treasured 17th-century violin made by Nicolo Amati were a feature at many professional gatherings. His competitive nature was legendary—many a novice skier joining the faculty was taken for an "easy run"—like Beaver Creek's double-black "Birds of Prey"! As a physician, he was a true "triple threat," winning awards from residents for his teaching skills, widely recognized as a master clinician, and most notably as a scientist who made fundamental contributions in neurovirology.




Emerging temporal trends in tissue plasminogen activator use: Results from the BASIC project

2016-11-21T12:45:30-08:00

Objective:

To explore temporal trends in tissue plasminogen activator (tPA) administration for acute ischemic stroke (AIS) in a biethnic community without an academic medical center and variation in trends by age, sex, ethnicity, and stroke severity.

Methods:

Cases of AIS were identified from 7 hospitals in the Brain Attack Surveillance in Corpus Christi (BASIC) project, a population-based surveillance study between January 1, 2000, and June 30, 2012. tPA, demographics, and stroke severity as assessed by the NIH Stroke Scale (NIHSS) were ascertained from medical records. Temporal trends were explored using generalized estimating equations, and adjustment made for age, sex, ethnicity, and NIHSS. Interaction terms were included to test for effect modification.

Results:

There were 5,277 AIS cases identified from 4,589 unique individuals. tPA use was steady at 2% and began increasing in 2006, reaching 11% in subsequent years. Stroke severity modified temporal trends (p = 0.003) such that cases in the highest severity quartile (NIHSS > 8) had larger increases in tPA use than those in lower severity quartiles. Although ethnicity did not modify the temporal trend, Mexican Americans (MAs) were less likely to receive tPA than non-Hispanic whites (NHWs) due to emerging ethnic differences in later years.

Conclusions:

Dramatic increases in tPA use were apparent in this community without an academic medical center. Primary stroke center certification likely contributed to this rise. Results suggest that increases in tPA use were greater in higher severity patients compared to lower severity patients, and a gap between MAs and NHWs in tPA administration may be emerging.




Stable incidence but declining case-fatality rates of subarachnoid hemorrhage in a population

2016-11-21T12:45:30-08:00

Objective:

To characterize temporal trends in subarachnoid hemorrhage (SAH) incidence and outcomes over 5 time periods in a large population-based stroke study in the United States.

Methods:

All SAHs among residents of the Greater Cincinnati/Northern Kentucky region at least 20 years of age were identified and verified via study physician review in 5 distinct year-long study periods between 1988 and 2010. We abstracted demographics, care patterns, and outcomes, and we compared incidence and case-fatality rates across the study periods.

Results:

The incidence of SAH in the 5 study periods (age-, race-, and sex-adjusted to the 2000 US population) was 8.8 (95% confidence interval 6.8–10.7), 9.2 (7.2–11.2), 10.0 (8.0–12.0), 9.0 (7.1–10.9), and 7.7 (6.0–9.4) per 100,000, respectively; the trend in incidence rates from 1988 to 2010 was not statistically significant (p = 0.22). Advanced neurovascular imaging, endovascular coiling, and neurologic intensive care unit availability increased significantly over time. All-cause 5-day (32%–18%, p = 0.01; for trend), 30-day (46%–25%, p = 0.001), and 90-day (49%–29%, p = 0.001) case-fatality rates declined from 1988 to 2010. When we included only proven or highly likely aneurysmal SAH, the declines in case-fatality were no longer statistically significant.

Conclusions:

Although the incidence of SAH remained stable in this population-based region, 5-day, 30-day, and 90-day case-fatality rates declined significantly. Advances in surgical and medical management, along with systems-based changes such as the emergence of neurocritical care units, are potential explanations for the reduced case-fatality.




Leukocyte response is regulated by microRNA let7i in patients with acute ischemic stroke

2016-11-21T12:45:30-08:00

Objective:

To evaluate microRNA let7i in ischemic stroke and its regulation of leukocytes.

Methods:

A total of 212 patients were studied: 106 with acute ischemic stroke and 106 controls matched for risk factors. RNA from circulating leukocytes was isolated from blood collected in PAXgene tubes. Let7i microRNA expression was assessed using TaqMan quantitative reverse transcription PCR. To assess let7i regulation of gene expression in stroke, messenger RNA (mRNA) from leukocytes was measured by whole-genome Human Transcriptome Array Affymetrix microarray. Given microRNAs act to destabilize and degrade their target mRNA, mRNAs that inversely correlated with let7i were identified. To demonstrate let7i posttranscriptional regulation of target genes, a 3' untranslated region luciferase assay was performed. Target protein expression was assessed using ELISA.

Results:

Let7i was decreased in patients with acute ischemic stroke (fold change –1.70, p < 0.00001). A modest inverse correlation between let7i and NIH Stroke Scale score at admission (r = –0.32, p = 0.02), infarct volume (r = –0.21, p = 0.04), and plasma MMP9 (r = –0.46, p = 0.01) was identified. The decrease in let7i was associated with increased expression of several of its mRNA targets, including CD86, CXCL8, and HMGB1. In vitro studies confirm let7i posttranscriptional regulation of target genes CD86, CXCL8, and HMGB1. Functional analysis predicted let7i regulates pathways involved in leukocyte activation, recruitment, and proliferation including canonical pathways of CD86 signaling in T helper cells, HMGB1 signaling, and CXCL8 signaling.

