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Recovering

2017-03-27T12:45:31-07:00




Clinical Reasoning: A 13-year-old boy with chronic ataxia and developmental delay

2017-03-27T12:45:31-07:00

A 13-year-old boy presented to the neurology clinic for evaluation of ataxia and intellectual disability. He was born at term via vaginal delivery after an uncomplicated pregnancy with no perinatal complications. Newborn screening (Virginia, 2012) was normal. He was first noted to be ataxic at age 6 months (when he began to sit with support) and his symptoms gradually worsened over time. He had global developmental delay. He began to sit at 14 months of age and walked at 20 months. He had his first words around age 2 and received physical and speech therapy early on. He had acute worsening of his symptoms at age 8 months in the setting of a flu-like illness and was admitted to a local hospital. Workup at the time was reportedly unrevealing and included a normal CT and a normal brain MRI with contrast. His ataxia remained fairly stable over time without regression. He had several episodes of acute worsening with febrile illnesses. He continued to have learning problems at school.




Emerging Subspecialties in Neurology: Headache medicine

2017-03-27T12:45:31-07:00

Headache disorders affect half of the adult population and are considered one of the top 3 medical causes of disability worldwide.1 There are over 300 different headache disorders. Hence, the diagnosis requires critical thinking.2 Patients' symptoms often improve, so the treatment process is rewarding. While headache subspecialists have been studying the causes and potential treatments for a long time, substantial progress is now being made in the headache field. The headache field is emerging with the growth of academic headache centers and headache fellowship programs, new understanding of the pathophysiology of headache disorders, expanding therapeutic options, and the development of neurostimulation devices and immunotherapy. Headache fellowship programs started to be accredited in 2005 and have been rapidly increasing in number.3 There are still not enough headache subspecialists to meet the national need and the majority of neurology residents are not exposed to the headache field while in residency.3–5 We describe the history of the headache field, recent advances, and information about training and working in the headache field.




Comment: Headache medicine as an emerging subspecialty--Irony and reality

2017-03-27T12:45:31-07:00

In a narrative review, Begasse de Dhaem and Minen reframe headache medicine as an emerging subspecialty of neurology.1 The authors provide a timeline spanning 2 millennia that chronicles historical, educational, scientific, diagnostic, and therapeutic developments in the field. Headache medicine as a discipline has existed for over half of a century, with organizational efforts long led by what is now known as the American Headache Society. The vast majority of headache specialists have been neurologists.




Teaching Video NeuroImages: Hyperekplexia: A syndrome of pathologic startle responses

2017-03-27T12:45:31-07:00

A 47-year-old man has had pathologic startles (video at Neurology.org) since early childhood. Unexpected stimuli triggered startles and rigid traumatic falls in full awareness. Clonazepam markedly reduced abnormal startle and limited falls. Two of his children have similar symptoms.




Migraine relief: Nonpainful stimulation for acute attacks

2017-03-27T12:45:31-07:00

In their article "Nonpainful remote electrical stimulation alleviates episodic migraine pain," Dr. Yarnitsky et al.1 investigated the use of nonpainful electrical stimulation of the skin of the arm in reducing migraine attacks. Therapeutic electrical stimulation has been widely used for pain treatment. It is believed to be effective when applying the stimulation next to the painful location. For example, the Food and Drug Administration has approved the first device for migraine prevention using electrical stimulation to the area above the eyes. A number of other neurostimulators are under investigation for migraine.2 The idea is to activate parts of the brain with connections to the spine. Triggering pain systems that are remote from the site of migraine pain can relieve pain. In this case, the authors used nonpainful stimulation as a trigger for relief. The idea was to create a conditioned response. This means that giving electrical stimulation at low intensity to a different part of the body will send signals to the brain that then stop or reduce the migraine attack. The authors thought it would be easier to apply electrical stimulation to the lower arm than the head (figure).




Spotlight on the March 28 issue

2017-03-27T12:45:31-07:00




Variation in MS outcome: Race, place, or both?

2017-03-27T12:45:31-07:00

The course of multiple sclerosis (MS) is highly variable, manifest by a wide range in age at onset, either relapsing or progressive course from onset, and major differences in attack severity and recovery.1 Not surprisingly, the rate and age at which severe and permanent disabilities are attained are also highly variable. Most of these descriptors of outcome are generally considered independently of one another, as are the clinical and radiologic features of disease; however, certain features cluster and may define unique subtypes of CNS demyelinating disease. For example, neuromyelitis optica spectrum disorders (NMOSD), which had been traditionally considered as a type of MS, are characterized by older age at onset, relative selectivity for certain parts of the nervous system, and lack of association with a progressive course despite being associated with severe attacks.2 Until it was recognized that these characteristics define a unique subtype of disease, NMOSD was included in studies of prototypic MS, thereby distorting the perceived clinical course of MS. Furthermore, because NMOSD is associated with black ancestry, spurious conclusions were made about an association of black ancestry with severe attacks and adverse outcomes of MS. Quantitative differences in MS course also associate with race/ethnicity in individuals with MS, even when patients with NMOSD are excluded. African Americans have a worse prognosis than whites3; whites have a worse prognosis than Japanese.4




Persistent brain injury after preeclampsia

2017-03-27T12:45:31-07:00

Preeclampsia, a common hypertensive disorder of pregnancy, contributes substantially to maternal and fetal morbidity and mortality worldwide. While the cause of preeclampsia remains debated, it is clear that there are both placental and maternal causes of preeclampsia, making it a heterogeneous disease.1 Abnormal trophoblast invasion of spiral arteries during placentation leads to placental ischemia and release of placental-derived soluble factors into the maternal circulation.2 These circulating proinflammatory and antiangiogenic factors appear to produce maternal vascular inflammation and cause endothelial dysfunction that underlies hypertension and proteinuria associated with preeclampsia.1,2 However, not all women with preeclampsia have placental dysfunction. In these cases, the physiologic burden of pregnancy, characterized by mild peripheral inflammation, is thought to unmask preexisting maternal vascular dysfunction.1 The presence of both maternal and placental disease leads to the most severe and early-onset form of the disorder.1 Because of this heterogeneity, preeclampsia has been subclassified by clinical severity determined by maternal and fetal characteristics. Preeclampsia is considered severe if it is complicated by fetal growth restriction, which is strongly associated with placental dysfunction and early-onset disease. Subclassification of preeclamptic disease relating to time of delivery has also facilitated understanding the cause and complications of preeclampsia. For example, early-onset preeclampsia is a severe form of the condition involving maternal and placental disease in which delivery occurs ≤34 weeks of gestation, whereas late-onset preeclampsia is typically a more mild form of disease in which delivery occurs >34 weeks of gestation.1




Fast multiple sclerosis progression in North Africans: Both genetics and environment matter

2017-03-27T12:45:31-07:00

Objective:

To compare multiple sclerosis (MS) disability progression among North Africans (NAs) living in France (NAF) and in Tunisia (NAT) and Caucasian patients born and living in France (CF).

Methods:

Patients with MS admitted to the day hospital in the Neurology Department at Pitié-Salpêtrière Hospital (France) and Razi Hospital (Tunisia) were questioned on their place of birth and the place of birth of their parents. To compare delay to outcomes, log-rank tests were used. Univariate and multivariate Cox models were used to determine factors influencing time to Expanded Disability Status Scale (EDSS) 6.

Results:

We consecutively included 462 patients: 171 CF, 151 NAT, and 140 NAF. Sex ratio, disease forms, and delay from disease onset to diagnosis were similar between the groups. NAF differed from other groups, with a shorter median time to reach EDSS 3, 4, and 6, and a more frequent incomplete recovery after first relapse (p < 0.0001). Furthermore, the NA second-generation group showed the youngest median age at onset (26.5 ± 8.8 years, p = 0.001), the shortest median time to EDSS 6 in relapsing-remitting patients, and an increased mean number of relapses during the first 5 years of the disease (6.1 ± 3.7, p = 0.01) compared to CF. The Cox proportional hazard models demonstrate that (1) NA ethnicity is a significant predictor of fast progression even when adjusting for major covariates and (2) treatment did not influence the models.

Conclusion:

Our study further supports severity of MS in NAs and unravels the particular severity in NAs living in France, mainly for the second generation.




Genetic heterogeneity of motor neuropathies

2017-03-27T12:45:31-07:00

Objective:

To study the prevalence, molecular cause, and clinical presentation of hereditary motor neuropathies in a large cohort of patients from the North of England.

Methods:

Detailed neurologic and electrophysiologic assessments and next-generation panel testing or whole exome sequencing were performed in 105 patients with clinical symptoms of distal hereditary motor neuropathy (dHMN, 64 patients), axonal motor neuropathy (motor Charcot-Marie-Tooth disease [CMT2], 16 patients), or complex neurologic disease predominantly affecting the motor nerves (hereditary motor neuropathy plus, 25 patients).

Results:

The prevalence of dHMN is 2.14 affected individuals per 100,000 inhabitants (95% confidence interval 1.62–2.66) in the North of England. Causative mutations were identified in 26 out of 73 index patients (35.6%). The diagnostic rate in the dHMN subgroup was 32.5%, which is higher than previously reported (20%). We detected a significant defect of neuromuscular transmission in 7 cases and identified potentially causative mutations in 4 patients with multifocal demyelinating motor neuropathy.

Conclusions:

Many of the genes were shared between dHMN and motor CMT2, indicating identical disease mechanisms; therefore, we suggest changing the classification and including dHMN also as a subcategory of Charcot-Marie-Tooth disease. Abnormal neuromuscular transmission in some genetic forms provides a treatable target to develop therapies.




Netrin-1 receptor antibodies in thymoma-associated neuromyotonia with myasthenia gravis

2017-03-27T12:45:31-07:00

Objective:

To identify cell-surface antibodies in patients with neuromyotonia and to describe the main clinical implications.

Methods:

Sera of 3 patients with thymoma-associated neuromyotonia and myasthenia gravis were used to immunoprecipitate and characterize neuronal cell-surface antigens using reported techniques. The clinical significance of antibodies against precipitated proteins was assessed with sera of 98 patients (neuromyotonia 46, myasthenia gravis 52, thymoma 42; 33 of them with overlapping syndromes) and 219 controls (other neurologic diseases, cancer, and healthy volunteers).