Conclusions:

Let7i is decreased in circulating leukocytes of patients with acute ischemic stroke. Mechanisms by which let7i regulates inflammatory response post stroke include targeting CD86, CXCL8, and HMGB1.




Seizure variables and their relationship to genotype and functional abilities in the CDKL5 disorder

2016-11-21T12:45:30-08:00

Objective:

To investigate seizure outcomes and their relationships to genotype and functional abilities in individuals with the cyclin-dependent kinase-like-5 (CDKL5) disorder.

Methods:

Using the International CDKL5 Disorder Database, we identified 172 cases with a pathogenic CDKL5 mutation. We categorized individual mutations into 4 groups based on predicted structural and functional consequences. Negative binomial regression was used to model the linear association between current seizure rate and mutation group, current level of assistance required to walk 10 steps, and the highest level of expressive communication used to convey refusal or request.

Results:

All but 3 (169/172) patients had a history of epilepsy. The median age at seizure onset was 6 weeks (range 1 week–1.5 years) and the median seizure rate at ascertainment was 2 per day (range 0–20 per day). After adjusting for walking ability and confounders including use or otherwise of polytherapy, seizure rate was lower in those with truncating mutations between aa172 and aa781 compared to those with no functional protein (incidence rate ratio [IRR] 0.57; 95% confidence interval [CI] 0.35–0.93). Ability to walk and use of spoken language were associated with lower rates of current seizures when compared to those with the least ability after adjusting for genotype (walking: IRR 0.62; 95% CI 0.39–0.99, communication: IRR 0.48; 95% CI 0.23–1.02). At a median age at questionnaire completion of 5 years, those previously treated with corticosteroids had more frequent seizures than those who have never been treated, whether or not there was a history of infantile spasms.

Conclusions:

Epilepsy is pervasive but not mandatory for the CDKL5 disorder. Genotype and functional abilities were related to seizure frequency, which appears refractory to antiepileptic drugs.




Long-term follow-up of psychogenic pseudosyncope

2016-11-21T12:45:30-08:00

Objective:

To determine the outcome of patients with psychogenic pseudosyncope (PPS) after communication of the diagnosis.

Methods:

This was a retrospective cohort study of patients with PPS referred in 2007 to 2015 to a tertiary referral center for syncope. We reviewed patient records and studied attack frequency, factors affecting attack frequency, health care use, and quality of life using a questionnaire. We explored influences on attack freedom and attack frequency in the 6 months before follow-up for age, sex, education level, duration until diagnosis, probability of diagnosis, additional syncope, and acceptance of diagnosis.

Results:

Forty-seven of 57 patients with PPS could be traced, of whom 35 (74%) participated. Twelve (34%) were attack-free for at least 6 months. The median time from diagnosis to follow-up was 50 months (range 6–103 months). Communicating and explaining the diagnosis resulted in immediate reduction of attack frequency (p = 0.007) from the month before diagnosis (median one attack, range 0–156) to the month after (median one attack, range 0–16). In the 6 months before follow-up, the number of admissions decreased from 19 of 35 to 0 of 35 (p = 0.002). The use of somatic and mental health care shifted toward the latter (p < 0.0001). Quality of life at follow-up (Short Form Health Survey 36) showed lower scores for 7 of 8 domains compared to matched Dutch control values; quality of life was not influenced by attack freedom.

Conclusions:

After communication of the diagnosis in PPS, attack frequency decreased and health care use shifted toward mental care. Low quality of life underlines that PPS is a serious condition.




Schwann cell and endothelial cell damage in transthyretin familial amyloid polyneuropathy

2016-11-21T12:45:31-08:00

Objective:

To examine the morphology of Schwann cells and endoneurial microvessels with electron microscopy.

Methods:

Sural nerve biopsy specimens from 49 patients with familial amyloid polyneuropathy (FAP) with transthyretin Val30Met mutation were assessed. Patients included 11 early-onset cases from endemic foci and 38 late-onset cases from nonendemic areas.

Results:

Loss of nerve fibers with or without neighboring amyloid deposition was a common feature. The amount of amyloid deposition was greater relative to the extent of nerve fiber loss in early-onset cases than in late-onset cases. The atrophy of Schwann cells, particularly nonmyelinating Schwann cells, that were apposed to amyloid fibrils was more conspicuous in early-onset cases than in late-onset cases. The numbers of endothelial cell nuclei, endothelial cell profiles, and occluded microvessels were significantly increased in the patients with FAP compared with 37 patients with nutritional/alcoholic neuropathies (p < 0.05, 0.01, and 0.01, respectively). Findings suggestive of the disruption of blood-nerve barriers such as the loss of tight junctions and the fenestration of endothelial cells were also found more frequently in the patients with FAP (p < 0.001), regardless of the presence or absence of amyloid deposition.

Conclusions:

These findings suggest that direct insult of amyloid fibrils causes Schwann cell damage, resulting in the predominant loss of small-fiber axons characteristic of early-onset cases. In addition, vasculopathy may participate in the pathogenesis of neuropathy, particularly in late-onset cases.




Safety of intrathecal autologous adipose-derived mesenchymal stromal cells in patients with ALS

2016-11-21T12:45:31-08:00

Objective:

To determine the safety of intrathecal autologous adipose-derived mesenchymal stromal cell treatment for amyotrophic lateral sclerosis (ALS).

Methods:

Participants with ALS were enrolled and treated in this phase I dose-escalation safety trial, ranging from 1 x 107 (single dose) to 1 x 108 cells (2 monthly doses). After intrathecal treatments, participants underwent standardized follow-up, which included clinical examinations, revised ALS Functional Rating Scale (ALSFRS-R) questionnaire, blood and CSF sampling, and MRI of the neuroaxis.

Results:

Twenty-seven patients with ALS were enrolled and treated in this study. The safety profile was positive, with the most common side effects reported being temporary low back and radicular leg pain at the highest dose level. These clinical findings were associated with elevated CSF protein and nucleated cells with MRI of thickened lumbosacral nerve roots. Autopsies from 4 treated patients did not show evidence of tumor formation. Longitudinal ALSFRS-R questionnaires confirmed continued progression of disease in all treated patients.

Conclusions:

Intrathecal treatment of autologous adipose-derived mesenchymal stromal cells appears safe at the tested doses in ALS. These results warrant further exploration of efficacy in phase II trials.

Classification of evidence:

This phase I study provides Class IV evidence that in patient with ALS, intrathecal autologous adipose-derived mesenchymal stromal cell therapy is safe.




Expanding the phenotype of BICD2 mutations toward skeletal muscle involvement

2016-11-21T12:45:31-08:00

Objective:

To expand the spectrum of bicaudal D, Drosophila, homologue 2 (BICD2) generelated diseases, which so far includes autosomal dominant spinal muscular atrophy with lower extremity predominance 2 and hereditary spastic paraplegia due to mutations in the BICD2 gene.

Methods:

We analyzed 2 independent German families with clinical, genetic, and muscle MRI studies. In both index patients, muscle histopathologic studies were performed. Transfection studies were carried out to analyze the functional consequences of the disease-causing mutations.

Results:

We identified the mutations p.Ser107Leu and p.Thr703Met in the BICD2 gene in the 2 families, respectively. In contrast to other patients carrying the same mutations, our patients present features of a myopathy with slow progression. Immunofluorescence studies and immunoelectron microscopy showed striking impairment of Golgi integrity, vesicle pathology, and abnormal BICD2 accumulation either within the nuclei (p.Ser107Leu) or in the perinuclear region (p.Thr703Met). Transfection studies confirmed BICD2 aggregation in different subcellular locations.

Conclusions:

Our findings extend the phenotypic spectrum of BICD2-associated disorders by features of a chronic myopathy and show a pathomechanism of BICD2 defects in skeletal muscle.




Predicting survival after acute civilian penetrating brain injuries: The SPIN score

2016-11-21T12:45:31-08:00

Objective:

To identify predictors associated with survival in civilian penetrating traumatic brain injury (pTBI) utilizing a contemporary, large, diverse 2-center cohort, and to develop a parsimonious survival prediction score for pTBI.

Methods:

Our cohort comprised 413 pTBI patients retrospectively identified from the local trauma registries at 2 US level 1 trauma centers, of which one was predominantly urban and the other predominantly rural. Predictors of in-hospital and 6-month survival identified in univariate and multivariable logistic regression were used to develop the simple Surviving Penetrating Injury to the Brain (SPIN) score.

Results:

The mean age was 33 ± 16 years and patients were predominantly male (87%). Survival at hospital discharge as well as 6 months post pTBI was 42.4%. Higher motor Glasgow Coma Scale subscore, pupillary reactivity, lack of self-inflicted injury, transfer from other hospital, female sex, lower Injury Severity Score, and lower international normalized ratio were independently associated with survival (all p < 0.001; model area under the curve 0.962). Important radiologic factors associated with survival were also identified but their addition to the full multivariable would have resulted in model overfitting without much gain in the area under the curve.

Conclusions:

The SPIN score, a logistic regression–based clinical risk stratification scale estimating survival after pTBI, was developed in this large, diverse 2-center cohort. While this preliminary clinical survival prediction tool does not include radiologic factors, it may support clinical decision-making after civilian pTBI if external validation confirms the probability estimates.




Introducing the Axon Registry: An opportunity to improve quality of neurologic care

2016-11-21T12:45:31-08:00

Clinical quality data registries are increasingly popular tools used by providers to improve the quality of clinical care and satisfy growing numbers of regulatory and reporting requirements. Specialty societies use registries to provide value to their members and guide improvements in care at the population level. In this article, we outline the rationale, structure, function, and challenges related to the American Academy of Neurology's development of its own clinical quality data registry: the Axon Registry.




Charter on Physician Professional Flourishing

2016-11-21T12:45:31-08:00

Medical care delivery has adapted to scientific and societal change in the past. However, today's advancing scientific accomplishments and care capabilities, in the context of current societal and economic developments and our emerging digital age, are challenging physician resilience and endurance and trust in the medical profession. Why has this happened and can these characteristics and perceptions of physicians be reversed? The Charter on Physician Professional Flourishing is a method designed to restore the promise of the medical profession and trust in it. It describes a process to reinvigorate patient-centered care from the caregiving physician's perspective. It integrates discipline ethics, behavioral character ethics, and optimized physician–patient dialogue, while considering past, current, and predicted future context and professional sustainability. Its primary outcomes are enhanced quality of care and cost containment and the ability to reassert the voice of the patient in health care planning negotiations.