Results:

Immunoprecipitation studies identified 3 targets, including the Netrin-1 receptors DCC (deleted in colorectal carcinoma) and UNC5A (uncoordinated-5A) as well as Caspr2 (contactin-associated protein-like 2). Cell-based assays with these antigens showed that among the indicated patients, 9 had antibodies against Netrin-1 receptors (7 with additional Caspr2 antibodies) and 5 had isolated Caspr2 antibodies. Only one of the 219 controls had isolated Caspr2 antibodies with relapsing myelitis episodes. Among patients with neuromyotonia and/or myasthenia gravis, the presence of Netrin-1 receptor or Caspr2 antibodies predicted thymoma (p < 0.05). Coexisting Caspr2 and Netrin-1 receptor antibodies were associated with concurrent thymoma, myasthenia gravis, and neuromyotonia, often with Morvan syndrome (p = 0.009). Expression of DCC, UNC5A, and Caspr2 proteins was demonstrated in paraffin-embedded thymoma samples (3) and normal thymus.

Conclusions:

Antibodies against Netrin-1 receptors (DCC and UNC5a) and Caspr2 often coexist and associate with thymoma in patients with neuromyotonia and myasthenia gravis.

Classification of evidence:

This study provides Class III evidence that antibodies against Netrin-1 receptors can identify patients with thymoma (sensitivity 21.4%, specificity 100%).




Behavioral measures of cortical hyperexcitability assessed in people who experience visual snow

2017-03-27T12:45:31-07:00

Objective:

To determine whether visual perceptual measures in people who experience visual snow are consistent with an imbalance between inhibition and excitation in visual cortex.

Methods:

Sixteen patients with visual snow and 18 controls participated. Four visual tasks were included: center-surround contrast matching, luminance increment detection in noise, and global form and global motion coherence thresholds. Neuronal architecture capable of encoding the luminance and contrast stimuli is present within primary visual cortex, whereas the extraction of global motion and form signals requires extrastriate processing. All these tasks have been used previously to investigate the balance between inhibition and excitation within the visual system in both healthy and diseased states.

Results:

The visual snow group demonstrated reduced center-surround contrast suppression (p = 0.03) and elevated luminance increment thresholds in noise (p = 0.02). Groups did not differ on the global form or global motion task.

Conclusion:

Our study demonstrates that visual perceptual measures involving the suprathreshold processing of contrast and luminance are abnormal in a group of individuals with visual snow. Our data are consistent with elevated excitability in primary visual cortex; however, further research is required to provide more direct evidence for this proposed mechanism. The ability to measure perceptual differences in visual snow reveals promise for the future development of clinical tests to assist in visual snow diagnosis and possibly a method for quantitatively assaying any benefits of treatments.




Nonpainful remote electrical stimulation alleviates episodic migraine pain

2017-03-27T12:45:31-07:00

Objective:

To evaluate the efficacy of remote nonpainful electrical upper arm skin stimulation in reducing migraine attack pain.

Methods:

This is a prospective, double-blinded, randomized, crossover, sham-controlled trial. Migraineurs applied skin electrodes to the upper arm soon after attack onset for 20 minutes, at various pulse widths, and refrained from medications for 2 hours. Patients were asked to use the device for up to 20 attacks.

Results:

In 71 patients (299 treatments) with evaluable data, 50% pain reduction was obtained for 64% of participants based on best of 200-μs, 150-μs, and 100-μs pulse width stimuli per individual vs 26% for sham stimuli. Greater pain reduction was found for active stimulation vs placebo; for those starting at severe or moderate pain, reduction (1) to mild or no pain occurred in 58% (25/43) of participants (66/134 treatments) for the 200-μs stimulation protocol and 24% (4/17; 8/29 treatments) for placebo (p = 0.02), and (2) to no pain occurred in 30% (13/43) of participants (37/134 treatments) and 6% (1/17; 5/29 treatments), respectively (p = 0.004). Earlier application of the treatment, within 20 minutes of attack onset, yielded better results: 46.7% pain reduction as opposed to 24.9% reduction when started later (p = 0.02).

Conclusion:

Nonpainful remote skin stimulation can significantly reduce migraine pain, especially when applied early in an attack. This is presumably by activating descending inhibition pathways via the conditioned pain modulation effect. This treatment may be proposed as an attractive nonpharmacologic, easy to use, adverse event free, and inexpensive tool to reduce migraine pain.

ClinicalTrials.gov identifier:

NCT02453399.

Classification of evidence:

This study provides Class III evidence that for patients with an acute migraine headache, remote nonpainful electrical stimulation on the upper arm skin reduces migraine pain.




Long-term cerebral white and gray matter changes after preeclampsia

2017-03-27T12:45:31-07:00

Objective:

To determine whether changes in cerebral structure are present after preeclampsia that may explain increased cerebrovascular risk in these women.

Methods:

We conducted a case control study in women between 5 and 15 years after either a preeclamptic or normotensive pregnancy. Brain MRI was performed. Analysis of white matter structure was undertaken using voxel-based segmentation of fluid-attenuation inversion recovery sequences to assess white matter lesion volume and diffusion tensor imaging to measure microstructural integrity. Voxel-based analysis of gray matter volumes was performed with adjustment for skull size.

Results:

Thirty-four previously preeclamptic women (aged 42.8 ± 5.1 years) and 49 controls were included. Previously preeclamptic women had reduced cortical gray matter volume (523.2 ± 30.1 vs 544.4 ± 44.7 mL, p < 0.05) and, although both groups displayed white matter lesions, changes were more extensive in previously preeclamptic women. They displayed increased temporal lobe white matter disease (lesion volume: 23.2 ± 24.9 vs 10.9 ± 15.0 μL, p < 0.05) and altered microstructural integrity (radial diffusivity: 538 ± 19 vs 526 ± 18 x 10–6 mm2/s, p < 0.01), which also extended to occipital and parietal lobes. The degree of temporal lobe white matter change in previously preeclamptic women was independent of their current cardiovascular risk profile (p < 0.05) and increased with time from index pregnancy (p < 0.05).

Conclusion:

A history of preeclampsia is associated with temporal lobe white matter changes and reduced cortical volume in young women, which is out of proportion to their classic cardiovascular risk profile. The severity of changes is proportional to time since pregnancy, which would be consistent with continued accumulation of damage after pregnancy.




Corpus callosal atrophy and associations with cognitive impairment in Parkinson disease

2017-03-27T12:45:31-07:00

Objective:

To investigate atrophy of the corpus callosum on MRI in Parkinson disease (PD) and its relationship to cognitive impairment.

Methods:

One hundred patients with PD and 24 healthy control participants underwent clinical and neuropsychological evaluations and structural MRI brain scans. Participants with PD were classified as cognitively normal (PD-NC; n = 28), having mild cognitive impairment (PD-MCI; n = 47), or having dementia (PDD; n = 25) by Movement Disorder Society criteria. Cognitive domain (attention/working memory, executive function, memory, language, visuospatial function) z scores were calculated. With the use of FreeSurfer image processing, volumes for total corpus callosum and its subsections (anterior, midanterior, central, midposterior, posterior) were computed and normalized by total intracranial volume. Callosal volumes were compared between participants with PD and controls and among PD cognitive groups, covarying for age, sex, and PD duration and with multiple comparison corrections. Regression analyses were performed to evaluate relationships between callosal volumes and performance in cognitive domains.

Results:

Participants with PD had reduced corpus callosum volumes in midanterior and central regions compared to healthy controls. Participants with PDD demonstrated decreased callosal volumes involving multiple subsections spanning anterior to posterior compared to participants with PD-MCI and PD-NC. Regional callosal atrophy predicted cognitive domain performance such that central volumes were associated with the attention/working memory domain; midposterior volumes with executive function, language, and memory domains; and posterior volumes with memory and visuospatial domains.

Conclusions:

Notable volume loss occurs in the corpus callosum in PD, with specific neuroanatomic distributions in PDD and relationships of regional atrophy to different cognitive domains. Callosal volume loss may contribute to clinical manifestations of PD cognitive impairment.




Differentiating cognitive impairment due to corticobasal degeneration and Alzheimer disease

2017-03-27T12:45:31-07:00

Objective:

To identify clinical features that reliably differentiate individuals with cognitive impairment due to corticobasal degeneration (CBD) and Alzheimer disease (AD).

Methods:

Clinical features were compared between individuals with autopsy-proven CBD (n = 17) and AD (n = 16). All individuals presented with prominent cognitive complaints and were evaluated annually with semistructured interviews, detailed neurologic examinations, and neuropsychological testing.

Results:

Substantial overlap was observed between individuals with dementia due to CBD and AD concerning presenting complaints, median (range) duration of symptoms before assessment (CBD = 3.0 [0–5.0] years, AD = 2.5 [0–8.0] years; p = 0.96), and median (range) baseline dementia severity (Clinical Dementia Rating Sum of Boxes: CBD = 3.5 [0–12.0], AD = 4.25 [0.5–9.0], p = 0.49). Subsequent emergence of asymmetric motor/sensory signs, hyperreflexia, gait abnormalities, parkinsonism, falls, urinary incontinence, and extraocular movement abnormalities identified individuals with CBD, with ≥3 discriminating features detected in 80% of individuals within 3.1 years (95% confidence interval 2.9–3.3) of the initial assessment. Individuals with CBD exhibited accelerated worsening of illness severity and declines in episodic memory, executive functioning, and letter fluency. Semiquantitative pathologic assessment revealed prominent tau pathology within the frontal and parietal lobes of CBD cases. Comorbid AD neuropathologic change was present in 59% (10 of 17) of CBD cases but did not associate with the clinical phenotype, rate of dementia progression, or dementia duration.

Conclusions:

CBD may mimic AD dementia early in its disease course. Interval screening for discriminating clinical features may improve antemortem diagnosis in individuals with CBD and prominent cognitive symptoms.




Clinical implications of the melanopsin-based non-image-forming visual system

2017-03-27T12:45:31-07:00

Since the discovery of the non–image-forming visual system, tremendous research efforts have been dedicated to understanding its mechanisms and functional roles. Original functions associated with the melanopsin system include the photoentrainment of circadian sleep-wake cycles and the pupillary light reflex. Recent findings, however, suggest a much broader involvement of this system in an array of physiologic responses to light. This newfound insight into the underlying function of the non–image-forming system has revealed the many connections to human pathology and attendant disease states, including seasonal affective disorder, migraine, glaucoma, inherited mitochondrial optic neuropathy, and sleep dysregulation of aging. In this review, the authors discuss in detail the clinical implications of the melanopsin system.