Formal faculty observation and assessment of bedside skills for 3rd-year neurology clerks

2016-11-21T12:45:31-08:00

Objective:

To evaluate the feasibility and utility of instituting a formalized bedside skills evaluation (BSE) for 3rd-year medical students on the neurology clerkship.

Methods:

A neurologic BSE was developed for 3rd-year neurology clerks at the University of Rochester for the 2012–2014 academic years. Faculty directly observed 189 students completing a full history and neurologic examination on real inpatients. Mock grades were calculated utilizing the BSE in the final grade, and number of students with a grade difference was determined when compared to true grade. Correlation was explored between the BSE and clinical scores, National Board of Medical Examiners (NBME) scores, case complexity, and true final grades. A survey was administered to students to assess their clinical skills exposure and the usefulness of the BSE.

Results:

Faculty completed and submitted a BSE form for 88.3% of students. There was a mock final grade change for 13.2% of students. Correlation coefficients between BSE score and clinical score/NBME score were 0.36 and 0.35, respectively. A statistically significant effect of BSE was found on final clerkship grade (F2,186 = 31.9, p < 0.0001). There was no statistical difference between BSE score and differing case complexities.

Conclusions:

Incorporating a formal faculty-observed BSE into the 3rd year neurology clerkship was feasible. Low correlation between BSE score and other evaluations indicated a unique measurement to contribute to student grade. Using real patients with differing case complexity did not alter the grade.




The urgent need for contemporary clinical trials in patients with asymptomatic carotid stenosis

2016-11-21T12:45:31-08:00

Asymptomatic extracranial internal carotid artery atherosclerotic stenosis increases with age and is more common in men. Studies performed more than 2 decades ago showed that carotid endarterectomy reduced the rate of stroke in carefully selected patients with asymptomatic carotid stenosis compared with medical therapy in the long term. Those trials were completed more than 20 years ago and with advances in the treatment of atherosclerotic disease, the question has been raised to as to whether endarterectomy is still of value for patients with asymptomatic narrowing. Perioperative risk of carotid revascularization procedures has also declined. Due to improvements in both medical and surgical treatments for carotid artery stenosis, it is timely to reevaluate the efficacy of carotid intervention relative to medical treatment for patients with asymptomatic stenosis.




Three-dimensional modeling of Eagle syndrome

2016-11-21T12:45:31-08:00

A 63-year-old man presented with transient episodes of left-hand weakness and right-eye vision loss following a lengthy airplane trip. The patient had reported right neck pain after sleeping awkwardly on the flight. Carotid dissection, paradoxical embolism, atherosclerotic occlusion, and thrombotic occlusion were considered possible etiologies of the associated carotid occlusion. Following a period of anticoagulation, a subsequent CT angiography (figure 1, A–C) revealed findings consistent with the styloid-carotid artery, or Eagle, syndrome.1 A 3-dimensional model was subsequently created (figure 2, A and B) utilizing a 3D printer, which provided the most versatile, safe, and cost-efficient option2 to visualize the patient's unique anatomy and plan for surgical intervention.




Atypical meningioma mimicking high-grade glioma

2016-11-21T12:45:31-08:00

A 52-year-old man presented following a motor vehicle collision. Examination revealed a Glasgow Coma Scale score of 15, with right lower extremity paresis. Noncontrast CT demonstrated a left frontal lesion. MRI further characterized the mass within the left superior frontal gyrus, suspicious for high-grade glioma (figure 1). Intraoperatively, the mass exhibited invasive margins, gross hypervascularity, and hemorrhage, without apparent dural attachment. Preliminary diagnosis was glial neoplasm. Final pathology was consistent with meningioma with focal brain invasion and rhabdoid differentiation, without anaplastic features, World Health Organization (WHO) grade II (figure 2). Outcome is correlated with WHO grade.1 Brain invasion is a new WHO diagnostic criterion of atypical meningioma.2













Pearls & Oy-sters: Plasma cell meningitis: An uncommon complication of multiple myeloma

2016-11-14T12:45:26-08:00

We report a case of plasma cell meningitis (PCM) presenting as a first-time seizure.




Right brain: The neurologist's blessing

2016-11-14T12:45:26-08:00




Teaching NeuroImages: Meningoencephalocele and CSF leak in chronic idiopathic intracranial hypertension

2016-11-14T12:45:26-08:00

A 63-year-old woman with epilepsy and chronic headaches was admitted for status epilepticus. A lumbar puncture revealed increased opening pressure of 320 mm H2O and bacterial meningitis. MRI brain demonstrated a partial empty sella, tortuous optic nerve sheaths, flattening of the optic papillae, and numerous prominent arachnoid granulations, consistent with chronic idiopathic intracranial hypertension (IIH), as well as bright CSF signal and brain parenchyma within a left meningoencephalocele (figure, A). A CT cisternogram confirmed communication of the subarachnoid space of the meningoencephalocele with the left sphenoid sinus through a small osseous defect (figure, B). While most CSF leaks are related to trauma, IIH is increasingly recognized as a cause of spontaneous leaks.1,2 While the increased opening pressure may have been due to her acute meningitis, her headache symptoms and MRI findings are suggestive of longstanding intracranial hypertension. Monitoring and medical treatment of IIH must accompany surgical repair to avoid recurrence.2




Teaching NeuroImages: Dynamic vertebral artery insufficiency

2016-11-14T12:45:26-08:00

A 20-year-old healthy man presented with transient right upper monoparesis and brain MRI (figure, A) demonstrated left thalamic infarct. He presented 2 weeks later with left hemiparesis at basketball practice and right thalamic infarct (figure, B). Stroke risk factor workup was unrevealing. Conventional angiography demonstrated normal left vertebral artery course (figure, C and E), but dynamic left vertebral artery occlusion during 36° rightward head turn (figure, D and F). Bow hunter syndrome, first described in an archer,1 is eponymous for positional occlusion of the vertebral artery. This is associated with strokes from dynamic hypoperfusion. The patient remains symptom-free 1 month after microsurgical clip sacrifice of the left vertebral artery.