BRAF/MEK double blockade in refractory anaplastic pleomorphic xanthoastrocytoma

2017-03-27T12:45:31-07:00

A 32-year-old woman was diagnosed in February 2012 with a grade II pleomorphic xanthoastrocytoma (PXA) of the right parietal lobe. A complete excision was performed, followed by tumor bed irradiation (66 Gy). A local relapse occurred in September 2013, for which a partial resection was performed, confirming a grade II PXA. Immunohistochemical analysis indicated the presence of a BRAFV600E mutated protein, and combined treatment with vemurafenib and bevacizumab was initiated. A partial response was rapidly obtained, sustained for 12 months. In June 2015, a third surgery was performed for an extended relapse invading the right cerebral hemisphere. Histopathologic examination revealed anaplastic (grade III) PXA and confirmed the presence of the BRAFV600E mutation (figure, A and B). After unsuccessful treatment with bevacizumab and lomustine, tumor treating fields therapy was applied between August and December 2015. Treatment was complicated by severe skin toxicity, with progressive appearance of a 4-cm scalp wound. Concurrently, the patient developed a severe left hemiparesis with ataxia, hemispatial neglect, and central facial palsy. MRI revealed major disease progression. The patient was subsequently referred to our institution.




Spontaneous intracranial hypotension diagnosed as Chiari I malformation

2017-03-27T12:45:31-07:00

A 44-year-old man presented for evaluation with a recent MRI diagnosis of a Chiari I malformation without hydrocephalus and a 5-month history of gradually worsening daily headache. He described 10/10 occipital pressure spreading holocranially, triggered by Valsalva, and worsened with prolonged standing. He was pain-free within 10 minutes of lying supine. His initial imaging showed a 17-mm Chiari I malformation. Repeat imaging is demonstrated in the figure. Several upper thoracic disc extrusions are potential etiologies for the leak, particularly at T1-T2. This case illustrates that a CSF leak can be mistaken for a Chiari I malformation radiographically.




Editors' Note

2017-03-27T12:45:31-07:00

Editors' Note: Commenting on "Zoonotic bacterial meningitis in human adults," Tan et al. share their experience with a large foodborne community outbreak of group B Streptococcus (GBS) ST283 with high incidence of purulent meningitis in Singapore. Brouwer et al., authors of the review, respond that although the specific strain was not previously described to colonize humans, few studies on GBS colonization in Southeast Asia are available.




Letter re: Zoonotic bacterial meningitis in human adults

2017-03-27T12:45:31-07:00

We read with interest the review by van Samkar et al.,1 which highlighted the importance of recognizing risk factors, clinical characteristics, complications, and outcomes of zoonotic bacterial meningitis.




Author response: Zoonotic bacterial meningitis in human adults

2017-03-27T12:45:31-07:00

We thank Tan et al. for the comment considering a fish consumption–related outbreak of S agalactiae or GBS disease, written in response to our review on zoonotic meningitis.1 The outbreak of sequence type ST283 GBS disease was found to frequently cause meningitis compared to non-ST283 strains, and farmed fish was the outbreak source.1 The specific strain was not previously described to colonize humans, but few studies on GBS colonization in Southeast Asia are available.2,3 The specific sequence type was previously reported to cause disease in both humans and fish, but the mode of transmission and primary reservoir of the pathogen is unclear.2 Zoonotic meningitis, as described in our review, is caused by pathogens that have a primary reservoir in animals and cause disease in humans following transmission, either by animal contact or food.1 GBS is generally not considered a zoonotic pathogen, being a commensal in humans. This does not influence the importance of the foodborne infection and warrants vigilance for public health officials and the fish industry. Locally performed studies on colonization of fish during life, in food processing procedures, and of healthy humans may shed light on the mode of transmission of this particular sequence type.




Letter re: A genome-wide association study in multiple system atrophy

2017-03-27T12:45:31-07:00

Sailer et al.1 conducted a genome-wide association study (GWAS) of 918 patients with multiple system atrophy (MSA) and 3,864 controls, and identified several loci potentially associated with MSA. This was the first GWAS ever conducted using such a large sample size, emphasizing the future direction of identifying MSA susceptibility genes using further larger sample sizes. Contrary to a previous study,2 Sailer et al.1 found no association of COQ2 with MSA.




Author response: A genome-wide association study in multiple system atrophy

2017-03-27T12:45:31-07:00

We thank Drs. Tsuji and Mitsui for the comment about COQ2 variants and risk for MSA. While our study of European ancestry patients and controls found no evidence for association of COQ2 variants,1 we agree that this does not exclude the possibility of variants in this gene underlying MSA in Asian populations. Nevertheless, even within Asia, there are conflicting data on the role of COQ2 in the pathogenesis of MSA.2–8 We eagerly anticipate additional replication studies involving pathologic-confirmed cases and well-matched controls that explore the role of COQ2 in the etiology of this fatal neurodegenerative illness.




Clinical Reasoning: A 43-year-old woman with right limb weakness

2017-03-20T12:45:31-07:00

A 43-year-old woman presented with a 4-day history of right limb weakness. While biking 4 days earlier, she felt a weakness in her right hand and leg. She had a history of hypertension for more than 2 years, and was taking extended-release nifedipine tablets (40 mg) and perindopril (4 mg) daily, but her blood pressure was difficult to control (fluctuations of 150–180/90–115 mm Hg). The patient did not smoke or drink alcohol, and had no family history of similar diseases.




Pearls & Oy-sters: Asymmetric meningeal involvement is a common feature of rheumatoid meningitis

2017-03-20T12:45:31-07:00

Rheumatoid meningitis is a rare complication of rheumatoid arthritis that requires a meningeal biopsy for diagnosis.




Teaching NeuroImages: Intracranial arterial dissection

2017-03-20T12:45:31-07:00

A 22-year-old previously fit man presented with acute seizures, left hemiparesis, and a Glasgow Coma Scale score of 7.




Teaching NeuroImages: Adult-onset leukoencephalopathy with intracranial calcifications and cysts (Labrune syndrome)

2017-03-20T12:45:31-07:00

A 42-year-old woman was admitted for a complex partial seizure. At age 18 years, she had transient diplopia, which was considered a simple strabismus. Current examination revealed a left VI cranial nerve palsy and right arm hyperreflexia. Neuroimaging showed multiple intraparenchymal cystic lesions in white matter (figure), multiple calcifications in basal ganglia, and extensive bilateral leukoencephalopathy. Lack of extraneurologic involvement and genetic testing (CTC1 gene) ruled out other disorders (mainly Coats plus syndrome). Leukoencephalopathy with intracranial calcifications and cysts is considered a diffuse microangiopathy affecting children.1 Adult-onset patients may present a heterogeneous and milder clinical picture, with slow progression.2




Spotlight on the March 21 issue

2017-03-20T12:45:31-07:00




Cancer and neurodegeneration: Time to move beyond Janus?

2017-03-20T12:45:31-07:00

While there are a number of investigations studying the mechanisms underlying neurodegeneration in cell and animal models, the number of comprehensive clinical studies is substantially lower. Large epidemiologic studies are less common since they are time-consuming and require a large cohort of well-documented patients. Such comprehensive surveys, however, are urgently needed for improved patient care via a better understanding of the spectrum of clinical presentation of a given disorder.




To PLEX or not to PLEX in natalizumab-associated PML

2017-03-20T12:45:31-07:00

Natalizumab (NTZ) is one of the most effective therapies available for the treatment of relapsing multiple sclerosis (MS).1 The most important adverse effect of treatment is the development of progressive multifocal leukoencephalopathy (PML), with ~700 cases having been reported since 2005.2 The incidence of NTZ-PML in patients with MS varies from as high as 1.3% among individuals who are JC virus (JCV) antibody–positive, have a history of prior immunosuppressant therapy, and have received more than 4 years of NTZ treatment, to less than 0.1% in those with none of these risk factors.3 PML results from reactivation of latent JCV and subsequent infection and death of oligodendrocytes leading to demyelination. There is currently no treatment of proven efficacy for PML; however, interventions that facilitate restoration of immunocompetence reduce disability and enhance survival. This is clearly seen in patients with HIV-associated PML, in whom prognosis improved dramatically after the introduction of highly active antiretroviral therapy.4 It is logical to assume that reversal of the NTZ-induced immunodeficiency state would be the most effective therapeutic option for patients with NTZ-PML.




PML in natalizumab-treated multiple sclerosis: Modeling errors and risk miscalculations

2017-03-20T12:45:31-07:00

The 2004 approval of natalizumab provided great hope for the multiple sclerosis (MS) community, while its withdrawal from the market shortly thereafter, following reports of treatment-related progressive multifocal leukoencephalopathy (PML),1 was a crushing blow. Its reintroduction in 2006 was accompanied by a formal safety monitoring program.2 Subsequently, risk factors were identified for natalizumab-associated PML: a history of prior immunosuppression, length of natalizumab therapy, and baseline positive JC virus (JCV) serostatus.1 Among those who have not previously used immunosuppressive therapies, the JCV antibody titer may help further characterize PML risk.3 Those with a detectable but low JCV antibody titer (≤0.9) carry a small risk of the complication, while those with titers >1.5 appear to be at much higher risk of PML. One calculation suggested increasing risk based on epochs of treatment, defined as 1–24, 25–48, or 49–72 months. The apparent risk inflection point that occurs after 24 months has led some neurologists to counsel patients that the risk of PML is very low within the 2 years on nataluzimab.4




Richard F. Mayer, MD (1929-2016)

2017-03-20T12:45:31-07:00

Our friend and colleague Dick Mayer passed away on November 22, 2016. Dick was on the faculty at the University of Maryland School of Medicine in Baltimore for 50 years. He was a kind and generous man who enhanced the lives of patients with neuromuscular diseases and the many students and physicians who had the opportunity to work and learn with him. He was a dedicated academic neurologist who, just 2 weeks prior to his death, was teaching neuromuscular fellows and participating in the academic life of the Department of Neurology. Not only did Dick positively influence many others as a neurologist, but he cherished his wife Janet, to whom he was married for 56 years, and was a dedicated and loving father to his 5 children.




Low cancer prevalence in polyglutamine expansion diseases

2017-03-20T12:45:31-07:00

Objective:

Polyglutamine (PolyQ) diseases are dominantly transmitted neurologic disorders, caused by coding and expanded CAG trinucleotide repeats. Cancer was reported retrospectively to be rare in patients with PolyQ diseases and we aimed to investigate its prevalence in France.

Methods:

Consecutive patients with Huntington disease (HD) and spinocerebellar ataxia (SCA) were questioned about cancer, cardiovascular diseases, and related risk factors in 4 university hospitals in Paris, Toulouse, Strasbourg, and Montpellier. Standardized incidence ratios (SIR), based on age- and sex-adjusted rate of the French population, were assessed for different types of cancer.

Results:

We questioned 372 patients with HD and 134 patients with SCA. SIR showed significantly reduced risk of cancer in HD: 23 observed cases vs 111.05 expected ones (SIR 0.21, 95% confidence interval [CI] 0.13–0.31), as well as in SCA: 7 observed cases vs 34.73 expected (SIR 0.23, 95% CI 0.08–0.42). This was surprising since risk behavior for cancer was increased in these patients, with significantly greater tobacco and alcohol consumption in patients with HD vs patients with SCA (p < 0.0056). There was no association between CAG repeat size and cancer or cardiovascular disease. However, in patients with HD, skin cancers were more frequent than expected (5 vs 0.98, SIR 5.11, 95% CI 1.65–11.95).

Conclusions:

There was a decreased cancer rate in PolyQ diseases despite high incidence of risk factors. Intriguingly, skin cancer incidence was higher, suggesting a crosstalk between neurodegeneration and skin tumorigenesis.




Reduced cognitive function in patients with Parkinson disease and obstructive sleep apnea

2017-03-20T12:45:31-07:00

Objective:

To assess the association between obstructive sleep apnea (OSA) and nonmotor symptoms (NMS), including cognitive dysfunction, in patients with Parkinson disease (PD).

Methods:

Patients with idiopathic PD, recruited from a movement disorder clinic, underwent overnight polysomnography. OSA was defined as an apnea-hypopnea index (AHI) ≥15/h. PD severity was assessed using the Hoehn & Yahr (H&Y) scale and the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). NMS were assessed using the Montreal Cognitive Assessment (MoCA), Epworth Sleepiness Scale (ESS), Fatigue Severity Scale, Apathy Scale, Beck Depression Inventory, Hospital Depression and Anxiety Scale, and PD sleep Scale.

Results:

Sixty-seven patients (61.2% male), mean age 64.4 (SD 9.9) years and motor MDS-UPDRS 21.9 (12.6) using levodopa equivalent dose (LED) 752.4 (714.6) mg/d, were studied. OSA occurred in 47 patients (61.6%, mean AHI 27.1/h, SD 20.2/h), and NMS in 57 patients (85%). ESS and MoCA were associated with the AHI (ESS β = 0.0670, p = 0.031; MoCA β = –0.0520, p = 0.043, adjusted for age, sex, body mass index, LED, and H&Y). ESS was associated with respiratory arousals (β = 0.1015, p = 0.011) and intermittent hypoxemia (β = 0.1470, p = 0.006). MoCA was negatively associated with respiratory arousals (β = –0.0596, p = 0.049) but not intermittent hypoxemia.

Conclusions:

OSA is associated with sleepiness and cognitive dysfunction in PD, suggesting that OSA may be a reversible contributor to these NMS. Further studies will be required to evaluate whether OSA treatment can improve excessive sleepiness and cognitive dysfunction in PD.




Pure autonomic failure: Predictors of conversion to clinical CNS involvement

2017-03-20T12:45:31-07:00

Objective:

Based on the observation that a subset of patients originally diagnosed with pure autonomic failure (PAF) eventually develops extrapyramidal or cerebellar involvement consistent with multiple system atrophy (MSA), Parkinson disease (PD), or dementia with Lewy bodies (DLB), we aimed to identify predictors of progression of PAF to more sinister synucleinopathies.

Methods:

In this retrospective cohort study, we reviewed patients seen at Mayo Clinic Rochester by autonomic specialists between 2001 and 2011 and during initial evaluation diagnosed with orthostatic hypotension consistent with PAF (possible PAF). In order to assess for the presence or absence of progression, we identified patients with 3 years or more of in-person follow-up (stable PAF) or documented progression to another synucleinopathy (converters). To identify predictors of conversion, we assessed odds of conversion based on clinical, autonomic, and laboratory variables.

Results:

Among 318 patients fulfilling criteria for possible PAF, we identified 41 with stable PAF and 37 (12%) converters. Of those who evolved, 22 developed MSA, 11 developed PD/DLB, and 4 remained indeterminate. Several variables were identified to predict conversion to MSA: (1) mild degree of cardiovagal impairment, (2) preganglionic pattern of sweat loss, (3) severe bladder dysfunction, (4) supine norepinephrine >100 pg/mL, and (5) subtle motor signs at first presentation. Separate variables were found to predict conversion to PD/DLB. Composite conversion scores were generated based on individual predictors.

Conclusions:

Over 10% of patients originally diagnosed with PAF eventually evolve to develop CNS involvement, most commonly MSA. A combination of variables allows for prediction of conversion.




Urinary p75: A prognostic, disease progression, and pharmacodynamic biomarker in ALS

2017-03-20T12:45:31-07:00

Objective:

To evaluate urinary neurotrophin receptor p75 extracellular domain (p75ECD) levels as disease progression and prognostic biomarkers in amyotrophic lateral sclerosis (ALS).

Methods:

The population in this study comprised 45 healthy controls and 54 people with ALS, 31 of whom were sampled longitudinally. Urinary p75ECD was measured using an enzyme-linked immunoassay and validation included intra-assay and inter-assay coefficients of variation, effect of circadian rhythm, and stability over time at room temperature, 4°C, and repeated freeze-thaw cycles. Longitudinal changes in urinary p75ECD were examined by mixed model analysis, and the prognostic value of baseline p75ECD was explored by survival analysis.

Results:

Confirming our previous findings, p75ECD was higher in patients with ALS (5.6 ± 2.2 ng/mg creatinine) compared to controls (3.6 ± 1.4 ng/mg creatinine, p < 0.0001). Assay reproducibility was high, with p75ECD showing stability across repeated freeze-thaw cycles, at room temperature and 4°C for 2 days, and no diurnal variation. Urinary p75ECD correlated with the revised ALS Functional Rating Scale at first evaluation (r = –0.44, p = 0.008) and across all study visits (r = –0.36, p < 0.0001). p75ECD also increased as disease progressed at an average rate of 0.19 ng/mg creatinine per month (p < 0.0001). In multivariate prognostic analysis, bulbar onset (hazard ratio [HR] 3.0, p = 0.0035), rate of disease progression from onset to baseline (HR 4.4, p < 0.0001), and baseline p75ECD (HR 1.3, p = 0.0004) were predictors of survival.

Conclusions:

The assay for urinary p75ECD is analytically robust and shows promise as an ALS biomarker with prognostic, disease progression, and potential pharmacodynamic application. Baseline urinary p75ECD provides prognostic information and is currently the only biological fluid–based biomarker of disease progression.




No evidence of beneficial effects of plasmapheresis in natalizumab-associated PML

2017-03-20T12:45:31-07:00

Objective:

To examine retrospectively the effects of plasmapheresis (PLEX) on the survival and clinical outcomes of patients with multiple sclerosis (MS) and natalizumab (NTZ)–associated progressive multifocal leukoencephalopathy (PML).

Methods:

The medical literature was searched for the terms natalizumab and progressive multifocal leukoencephalopathy. A total of 193 international and 34 Italian NTZ-PML cases were included. Clinical outcome was determined by comparing the patients' clinical status at PML diagnosis with status after PML resolution. The effects on survival and clinical outcome of PLEX, sex, age, country, pre-PML Expanded Disability Status Scale score, NTZ infusion number, prior immunosuppressant exposure, PML symptoms, PML lesion location at diagnosis, CSF JC virus status and copies, additional PML treatments and steroids, and PML immune reconstitution inflammatory syndrome (IRIS) development were investigated with both univariate and multivariate analyses.

Results:

A total of 219 NTZ-PML cases were analyzed, and 184 (84%) underwent PLEX, which did not reduce the mortality risk or the likelihood of poor vs favorable outcomes. Country was predictive of mortality and poor outcome, while PML-IRIS development was predictive of poor outcome.

Conclusions:

PLEX did not improve the survival or clinical outcomes of Italian or international patients with MS and NTZ-PML, suggesting that this treatment should be performed cautiously in the future.

Classification of evidence:

This study provides Class III evidence that for patients with NTZ-PML, PLEX does not improve survival. The study lacks the statistical precision to exclude an important benefit or harm of PLEX.




Congenital myopathy associated with the triadin knockout syndrome

2017-03-20T12:45:31-07:00

Objective:

Triadin is a component of the calcium release complex of cardiac and skeletal muscle. Our objective was to analyze the skeletal muscle phenotype of the triadin knockout syndrome.

Methods:

We performed clinical evaluation, analyzed morphologic features by light and electron microscopy, and immunolocalized triadin in skeletal muscle.

Results:

A 6-year-old boy with lifelong muscle weakness had a triadin knockout syndrome caused by compound heterozygous null mutations in triadin. Light microscopy of a deltoid muscle specimen shows multiple small abnormal spaces in all muscle fibers. Triadin immunoreactivity is absent from type 1 fibers and barely detectable in type 2 fibers. Electron microscopy reveals focally distributed dilation and degeneration of the lateral cisterns of the sarcoplasmic reticulum and loss of the triadin anchors from the preserved lateral cisterns.

Conclusions:

Absence of triadin in humans can result in a congenital myopathy associated with profound pathologic alterations in components of the sarcoplasmic reticulum. Why only some triadin-deficient patients develop a skeletal muscle phenotype remains an unsolved question.




MRI-visible perivascular spaces in cerebral amyloid angiopathy and hypertensive arteriopathy

2017-03-20T12:45:31-07:00

Objective:

To assess MRI-visible enlarged perivascular spaces (EPVS) burden and different topographical patterns (in the centrum semiovale [CSO] and basal ganglia [BG]) in 2 common microangiopathies: cerebral amyloid angiopathy (CAA) and hypertensive arteriopathy (HA).

Methods:

Consecutive patients with spontaneous intracerebral hemorrhage (ICH) from a prospective MRI cohort were included. Small vessel disease MRI markers, including cerebral microbleeds (CMBs), cortical superficial siderosis (cSS), and white matter hyperintensities (WMH), were rated. CSO-EPVS/BG-EPVS were assessed on a validated 4-point visual rating scale (0 = no EPVS, 1 = <10, 2 = 11–20, 3 = 21–40, and 4 = >40 EPVS). We tested associations of predefined high-degree (score >2) CSO-EPVS and BG-EPVS with other MRI markers in multivariable logistic regression. We subsequently evaluated associations with CSO-EPVS predominance (i.e., CSO-EPVS > BG-EPVS) and BG-EPVS predominance pattern (i.e., BG-EPVS > CSO-EPVS) in adjusted multinomial logistic regression (reference group, BG-EPVS = CSO-EPVS).