Spotlight on the November 15 issue

2016-11-14T12:45:26-08:00




Rituximab for treating multiple sclerosis: Off-label but on target

2016-11-14T12:45:26-08:00

Physicians commonly use drugs off-label. A medication approved by the Food and Drug Administration and other regulatory agencies for one indication may be useful for treating others. An example is rituximab, which is a chimeric monoclonal antibody that targets CD20 on B cells. Rituximab lyses the targeted cells, resulting in prolonged depletion of circulating B cells. It is approved to treat B-cell malignancies, rheumatoid arthritis, Wegener granulomatosis, and microscopic polyarteritis. However, neurologists have successfully used rituximab off-label to treat neuroimmunologic diseases, including neuromyelitis optica, myasthenia gravis, autoimmune encephalitis, and autoimmune neuropathies and myopathies.1




Aerobic exercise: A possible therapy for vascular cognitive impairment

2016-11-14T12:45:26-08:00

Cerebrovascular disease is the second most common cause of cognitive impairment and dementia and contributes to cognitive decline in the neurodegenerative dementias.1 Vascular cognitive impairment (VCI) refers to all forms of mild to severe cognitive impairment associated with cerebrovascular disease. VCI is therefore heterogeneous not only because of the nature of the underlying lesions (associated with stroke or not) but also because of the various brain structures involved (damage to large or small vessels).2 It is also heterogeneous clinically, the term encompassing all cognitive disorders from subtle cognitive impairment to dementia.3,4 Despite this heterogeneity, some common risk factors are associated with VCI; these include usual vascular risk factors, but also aging and low physical activity.5 Although better management of vascular risk factors is associated with a lower incidence of stroke, the effect on the risk of dementia is less clear.1,4 Further, while numerous studies have shown that physical activity is associated with a reduced risk of cognitive decline and progression to dementia, the evidence for trials of physical activity interventions are sparse and short-term.6–8 The benefits of physical activity are several-fold and may include a reduced risk of cardiovascular disease, but other more complex mechanisms, such as an increase of brain neurotrophins or an effect on neurogenesis, may be involved.4 To date, no trials have focused on the target group of patients with VCI.




Rituximab in multiple sclerosis: A retrospective observational study on safety and efficacy

2016-11-14T12:45:26-08:00

Objective: To investigate the safety and efficacy of rituximab in multiple sclerosis (MS). Methods: In this retrospective uncontrolled observational multicenter study, off-label rituximab-treated patients with MS were identified through the Swedish MS register. Outcome data were collected from the MS register and medical charts. Adverse events (AEs) grades 2–5 according to the Common Terminology Criteria for Adverse Events were recorded. Results: A total of 822 rituximab-treated patients with MS were identified: 557 relapsing-remitting MS (RRMS), 198 secondary progressive MS (SPMS), and 67 primary progressive MS (PPMS). At baseline, 26.2% had contrast-enhancing lesions (CELs). Patients were treated with 500 or 1,000 mg rituximab IV every 6–12 months, during a mean 21.8 (SD 14.3) months. During treatment, the annualized relapse rates were 0.044 (RRMS), 0.038 (SPMS), and 0.015 (PPMS), and 4.6% of patients displayed CELs. Median Expanded Disability Status Scale remained unchanged in RRMS (p = 0.42) and increased by 0.5 and 1.0 in SPMS and PPMS, respectively (p = 0.10 and 0.25). Infusion-related AEs occurred during 7.8% of infusions and most were mild. A total of 89 AEs grades ≥2 (of which 76 infections) were recorded in 72 patients. No case of progressive multifocal leukoencephalopathy was detected. Conclusions: This is the largest cohort of patients with MS treated with rituximab reported so far. The safety, clinical, and MRI findings in this heterogeneous real-world cohort treated with different doses of rituximab were similar to those reported in previous randomized controlled trials on B-cell depletion therapy in MS. Classification of evidence: This study provides Class IV evidence that for patien[...]



Aerobic exercise and vascular cognitive impairment: A randomized controlled trial

2016-11-14T12:45:26-08:00

Objective: To assess the efficacy of a progressive aerobic exercise training program on cognitive and everyday function among adults with mild subcortical ischemic vascular cognitive impairment (SIVCI). Methods: This was a proof-of-concept single-blind randomized controlled trial comparing a 6-month, thrice-weekly, progressive aerobic exercise training program (AT) with usual care plus education on cognitive and everyday function with a follow-up assessment 6 months after the formal cessation of aerobic exercise training. Primary outcomes assessed were general cognitive function (Alzheimer's Disease Assessment Scale–Cognitive subscale [ADAS-Cog]), executive functions (Executive Interview [EXIT-25]), and activities of daily living (Alzheimer's Disease Cooperative Study–Activities of Daily Living [ADCS-ADL]). Results: Seventy adults randomized to aerobic exercise training or usual care were included in intention-to-treat analyses (mean age 74 years, 51% female, n = 35 per group). At the end of the intervention, the aerobic exercise training group had significantly improved ADAS-Cog performance compared with the usual care plus education group (–1.71 point difference, 95% confidence interval [CI] –3.15 to –0.26, p = 0.02); however, this difference was not significant at the 6-month follow-up (–0.63 point difference, 95% CI –2.34 to 1.07, p = 0.46). There were no significant between-group differences at intervention completion and at the 6-month follow-up in EXIT-25 or ADCS-ADL performance. Examination of secondary measures showed between-group differences at intervention completion favoring the AT group in 6-minute walk distance (30.35 meter differen[...]



Increasing comorbidity and health services utilization in older adults with prior stroke

2016-11-14T12:45:26-08:00

Objective: To characterize comorbid chronic conditions, describe health services use, and estimate health care costs among community-dwelling older adults with prior stroke. Methods: This is a retrospective cohort study using administrative data from Ontario, Canada. We identified all community-dwelling individuals aged 66 and over on April 1, 2008 (baseline), who had experienced a stroke at least 6 months prior. We estimated the prevalence of 14 comorbid conditions at baseline; we captured all physician visits, emergency department visits, hospital admissions, home care contacts, and associated costs over 5 years stratifying by number of comorbid conditions. Where possible, we distinguished between health services use for stroke- and non-stroke-related reasons. Results: A total of 29,673 individuals met our criteria. Only 1% had no comorbid conditions, while 74.9% had 3 or more. The most common conditions were hypertension (89.8%) and arthritis (65.8%); 5 other conditions had a prevalence of 20% or more (ischemic heart disease, diabetes, chronic obstructive pulmonary disease, inflammatory bowel disease, and dementia). Use of all health services doubled with increasing comorbidity and was largely attributed to non-stroke-related reasons. Total and per-patient costs increased with comorbidity. Main cost drivers shifted from physician and home care visits to hospital admissions with greater comorbidity. Conclusions: Our findings demonstrate the importance of community-based patient-centered care strategies for stroke survivors that address their range of health needs and prevent more costly acute care use. [...]



Electromyographic decoding of response to command in disorders of consciousness

2016-11-14T12:45:26-08:00

Objective:

To propose a new methodology based on single-trial analysis for detecting residual response to command with EMG in patients with disorders of consciousness (DOC), overcoming the issue of trial dependency and decreasing the influence of a patient's fluctuation of vigilance or arousal over time on diagnostic accuracy.

Methods:

Forty-five patients with DOC (18 with vegetative/unresponsive wakefulness syndrome [VS/UWS], 22 in a minimally conscious state [MCS], 3 who emerged from MCS [EMCS], and 2 with locked-in syndrome [LIS]) and 20 healthy controls were included in the study. Patients were randomly instructed to either move their left or right hand or listen to a control command ("It is a sunny day") while EMG activity was recorded on both arms.

Results:

Differential EMG activity was detected in all MCS cases displaying reproducible response to command at bedside on multiple assessments, even though only 6 of the 14 individuals presented a behavioral response to command on the day of the EMG assessment. An EMG response was also detected in all EMCS and LIS patients, and 2 MCS patients showing nonreflexive movements without command following at the bedside. None of the VS/UWS presented a response to command with this method.

Conclusions:

This method allowed us to reliably distinguish between different levels of consciousness and could potentially help decrease diagnostic errors in patients with motor impairment but presenting residual motor activity.




Heterogeneous cortical atrophy patterns in MCI not captured by conventional diagnostic criteria

2016-11-14T12:45:26-08:00

Objective: We investigated differences in regional cortical thickness between previously identified empirically derived mild cognitive impairment (MCI) subtypes (amnestic MCI, dysnomic MCI, dysexecutive/mixed MCI, and cluster-derived normal) in order to determine whether these cognitive subtypes would show different patterns of cortical atrophy. Methods: Participants were 485 individuals diagnosed with MCI and 178 cognitively normal individuals from the Alzheimer's Disease Neuroimaging Initiative. Cortical thickness estimates were computed for 32 regions of interest per hemisphere. Statistical group maps compared each MCI subtype to cognitively normal participants and to one another. Results: The pattern of cortical thinning observed in each MCI subtype corresponded to their cognitive profile. No differences in cortical thickness were found between the cluster-derived normal MCI subtype and the cognitively normal group. Direct comparison between MCI subtypes suggested that the cortical thickness patterns reflect increasing disease severity. Conclusions: There is an ordered pattern of cortical atrophy among patients with MCI that coincides with their profiles of increasing cognitive dysfunction. This heterogeneity is not captured when patients are grouped by conventional diagnostic criteria. Results in the cluster-derived normal group further support the premise that the conventional MCI diagnostic criteria are highly susceptible to false-positive diagnostic errors. Findings suggest a need to (1) improve the diagnostic criteria by reducing reliance on conventional screening measures, rating scales, and a sin[...]