Results:

We included 315 patients with CAA-ICH and 137 with HA-ICH. High-degree CSO-EPVS prevalence was greater in CAA-related ICH vs HA-related ICH (43.8% vs 17.5%, p < 0.001). In multivariable logistic regression, high-degree CSO-EPVS was associated with lobar CMB (odds ratio [OR] 1.33, 95% confidence interval [CI] 1.10–1.61, p = 0.003) and cSS (OR 2.08, 95% CI 1.30–3.32, p = 0.002). Deep CMBs (OR 2.85, 95% CI 1.75–4.64, p < 0.0001) and higher WMH volume (OR 1.02, 95% CI 1.01–1.04, p = 0.010) were predictors of high-degree BG-EPVS. A CSO-EPVS–predominant pattern was more common in CAA-ICH than in HA-ICH (75.9% vs 39.4%, respectively, p < 0.0001). CSO-PVS predominance was associated with lobar CMB burden and cSS, while BG-EPVS predominance was associated with HA-ICH and WMH volumes.

Conclusions:

Different patterns of MRI-visible EPVS provide insights into the dominant underlying microangiopathy type in patients with spontaneous ICH.




Effect of topiramate and zonisamide on fMRI cognitive networks

2017-03-20T12:45:31-07:00

Objective:

To investigate the effects of topiramate (TPM), zonisamide (ZNS), and levetiracetam (LEV) on cognitive network activations in patients with focal epilepsy using an fMRI language task.

Methods:

In a retrospective, cross-sectional study, we identified patients from our clinical database of verbal fluency fMRI studies who were treated with either TPM (n = 32) or ZNS (n = 51). We matched 62 patients for clinical measures who took LEV but not TPM or ZNS. We entered antiepileptic comedications as nuisance variables and compared out-of-scanner psychometric measures for verbal fluency and working memory between groups.

Results:

Out-of-scanner psychometric data showed overall poorer performance for TPM compared to ZNS and LEV and poorer working memory performance in ZNS-treated patients compared to LEV-treated patients. We found common fMRI effects in patients taking ZNS and TPM, with decreased activations in cognitive frontal and parietal lobe networks compared to those taking LEV. Impaired deactivation was seen only with TPM.

Conclusions:

Our findings suggest that TPM and ZNS are associated with similar dysfunctions of frontal and parietal cognitive networks, which are associated with impaired performance. TPM is also associated with impaired attenuation of language-associated deactivation. These studies imply medication-specific effects on the functional neuroanatomy of language and working memory networks.

Classification of evidence:

This study provides Class III evidence that in patients with focal epilepsy, TPM and ZNS compared to LEV lead to disruption of language and working memory networks.




Prolonged sleep duration as a marker of early neurodegeneration predicting incident dementia

2017-03-20T12:45:31-07:00

Objective:

To evaluate the association between sleep duration and the risk of incident dementia and brain aging.

Methods:

Self-reported total hours of sleep were examined in the Framingham Heart Study (n = 2,457, mean age 72 ± 6 years, 57% women) as a 3-level variable: <6 hours (short), 6–9 hours (reference), and >9 hours (long), and was related to the risk of incident dementia over 10 years, and cross-sectionally to total cerebral brain volume (TCBV) and cognitive performance.

Results:

We observed 234 cases of all-cause dementia over 10 years of follow-up. In multivariable analyses, prolonged sleep duration was associated with an increased risk of incident dementia (hazard ratio [HR] 2.01; 95% confidence interval [CI] 1.24–3.26). These findings were driven by persons with baseline mild cognitive impairment (HR 2.83; 95% CI 1.06–7.55) and persons without a high school degree (HR 6.05; 95% CI 3.00–12.18). Transitioning to sleeping >9 hours over a mean period of 13 years before baseline was associated with an increased risk of all-cause dementia (HR 2.43; 95% CI 1.44–4.11) and clinical Alzheimer disease (HR 2.20; 95% CI 1.17–4.13). Relative to sleeping 6–9 hours, long sleep duration was also associated cross-sectionally with smaller TCBV (β ± SE, –1.08 ± 0.41 mean units of TCBV difference) and poorer executive function (β ± SE, –0.41 ± 0.13 SD units of Trail Making Test B minus A score difference).

Conclusions:

Prolonged sleep duration may be a marker of early neurodegeneration and hence a useful clinical tool to identify those at a higher risk of progressing to clinical dementia within 10 years.




Polygenic risk scores in familial Alzheimer disease

2017-03-20T12:45:31-07:00

Objective:

To investigate the association between a genetic risk score (GRS) and familial late-onset Alzheimer disease (LOAD) and its predictive value in families multiply affected by the disease.

Methods:

Using data from the National Institute on Aging Genetics Initiative for Late-Onset Alzheimer Disease (National Institute on Aging–Late-Onset Alzheimer's Disease Family Study), mixed regression models tested the association of familial LOAD with a GRS based on single nucleotide polymorphisms (SNPs) previously associated with LOAD. We modeled associations using unweighted and weighted scores with estimates derived from the literature. In secondary models, we adjusted subsequent models for presence of the APOE 4 allele and further tested the interaction between APOE 4 and the GRS. We constructed a similar GRS in a cohort of Caribbean Hispanic families multiply affected by LOAD by selecting the SNP with the strongest p value within the same regions.

Results:

In the NIA-LOAD families, the GRS was significantly associated with LOAD (odds ratio [OR] 1.29; 95% confidence interval 1.21–1.37). The results did not change after adjusting for APOE 4. In Caribbean Hispanic families, the GRS also significantly predicted LOAD (OR 1.73; 1.57–1.93). Higher scores were associated with lower age at onset in both cohorts.

Conclusions:

High GRS increases the risk of familial LOAD and lowers the age at onset, regardless of ethnic group.




Nucleus of the solitary tract, medullary reflexes, and clinical implications

2017-03-20T12:45:31-07:00

The nucleus of the solitary tract (solitary nucleus, nucleus tractus solitarii [NTS]), located in the dorsomedial medulla, is the first relay station for general visceral and taste afferents carried by the cranial nerves and has a critical role in the initiation and integration of a wide variety of reflexes controlling cardiovascular function, respiration, and gastrointestinal motility. Though isolated bilateral involvement of the NTS in neurologic disorders is infrequent, its intimate anatomical relationship with the fourth ventricle and the area postrema may underlie its major role in clinical manifestations such as those described in this representative case.




Natalizumab-associated PML: Challenges with incidence, resulting risk, and risk stratification

2017-03-20T12:45:31-07:00

Progressive multifocal leukoencephalopathy (PML) associated with natalizumab treatment continues to be a severe problem of clinically successful therapy. This is an update of risk stratification developments and discusses the current approach to depict and calculate PML incidence and PML risk. (1) PML incidence and resulting risk used in today's clinical practice are potentially outdated and the risk for patients with prior immunosuppression might have been underestimated. (2) Risk stratification according to treatment duration epochs likely suggests lower risk due to patients stopping treatment within a given epoch. PML incidence within the complete treatment epoch is statistically lowered due to the fact that patients at the beginning of an epoch presumably have a lower PML risk than the patients at the end. Periodic risk is not accurate in assessing risk for long treatment durations. (3) The JC virus (JCV) serostatus risk factor has low specificity concerning PML prediction and anti-JCV seroconversion during treatment with natalizumab further lowers its specificity over time. Specificity of the risk factor treatment duration varies depending on the average treatment duration and the number of short-term patients. These short-term patients reduce overall average treatment duration and thus enhance the specificity of the risk factor and reduce overall PML incidence. It is also suggested that short-term natalizumab patients are exclusively non-PML, even though they might still develop PML. Clinicians have to consider the cumulative risk of patients to stratify efficiently.




Distribution map of gadolinium deposition within the cerebellum following GBCA administration

2017-03-20T12:45:31-07:00

Gadolinium-based contrast agents (GBCAs) are an essential tool in clinical MRI. Millions of doses are administered annually to patients worldwide.1 However, free gadolinium, the basis of GBCAs, is extremely toxic in only small amounts. Gadolinium has an atomic radius similar to that of calcium and can interfere with calcium-dependent processes such as voltage-gated calcium channels or calcium-activated enzymes.1 To reduce toxicity, GBCAs are composed of gadolinium in chelated form. Following GBCA administration, presumably the gadolinium–chelate complex is excreted intact by the kidneys in patients with normal renal function. Each of the 9 Food and Drug Administration–approved MRI contrast agents has its own specific chelate, leading to variation in stabilities of the gadolinium–chelate complex. GBCAs are generally classified as either linear or macrocyclic based on chelate structure. An ionic, macrocyclic structure has the highest kinetic and thermodynamic stabilities.1




Microstructure of internal carotid blood blister aneurysms under scanning electron microscope

2017-03-20T12:45:31-07:00

Blood blister aneurysm (BBA) represents approximately 0.5%–2% of all ruptured aneurysms.1 The typical morphology of BBA is a small and fragile aneurysm sac with wide-necked hemispheric bulges at nonbranching sites of the supraclinoid internal carotid artery (ICA). BBA may originate from subadventitial dissection of the ICA. The focal gap is present in the internal elastic lamina and media, which is most often covered with thin lacerated fragmented adventitia and clot. We saw a Tibetan woman with a right BBA of ICA (figure 1). The patient underwent clipping surgery after the BBA ruptured. We present the different microstructure of BBA and ordinary aneurysm under scanning electron microscope (figure 2).




Editors' Note

2017-03-20T12:45:31-07:00

Editors' Note: In WriteClick this week, letters consider Kister and Corboy's article "Reducing costs while enhancing quality of care in MS" and its accompanying editorial. Dr. Yanofsky and Dr. Giannouli, in separate letters, both question the authors' suggestions to use lower doses of medications or off-label prescribing as cost-saving measures.




Letter re: Reducing costs while enhancing quality of care in MS

2017-03-20T12:45:31-07:00

I read with interest the article by Drs. Kister and Corboy1 and the accompanying editorial by Drs. Bourdette and Whitham.2 The wholesale price of a number of injectable disease-modifying therapies, some more than 20 years old, are now in the range of $65,000–$75,000 per year. The average neurologic care bill of a patient with multiple sclerosis (MS) over a year's time (including office visits, phone calls, and cognitive interventions) is under $1,000, yet the Centers for Medicare & Medicaid Services (CMS) will withhold payments for neglecting quality measures such as discussing obesity with patients with a body mass index >30 during every office visit, diverting physicians from the true mission of patient care.