Death with dignity in Washington patients with amyotrophic lateral sclerosis

2016-11-14T12:45:26-08:00

Objectives: To describe the amyotrophic lateral sclerosis (ALS) patients who sought medication under the Washington State Death with Dignity (DWD) Act since its inception in 2009. Methods: Chart review at 3 tertiary medical centers in the Seattle/Puget Sound region and comparison to publicly available data of ALS and all-cause DWD cohorts from Washington and Oregon. Results: In Washington State, 39 patients with ALS requested DWD from the University of Washington, Virginia Mason, and Swedish Medical Centers beginning in 2009. The median age at death was 65 years (range 46–86). Seventy-seven percent of the patients used the prescriptions. All of the patients who used the medications passed away without complications. The major reasons for patients to request DWD as reported by participating physicians were loss of autonomy and dignity and decrease in enjoyable activities. Inadequate pain control, financial cost, and loss of bodily control were less commonly indicated. These findings were similar to those of the 92 patients who sought DWD in Oregon. In Washington and Oregon, the percentage of patients with ALS seeking DWD is higher compared to the cancer DWD cohort. Furthermore, compared to the all-cause DWD cohort, patients with ALS are more likely to be non-Hispanic white, married, educated, enrolled in hospice, and to have died at home. Conclusions: Although a small number, ALS represents the disease with the highest proportion of patients seeking to participate in DWD. Patients with ALS who choose DWD are well-educated and have access to palliative or life-prolonging care.[...]



Efficacy and safety of deflazacort vs prednisone and placebo for Duchenne muscular dystrophy

2016-11-14T12:45:26-08:00

Objective: To assess safety and efficacy of deflazacort (DFZ) and prednisone (PRED) vs placebo in Duchenne muscular dystrophy (DMD). Methods: This phase III, double-blind, randomized, placebo-controlled, multicenter study evaluated muscle strength among 196 boys aged 5–15 years with DMD during a 52-week period. In phase 1, participants were randomly assigned to receive treatment with DFZ 0.9 mg/kg/d, DFZ 1.2 mg/kg/d, PRED 0.75 mg/kg/d, or placebo for 12 weeks. In phase 2, placebo participants were randomly assigned to 1 of the 3 active treatment groups. Participants originally assigned to an active treatment continued that treatment for an additional 40 weeks. The primary efficacy endpoint was average change in muscle strength from baseline to week 12 compared with placebo. The study was completed in 1995. Results: All treatment groups (DFZ 0.9 mg/kg/d, DFZ 1.2 mg/kg/d, and PRED 0.75 mg/kg/d) demonstrated significant improvement in muscle strength compared with placebo at 12 weeks. Participants taking PRED had significantly more weight gain than placebo or both doses of DFZ at 12 weeks; at 52 weeks, participants taking PRED had significantly more weight gain than both DFZ doses. The most frequent adverse events in all 3 active treatment arms were Cushingoid appearance, erythema, hirsutism, increased weight, headache, and nasopharyngitis. Conclusions: After 12 weeks of treatment, PRED and both doses of DFZ improved muscle strength compared with placebo. Deflazacort was associated with less weight gain than PRED. Classification of evidence: This st[...]



Evaluation of dysphagia by novel real-time MRI

2016-11-14T12:45:26-08:00

Objective: To assess safety and feasibility of real-time (RT) MRI for evaluation of dysphagia and to compare this technique to standard assessment by flexible endoscopic evaluation of swallowing (FEES) and videofluoroscopy (VF) in a cohort of patients with inclusion body myositis (IBM). Methods: Using RT-MRI, FEES, and VF, an unselected cohort of 20 patients with IBM was studied as index disease with a uniform dysphagia. Symptoms of IBM and dysphagia were explored by standardized tools including Swallowing-Related Quality of Life Questionnaire (SWAL-QoL), IBM Functional Rating Scale, Patient-Reported Functional Assessment, and Medical Research Council Scale. Results: Dysphagia was noted in 80% of the patients and SWAL-QoL was impaired in patients with IBM compared to published reference values of healthy elderly. Swallowing in a supine position during RT-MRI was well-tolerated by all patients. RT-MRI equally revealed dysphagia compared to VF and FEES and correlated well with the SWAL-QoL. Only RT-MRI allowed precise time measurements and identification of the respective tissue morphology. The pharyngeal transit times were 2-fold longer compared to published reference values and significantly correlated with morphologic abnormalities. Conclusions: RT-MRI is safe and equally capable as VF to identify the cause of dysphagia in IBM. Advantages of RT-MRI include visualization of soft tissue, more reliable timing analysis, and lack of X-ray exposure. RT-MRI may become a routine diagnostic tool for detailed assessment of the esophagu[...]



Increased risk for clinical onset of myasthenia gravis during the postpartum period

2016-11-14T12:45:26-08:00

Objective: To study the risk of clinical onset of myasthenia gravis (MG) in pregnancy and during the first 6 months postpartum because an association between pregnancy or the postpartum period and the onset of autoimmune MG is widely assumed but not proven. Methods: The design was a cross-sectional population-based cohort study of 2 MG cohorts (Norway and the Netherlands) with 1,038 healthy controls from Norway. Data were obtained on 246 women with MG (age at onset 15–45 years). Data on pregnancy, hormonal factors, and clinical symptoms were collected by a previously validated environmental MG questionnaire. Relative risk of MG onset before, during, and after pregnancy was calculated by multinomial logistic regression for Norwegian women reaching 45 years of age, adjusted for the observed distribution of person-years in the corresponding control group. Results: Of the included women with MG, 13 (11.5%) of the Dutch and 24 (18.0%) of the Norwegian patients had their first myasthenia symptoms during the pregnancy or postpartum period. The postpartum period was confirmed to be significantly associated with the onset of symptoms of MG in Norwegian women with MG (relative risk 5.5, 95% confidence interval 2.6–11.6). The risk was highest after the first childbirth. Conclusions: Women have a high-risk period for the onset of clinical symptoms of MG in the postpartum period, in particular after the first childbirth. Future studies should aim at elucidating the role of the hormonal-immunological-g[...]



Objective, computerized video-based rating of blepharospasm severity

2016-11-14T12:45:26-08:00

Objective:

To compare clinical rating scales of blepharospasm severity with involuntary eye closures measured automatically from patient videos with contemporary facial expression software.

Methods:

We evaluated video recordings of a standardized clinical examination from 50 patients with blepharospasm in the Dystonia Coalition's Natural History and Biorepository study. Eye closures were measured on a frame-by-frame basis with software known as the Computer Expression Recognition Toolbox (CERT). The proportion of eye closure time was compared with 3 commonly used clinical rating scales: the Burke-Fahn-Marsden Dystonia Rating Scale, Global Dystonia Rating Scale, and Jankovic Rating Scale.

Results:

CERT was reliably able to find the face, and its eye closure measure was correlated with all of the clinical severity ratings (Spearman = 0.56, 0.52, and 0.56 for the Burke-Fahn-Marsden Dystonia Rating Scale, Global Dystonia Rating Scale, and Jankovic Rating Scale, respectively, all p < 0.0001).

Conclusions:

The results demonstrate that CERT has convergent validity with conventional clinical rating scales and can be used with video recordings to measure blepharospasm symptom severity automatically and objectively. Unlike EMG and kinematics, CERT requires only conventional video recordings and can therefore be more easily adopted for use in the clinic.




Thalamo-cortical network activity during spontaneous migraine attacks

2016-11-14T12:45:26-08:00

Objective: We used MRI to search for changes in thalamo-cortical networks and thalamic microstructure during spontaneous migraine attacks by studying at the same time structure with diffusion tensor imaging and resting state function in interconnected brain networks with independent component analysis. Methods: Thirteen patients with untreated migraine without aura (MI) underwent 3T MRI scans during an attack and were compared to a group of 19 healthy controls (HC). We collected resting state data in 2 selected networks identified using group independent component (IC) analysis. Fractional anisotropy (FA) values of bilateral thalami were calculated in the same participants and correlated with resting state IC z scores. Results: Functional connectivity between the executive and the dorso-ventral attention networks was reduced in MI compared to HC. In HC, but not in MI, the higher the IC24 z score, encompassing interconnected areas of the dorso-ventral attention system, the lower the bilateral thalamic FA values. In patients, the higher the executive control network z scores, the lower the number of monthly migraine days. Conclusions: These results provide evidence for abnormal connectivity between the thalamus and attentional cerebral networks at rest during migraine attacks. This abnormality could subtend the known ictal impairment of cognitive performance and suggests that the latter might worsen with increasing attack frequency. [...]



Mediodorsal nucleus and its multiple cognitive functions

2016-11-14T12:45:26-08:00

The mediodorsal nucleus of the thalamus (MDT) is one of the largest thalamic nuclei and is a typical association nucleus, participating in several cortico-subcortical networks, primarily those involving the prefrontal cortex.1–3 Pathologic involvement of the MDT or its cortical connections contributes to the cognitive, emotional, and behavioral manifestations of stroke4–6; metabolic disorders, such as Wernicke encephalopathy7; inflammatory disorders, such as multiple sclerosis8; prion disorders, such as fatal familial insomnia9 and Creutzfeldt-Jakob disease10; and neurodegenerative diseases, such as Alzheimer disease,11 dementia with Lewy bodies,12 and Parkinson disease.13 The MDT also participates in the pathophysiology of epilepsy14,15 and schizophrenia.16 The following case shows that its involvement affects wide cortical areas and produces disabling symptoms that may not be associated with objective abnormalities in neuropsychometric testing.




Recurrent cryptogenic stroke in young adult linked to congenital left ventricular diverticulum

2016-11-14T12:45:26-08:00

A 47-year-old man had an acute ischemic stroke (IS); brain MRI revealed multiple silent old IS (figure 1A). A comprehensive workup, including prolonged cardiac monitoring (cumulated duration of 25 days) and cardiac transthoracic/transesophageal echography, was negative. Eleven months later, despite statin and aspirin therapy, a new symptomatic embolic IS of undetermined source occurred (figure 1B). Cardiac MRI1 revealed a left apical dyskinetic saccular evagination (figure 2, A–C) consistent with a congenital left ventricular diverticulum confirmed on left ventriculography (figure 2D) and the presumed source of recurrent embolic IS.2 No IS occurred after 30 months of warfarin therapy.




A huge intramedullary solitary fibrous tumor

2016-11-14T12:45:26-08:00

A 31-year-old man presented with a 3-year history of progressive weakness and paresthesias of both legs. Spinal MRI revealed a 10-cm intraspinal tumor at T1-T5 with syringomyelia on both ends (figure, A–C). Surgery successfully resected the intramedullary tumor grossly (figure, D and E). Pathology suggested the diagnosis of solitary fibrous tumor (figure, F–P). Intramedullary solitary fibrous tumors are rare, with approximately 17 cases reported and none longer than 2 vertebrae.1