Letter re: Reducing costs while enhancing quality of care in MS

2017-03-20T12:45:31-07:00

I read with interest the article by Drs. Kister and Corboy,1 the accompanying editorial by Drs. Bourdette and Whitham,2 and the online correspondence by Dr. Yanofsky.3 Is it a good solution to propose lower doses of medicine or off-label prescribing for patients with multiple sclerosis (MS)?1 The unbridled rise in the cost of MS drugs resulted in a focus on drug prices.4 In countries facing economic crisis, the fear of high-cost medicine restricts health care access and makes health a prevalent problem, directly shaking the foundation of democracies.5 The cost of MS disease-modifying therapies has especially increased substantially over time, thus rendering nonurban uninsured residents in poor countries worldwide excluded from treatment. Two solutions seem more appropriate: (1) refocus on how to improve patient care by examining the expectations and perceptions of patients regarding the quality of health care they want; and (2) demand more government price controls and clarity regarding the so-called financial alliances. As the ancient philosopher Protagoras said, "Of all things the measure is Man."




Author response: Reducing costs while enhancing quality of care in MS

2017-03-20T12:45:31-07:00

We appreciate the interest of Drs. Yanofsky and Giannouli in our work and their comments. Our article's stated aim was to describe how neurologists, working within the existing US health care system, could help bring down medical costs without compromising quality of care.1 It was not our intent to address ways to fix systemic flaws in the health care delivery system in the United States or elsewhere. This could be the subject of a separate article with a different set of recommendations, which could include such items as allowing Medicare to negotiate drug prices, mandating transparency in drug costs to insurance carriers and specialty pharmacies, stimulating free market competition among generic drug manufacturers, easing restrictions on insurance coverage for off-label agents with solid evidence of efficacy, and stopping direct-to-consumer advertising (among others).




Child Neurology: Rocky Mountain spotted fever encephalitis

2017-03-13T12:45:28-07:00

A 27-month-old previously healthy boy developed irritability and a fever the day after getting his 2-year vaccinations. Three days later, he developed a centripetally spreading petechial rash. A tick was removed from his neck. He was taken to an outside hospital several times over the course of 3–4 days and was discharged with amoxicillin the first time and ceftriaxone on a subsequent visit. Eight days into his illness, he developed depressed level of consciousness and had what was described as a generalized clonic seizure. He was intubated with paralytics and fentanyl and transferred to our hospital for evaluation and management. The remaining history was unremarkable.




Clinical Reasoning: A 14-year-old boy with fatigue and episodic worsening of weakness

2017-03-13T12:45:28-07:00

A 14-year-old right-handed boy was evaluated for fluctuating weakness and fatigue. He had normal motor milestones. At age 3 years, it was first noticed that he was not able to keep up with other children and had difficulty running. When he was 9 years old, his symptoms progressed, with easy fatigability and frequent falls. One of the striking features of his weakness was day to day variability. Some days he would be able to perform most of his daily activities and some days he could barely walk. In addition, he had episodes of severe weakness following febrile or viral illness, where he would become wheelchair-dependent lasting for days to weeks. He had shortness of breath with fatigability and intermittent wheezing, which was initially diagnosed as asthma but conventional asthma therapy did not help. Eventually, ear, nose, and throat evaluation determined that he had stridor. He denied diplopia, difficulty swallowing, or sensory symptoms.




Teaching NeuroImages: A spiritual visual hallucination from a right parieto-occipital seizure: Ictal guardian angel

2017-03-13T12:45:28-07:00

A 59-year-old woman with epilepsy reported episodes of dizziness, blurred vision, and an occasional stereotyped visual hallucination of a guardian angel. She had experienced this recurrent hallucination since childhood, and could draw it in detail (figure 1). MRI brain revealed a right parieto-occipital lesion (figure 2A). Inpatient EEG monitoring captured multiple seizures evolving over the right posterior quadrant. With one typical electrographic seizure (figure 2B), she awakened from stage II sleep, reporting seeing her guardian angel at bedside within 10 seconds of electrographic seizure offset. Among focal epilepsy patients, 0.4%–3.1% report ictal religious experiences.1




Spotlight on the March 14 issue

2017-03-13T12:45:28-07:00




G2A1B3AA receptor antibodies and their clinical associations

2017-03-13T12:45:28-07:00

The discovery of antibodies to the extracellular domains of different members of the ligand-gated ion channel superfamily (acetylcholine receptor, NMDA receptor, AMPA receptor, glycine receptor) and ion channel–related proteins (LGI1, CASPR2, DPPX) in CNS diseases has defined a group of largely immunotherapy-responsive conditions.1,2 It has enabled the association of autoantibodies with clinical features, some of which were not traditionally considered immunotherapy-responsive. Examples include faciobrachial dystonic seizures associated with LGI1 antibodies3 and a variety of encephalopathies now designated autoimmune.1,2




Investigations in GABAA receptor antibody-associated encephalitis

2017-03-13T12:45:28-07:00

Objective:

To report the clinical features, comorbidities, receptor subunit targets, and outcome in patients with anti-GABAA receptor (GABAAR) encephalitis.

Methods:

Clinical study of 26 patients, including 17 new (April 2013–January 2016) and 9 previously reported patients. Antibodies to α1, β3, and 2 subunits of the GABAAR were determined using reported techniques.

Results:

Patients' median age was 40.5 years (interquartile range 48.5 [13.75–62.35] years; the youngest 2.5 months old; 13 female). Symptoms included seizures (88%), alteration of cognition (67%), behavior (46%), consciousness (42%), or abnormal movements (35%). Comorbidities were identified in 11 (42%) patients, including 7 tumors (mostly thymomas), 2 herpesvirus encephalitis (herpes simplex virus 1, human herpesvirus 6; coexisting with NMDAR antibodies), and 2 myasthenia without thymoma. Brain MRI was abnormal in 23 (88%) patients, showing in 20 (77%) multifocal, asynchronous, cortical-subcortical T2/fluid-attenuated inversion recovery abnormalities predominantly involving temporal (95%) and frontal (65%) lobes, but also basal ganglia and other regions. Immunologic or tumor therapy resulted in substantial improvement in 18/21 (86%) assessable patients; the other 3 (14%) died (2 status epilepticus, 1 sepsis). Compared with adults, children were more likely to have generalized seizures (p = 0.007) and movement disorders (p = 0.01) and less likely to have a tumor (p = 0.01). The main epitope targets were in the α1/β3 subunits of the GABAAR.

Conclusions:

Anti-GABAAR encephalitis is characterized by frequent seizures and distinctive multifocal cortical-subcortical MRI abnormalities that provide an important clue to the diagnosis. The frequency of symptoms and comorbidities differ between children (more viral-related) and adults (more tumor-related). The disorder is severe but most patients respond to treatment.




Vesicular acetylcholine transporter defect underlies devastating congenital myasthenia syndrome

2017-03-13T12:45:28-07:00

Objective:

To identify the genetic basis of a recessive congenital neurologic syndrome characterized by severe hypotonia, arthrogryposis, and respiratory failure.

Methods:

Identification of the responsible gene by exome sequencing and assessment of the effect of the mutation on protein stability in transfected rat neuronal-like PC12A123.7 cells.

Results:

Two brothers from a nonconsanguineous Yemeni Jewish family manifested at birth with severe hypotonia and arthrogryposis. The older brother died of respiratory failure at 5 days of age. The proband, now 4.5 years old, has been mechanically ventilated since birth with virtually no milestones achievement. Whole exome sequencing revealed homozygosity of SLC18A3 c.1078G>C, p.Gly360Arg in the affected brothers but not in other family members. SLC18A3 p.Gly360Arg is not reported in world populations but is present at a carrier frequency of 1:30 in healthy Yemeni Jews. SLC18A3 encodes the vesicular acetylcholine transporter (VAChT), which loads newly synthesized acetylcholine from the neuronal cytoplasm into synaptic vesicles. Mice that are VAChT-null have been shown to die at birth of respiratory failure. In human VAChT, residue 360 is located in a conserved region and substitution of arginine for glycine is predicted to disrupt proper protein folding and membrane embedding. Stable transfection of wild-type and mutant human VAChT into neuronal-like PC12A123.7 cells revealed similar mRNA levels, but undetectable levels of the mutant protein, suggesting post-translational degradation of mutant VAChT.

Conclusion:

Loss of function of VAChT underlies severe arthrogryposis and respiratory failure. While most congenital myasthenic syndromes are caused by defects in postsynaptic proteins, VAChT deficiency is a presynaptic myasthenic syndrome.




Moderators and predictors of response to behavior therapy for tics in Tourette syndrome

2017-03-13T12:45:28-07:00

Objective: To examine moderators and predictors of response to behavior therapy for tics in children and adults with Tourette syndrome and chronic tic disorders. Methods: Data from 2 10-week, multisite studies (1 in children and 1 in adults; total n = 248) comparing comprehensive behavioral intervention for tics (CBIT) to psychoeducation and supportive therapy (PST) were combined for moderator analyses. Participants (177 male, 71 female) had a mean age of 21.5 ± 13.9 years (range 9–69). Demographic and clinical characteristics, baseline tic-suppressing medication, and co-occurring psychiatric disorders were tested as potential moderators for CBIT vs PST or predictors of outcome regardless of treatment assignment. Main outcomes measures were the Yale Global Tic Severity Scale Total Tic score and the Clinical Global Impression–Improvement score assessed by masked evaluators. Results: The presence of tic medication significantly moderated response to CBIT vs PST (p = 0.01). Participants showed tic reduction after CBIT regardless of tic medication status, but only participants receiving tic medication showed reduction of tics after PST. Co-occurring psychiatric disorders, age, sex, family functioning, tic characteristics, and treatment expectancy did not moderate response. Across both treatments, greater tic severity (p = 0.005) and positive participant expectancy (p = 0.01) predicted greater tic improvement. Anxiety disorders (p = 0.042) and premonitory urge severity (p = 0.005) predicted lower tic reduction. Conclusions: Presence of co-occurring attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, or anxiety disorders did not moderate response to CBIT. Although participants on tic medication showed improvement after CBIT, the difference between CBIT and PST was greater for participants who were not on tic-suppressing medication. ClinicalTrials.gov identifiers: The child and adult CBIT studies are listed on clinical trials.gov (NCT00218777 and NCT00231985, respectively). Classification of evidence: This study provides Class I evidence that CBIT is effective in reducing tic severity across subgroups of patients with chronic tic disorders, although the difference between treatments was smaller for participants on tic-suppressing medications, suggesting reduced efficacy in this subgroup. [...]



Clinical and genetic factors predicting Dravet syndrome in infants with SCN1A mutations

2017-03-13T12:45:28-07:00

Objective:

To explore the prognostic value of initial clinical and mutational findings in infants with SCN1A mutations.

Methods:

Combining sex, age/fever at first seizure, family history of epilepsy, EEG, and mutation type, we analyzed the accuracy of significant associations in predicting Dravet syndrome vs milder outcomes in 182 mutation carriers ascertained after seizure onset. To assess the diagnostic accuracy of all parameters, we calculated sensitivity, specificity, receiver operating characteristic (ROC) curves, diagnostic odds ratios, and positive and negative predictive values and the accuracy of combined information. We also included in the study demographic and mutational data of the healthy relatives of mutation carrier patients.

Results:

Ninety-seven individuals (48.5%) had Dravet syndrome, 49 (23.8%) had generalized/genetic epilepsy with febrile seizures plus, 30 (14.8%) had febrile seizures, 6 (3.5%) had focal epilepsy, and 18 (8.9%) were healthy relatives. The association study indicated that age at first seizure and frameshift mutations were associated with Dravet syndrome. The risk of Dravet syndrome was 85% in the 0- to 6-month group, 51% in the 6- to 12-month range, and 0% after the 12th month. ROC analysis identified onset within the sixth month as the diagnostic cutoff for progression to Dravet syndrome (sensitivity = 83.3%, specificity = 76.6%).

Conclusions:

In individuals with SCN1A mutations, age at seizure onset appears to predict outcome better than mutation type. Because outcome is not predetermined by genetic factors only, early recognition and treatment that mitigates prolonged/repeated seizures in the first year of life might also limit the progression to epileptic encephalopathy.




18F-FDG-PET patterns of surgical success and failure in mesial temporal lobe epilepsy

2017-03-13T12:45:28-07:00

Objective:

To search for [18F]-fluorodeoxyglucose (FDG)-PET patterns predictive of long-term prognosis in surgery for drug-resistant mesial temporal lobe epilepsy (MTLE) due to hippocampal sclerosis (HS).

Methods:

We analyzed metabolic data with [18F]-FDG-PET in 97 patients with MTLE (53 female participants; age range 15–56 years) with unilateral HS (50 left) and compared the metabolic patterns, electroclinical features, and structural atrophy on MRI in patients with the best outcome after anteromesial temporal resection (Engel class IA, completely seizure-free) to those with a non-IA outcome, including suboptimal outcome and failure. Imaging processing was performed with statistical parametric mapping (SPM5).

Results:

With a mean follow-up of >6 years (range 2–14 years), 85% of patients achieved a class I outcome, including 45% in class IA. Class IA outcome was associated with a focal anteromesial temporal hypometabolism, whereas non-IA outcome correlated with extratemporal metabolic changes that differed according to the lateralization: ipsilateral mesial frontal and perisylvian hypometabolism in right HS and contralateral fronto-insular hypometabolism and posterior white matter hypermetabolism in left HS. Suboptimal outcome presented a metabolic pattern similar to the best outcome but with a larger involvement of extratemporal areas, including the contralateral side in left HS. Failure was characterized by a mild temporal involvement sparing the hippocampus and relatively high extratemporal hypometabolism on both sides. These findings were concordant with electroclinical features reflecting the organization of the epileptogenic zone but were independent of the structural abnormalities detected on MRI.

Conclusions:

[18F]-FDG-PET patterns help refine the prognostic factors in MTLE and should be implemented in predictive models for epilepsy surgery.




Left frontal cortex connectivity underlies cognitive reserve in prodromal Alzheimer disease

2017-03-13T12:45:28-07:00

Objective:

To test whether higher global functional connectivity of the left frontal cortex (LFC) in Alzheimer disease (AD) is associated with more years of education (a proxy of cognitive reserve [CR]) and mitigates the association between AD-related fluorodeoxyglucose (FDG)-PET hypometabolism and episodic memory.

Methods:

Forty-four amyloid-PET–positive patients with amnestic mild cognitive impairment (MCI-Aβ+) and 24 amyloid-PET–negative healthy controls (HC) were included. Voxel-based linear regression analyses were used to test the association between years of education and FDG-PET in MCI-Aβ+, controlled for episodic memory performance. Global LFC (gLFC) connectivity was computed through seed-based resting-state fMRI correlations between the LFC (seed) and each voxel in the gray matter. In linear regression analyses, education as a predictor of gLFC connectivity and the interaction of gLFC connectivity x FDG-PET hypometabolism on episodic memory were tested.

Results:

FDG-PET metabolism in the precuneus was reduced in MCI-Aβ+ compared to HC (p = 0.028), with stronger reductions observed in MCI-Aβ+ with more years of education (p = 0.006). In MCI-Aβ+, higher gLFC connectivity was associated with more years of education (p = 0.021). At higher levels of gLFC connectivity, the association between precuneus FDG-PET hypometabolism and lower memory performance was attenuated (p = 0.027).

Conclusions:

Higher gLFC connectivity is a functional substrate of CR that helps to maintain episodic memory relatively well in the face of emerging FDG-PET hypometabolism in early-stage AD.




Postmenopausal hormone therapy and Alzheimer disease: A prospective cohort study

2017-03-13T12:45:28-07:00

Objective:

To explore the association between postmenopausal hormone therapy (HT) and Alzheimer disease (AD).

Methods:

Twenty-year follow-up data from the Kuopio Osteoporosis Risk Factor and Prevention study cohort were used. Self-administered questionnaires were sent to all women aged 47–56 years, residing in Kuopio Province starting in 1989 until 2009, every 5th year. Register-based information on HT prescriptions was available since 1995. Probable AD cases, based on DSM-IV and National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association criteria, were identified from the special reimbursement register (1999–2009). The study population included 8,195 women (227 cases of incident AD).

Results:

Postmenopausal estrogen use was not associated with AD risk in register-based or self-reported data (hazard ratio/95% confidence interval 0.92/0.68–1.2, 0.99/0.75–1.3, respectively). Long-term self-reported postmenopausal HT was associated with reduced AD risk (0.53/0.31–0.91). Similar results were obtained with any dementia diagnosis in the hospital discharge register as an outcome.

Conclusions:

Our results do not provide strong evidence for a protective association between postmenopausal HT use and AD or dementia, although we observed a reduced AD risk among those with long-term self-reported HT use.




Chronobiology differs between men and women with cluster headache, clinical phenotype does not

2017-03-13T12:45:28-07:00

Objective:

To describe differences between the sexes in the phenotype of cluster headache (CH) in a large, well-characterized clinical CH population.

Methods:

Patients from the Danish CH survey aged 18–65 years, diagnosed with CH according to International Classification of Headache Disorders, second edition, completed questionnaires and structured interviews.

Results:

A total of 351 patients with CH participated, with a male:female ratio of 2:1. The diurnal variation of attacks showed moments of peak prominence in men’s attack cycle to be advanced by 1 hour compared to women’s, despite no difference in self-reported bedtime or chronotype (p = 0.31). The onset of CH decreased with increasing age for both sexes. Diagnostic delay was numerically longer for men vs women (6.56 vs 5.50 years, p = 0.21); however, more women had previously been misdiagnosed (61.1% vs 45.5%, p < 0.01) and received the correct diagnosis at a tertiary headache center (38.8% vs 20.9%, p < 0.001). Only minor sex differences in clinical characteristics were found but chronic CH was more prevalent in women compared to men (44.0% vs 31.9%, p < 0.05).

Conclusions:

Despite a similar clinical phenotype, diurnal attack cycle is advanced by 1 hour in men with CH compared to women. Rhythmicity is a defining characteristic of CH and these findings suggest differences in the hypothalamus’ influence on attack occurrence between the sexes. In addition, women were more often misdiagnosed and diagnosis in the primary or secondary sector more often failed. Furthermore, women had chronic CH more frequently than men. A long diagnostic delay and frequent misdiagnosis emphasize the need for increased awareness of CH in both sexes.




Comment: Sex-specific differences in cluster headache--: Not a males-only disorder

2017-03-13T12:45:28-07:00

Cluster headache (CH) has long been regarded as a males-only disorder. However, the male to female ratio (M/F) of up to 6.2:1 in patients with CH onset before 1960 has fallen to 2.1:1 for patients with onset in the 1990s—similar to that found by Lund et al.1 Lifestyle changes may have contributed to this phenomenon, or an increased awareness of the condition in women.




CADASIL accelerated by acute hypotension: Arterial and venous contribution to leukoaraiosis

2017-03-13T12:45:28-07:00

Objective:

To underline the importance of blood pressure regulation in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and to describe changes that occur in the veins in this condition, specifically venous collagenosis associated with leukoaraiosis.

Methods:

Case report with neuroimaging and pathologic data.

Results:

A 61-year-old man with genetically confirmed CADASIL was initially lucid following a motor vehicle accident but subsequently became hypotensive (60/40 mm Hg) due to an open femur fracture and required intubation. Multiple new white matter infarcts appeared on brain imaging. A second hypotensive episode days later was associated with new coin-sized infarcts in the bilateral corona radiata and cerebellar peduncles, and resulted in quadriplegia. No embolic source was found on cardiac or vascular imaging. He died 5 weeks post trauma. Autopsy revealed extensive subcortical and periventricular leukoencephalopathy and multiple cavitations involving deep subcortical gray and white matter. Small arteries had thickened walls, disruption of the muscularis, and intimal periodic acid–Schiff (PAS)–positive material. Both larger periventricular and small caliber veins had thickened walls that were PAS-negative and trichrome-positive, consistent with venous collagenosis. There was no pathologic evidence of global hypoxia or diffuse axonal injury.

Conclusions:

The findings suggest rapid acceleration of CADASIL pathology from acute hypotension in the setting of impaired vasoreactivity. In addition, collagenosis of veins in the affected white matter regions suggests that the veins may play an important, though largely overlooked, role in maintaining white matter integrity.




Association of multiple infarctions and ICAS with outcomes of minor stroke and TIA

2017-03-13T12:45:28-07:00

Objective:

To estimate the association of different patterns of infarction and intracranial arterial stenosis (ICAS) with the prognosis of acute minor ischemic stroke and TIA.

Methods:

We derived data from the Clopidogrel in High-risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial. A total of 1,089 patients from 45 of 114 participating sites of the trial undergoing baseline MRI/angiography were included in this subgroup analysis. Patterns of infarction and ICAS were recorded for each individual. The primary efficacy outcome was an ischemic stroke at the 90-day follow-up. We assessed the associations between imaging patterns and prognosis of patients using multivariable Cox regression models.

Results:

Among the 1,089 patients included in this subgroup analysis, 93 (8.5%) patients had a recurrent ischemic stroke at 90 days. Compared with those without infarction or ICAS, patients with single infarction with ICAS (11.9% vs 1.3%, hazard ratio [HR] 6.25, 95% confidence intervals [CIs] 1.40–27.86, p = 0.02) and single infarction without ICAS (6.8% vs 1.3%, HR 4.65, 95% CI 1.05–20.64, p = 0.04) were all associated with an increased risk of ischemic stroke at 90 days. Patients with both multiple infarctions and ICAS were associated with approximately 13-fold risk of ischemic stroke at 90 days (18.0% vs 1.3%, HR 13.14, 95% CI 2.96–58.36, p < 0.001).

Conclusions:

The presence of multiple infarctions and ICAS were both associated with an increased risk of 90-day ischemic stroke in patients with minor stroke or TIA, while the presence of both imaging features had a combined effect.

ClinicalTrials.gov identifier:

NCT00979589.




Hans Jacob and brain research on Hamburg "euthanasia" victims: "Awaiting further brains!"

2017-03-13T12:45:28-07:00

Several neuropathologists conducted brain research on victims of so-called euthanasia programs carried out by the National Socialist (Nazi) regime in Germany from 1940 to 1945. Some published their results in German journals or books during and after the war. One of these neuropathologists was Hans Jacob of Hamburg, a former Nazi party member and the leader of the same laboratory previously run by Alfons Jakob (Creutzfeldt-Jakob disease). Though much has been published on the unethical actions of Jacob's fellow neuropathologist from Berlin, Julius Hallervorden, Jacob's actions were remarkably similar and have not been previously analyzed in the neuroscience literature. Jacob dissected at least 42 patient brains from euthanasia centers near Hamburg, and saved the specimens from at least 17 of them. He published a 1956 book chapter featuring 2 such specimens. Jacob was denazified, had a notable career, and never publicly addressed his actions during the war. His ethical violations may not have been on the same scale as Hallervorden’s, but the effect of his work echoes to the modern era. As responsible researchers, we must always be conscious of the provenance of material provided and not succumb to opportunistic temptation despite the ethical consequences.




Elevated 18F-AV-1451 PET tracer uptake detected in incidental imaging findings

2017-03-13T12:45:28-07:00

18F-AV-1451 is a tau PET radioligand, characterized by high affinity for paired helical filaments (PHF) of hyperphosphorylated tau in neurofibrillary tangles (NFTs). Postmortem tissue studies have shown AV-1451 binding selectively to tau (3R + 4R isoforms) but not β-amyloid pathology.1–3 Human studies evaluating AV-1451 tracer retention in aging and Alzheimer disease (AD) have indicated that in vivo binding patterns parallel existing neuropathologic staging of tau.4,5




Zika virus infection and myasthenia gravis: report of 2 cases

2017-03-13T12:45:28-07:00

Zika virus (ZIKV) infection is known as a benign infection usually presenting as an influenza-like illness.1 However, clusters of microcephaly cases and other neurologic disorders following ZIKV outbreaks in Brazil, as well as a cluster of Guillain-Barré syndrome following an outbreak in French Polynesia in 2014, constitute a Public Health Emergency of International Concern according to WHO.2,3 An outbreak of ZIKV infection in New Caledonia occurred in 2014 with 1,380 confirmed cases within a population of 263,000.4 We report 2 cases of myasthenia gravis (MG) with prior ZIKV infection.




Future selves

2017-03-13T12:45:28-07:00

At this child neurology clinic in Yerevan, Armenia, there is no privacy. My colleague and I stand with our patients' families in successive corners of a playroom. As we interview, the families stay together, closely knit, watching. The spring light of this beautiful city streams in through large windows.




Wild-type TTR neuropathy with cardiomyopathy presenting with burning feet

2017-03-13T12:45:28-07:00

A 79-year-old man presented with a 15-year history of burning feet. His neurologic examination showed absent ankle reflexes and reduced light touch, vibration, and heat pain at the feet. Nerve conductions showed absent sural and reduced peroneal (0.6 mV) and tibial (0.3 mV) motor responses, with normal needle EMG. Diabetes and monoclonal gammopathy were absent. At age 74, he had heart failure and atrial fibrillation. Cardiac SPECT-CT nuclear imaging utilizing (99m)Tc-pyrophosphate radiotracer1 supported cardiac transthyretin (TTR) amyloid infiltration (figure 1). Epidermal skin biopsy identified amyloid deposition (figure 2). TTR gene sequencing was normal and he was diagnosed with wild-type TTR neuropathy and cardiomyopathy.2




Editors' Note

2017-03-13T12:45:28-07:00

Editors' Note: In response to "Influence of sodium consumption and associated knowledge on poststroke hypertension in Uganda," Dr. Chin points out that in Uganda, most patients with hypertension are unaware of their blood pressure and the rapid urbanization in sub-Saharan Africa will increase invisible salt intake.




Letter re: Influence of sodium consumption and associated knowledge on poststroke hypertension in Uganda

2017-03-13T12:45:28-07:00

Kaddumukasa et al.1 should be commended for documenting the gaps in public knowledge of the health risks of high salt consumption in Uganda. Only 43% of the study participants had basic dietary salt knowledge.1 Since the participants were stroke survivors recruited from the national hospital and may have received some dietary counseling by health providers prior to enrollment in the study, rates of basic dietary salt knowledge are likely even lower in the general population. A corollary public health knowledge gap is the extremely low rate of awareness of hypertension in Uganda. A national cross-sectional survey conducted in 2014 found that only 7.7% of participants with hypertension were aware of their blood pressure.2 Rapid urbanization in sub-Saharan Africa is changing the dietary habits of Africans. Large grocery supermarkets are now commonplace in Kampala, Uganda, and other large cities. Consumption of invisible salt in factory-made breads, other baked goods, and snack foods is a new threat to the cardiovascular health of Africans.




Author response: Influence of sodium consumption and associated knowledge on poststroke hypertension in Uganda

2017-03-13T12:45:28-07:00

We thank Dr. Chin for the interest and comments on our article.1 We agree that stroke survivors in our study may have received some informal health education, supporting the case for even lower knowledge rates in the public population.1 In Uganda, suboptimal blood pressure control remains a challenge with varied prevalence and excessively low awareness, treatment, and control.2 We agree that the effect of invisible salt in Uganda's urban areas relates to an increasing prevalence of high blood pressure in this population. If not addressed, this portends a high burden of cardiovascular stroke events.3 Because hypertension is the single most important treatable risk factor for stroke, based on the results of our study,1 we agree that a public education campaign aimed at reducing added salt in the diet of Ugandans is urgently needed.




Letter re: The terrorist inside my husband's brain

2017-03-13T12:45:28-07:00

I read with appreciation the special editorial by Susan Schneider Williams,1 in which she shares personal details about the death of her husband, Robin Williams, in the face of Lewy body disease. The death of such a talented actor and comedian was a terrible loss to the world. I share my deepest condolences.




Clinical Reasoning: A young woman with respiratory failure, hearing loss, and paraplegia

2017-03-06T12:45:27-08:00

A 35-year-old woman with bipolar disorder presented to the emergency room (ER) obtunded with hypercapnic respiratory failure. Neurology was consulted because the patient had acute hearing loss and paraparesis. She was last seen normal the prior night by her ex-husband. Paramedics found her on the couch, obtunded, bradypneic, and hypoxic to 82% SpO2, blood pressure 116/79 mm Hg, heart rate 98 beats per minute, and normothermic. She awakened after 0.4 mg of naloxone administration. Home medications included oxycodone/acetaminophen for chronic pain and venlafaxine, alprazolam, and lamotrigine for bipolar disorder. Of note, 34 pills were missing from the oxycodone/acetaminophen bottle.




Teaching NeuroImages: Sonographic detection of intraneural perineurioma in therapy-refractory carpal tunnel syndrome

2017-03-06T12:45:27-08:00

A 55-year-old man with typical clinical and electrodiagnostic findings of carpal tunnel syndrome complained of progression of his symptoms. Since repeated surgical interventions did not provide any relief, sonographic examination was performed and depicted a massive median nerve enlargement with hyperechoic perineurial tissue (figure, A). Beyond postoperative perineural fibrosis, the findings were suspicious for an underlying tumor. MRI revealed a tumorous nerve swelling and surgical neurolysis of hypertrophic fascicles followed (figure, B and C). Histopathology confirmed the diagnosis of intraneural perineurioma, a rare, benign, slow-growing peripheral nerve sheath tumor of perineurial cell origin (figure, D and E).1 Nerve sonography is recommended in therapy-refractory cases, as it might uncover unusual causes of entrapment syndromes.2




Expanding medicines for neurologic disorders on the WHO Model List

2017-03-06T12:45:27-08:00

The WHO Model List of Essential Medicines is a recommended formulary for high-priority diseases based on public health trends and epidemiology patterns. The biennial publication serves as a guide for countries, particularly low- and lower-middle-income countries, to develop their own national essential medicines list (EML), and many nongovernmental organizations base their medication supplies on the WHO EML. Over the last 40 years, WHO has expanded the EML in response to treatment gaps for infectious diseases, pediatrics, palliative care, and cancer. In contrast, neurotherapeutics are poorly represented on the Model List despite the global burden of neurologic disorders, which have continued to increase in the last decade. It is imperative that the neurology community advocate for more evidence-based neurologic medicines on the WHO EML. Equitable access to essential neurologic medicines is a crucial step toward reducing the treatment gap for high-burden neurologic disorders worldwide.




Spotlight on the March 7 issue

2017-03-06T12:45:27-08:00




Neurofilament light: A heavyweight diagnostic biomarker in neurodegenerative parkinsonism?

2017-03-06T12:45:27-08:00

Neurodegenerative parkinsonian disorders were historically divided into 2 major groups based on their clinical picture, treatment response, and prognosis. One group encompassed Parkinson disease (PD), characterized at onset by usually asymmetrical extrapyramidal motor symptoms showing a marked and sustained response to levodopa, and subsequent slow motor decline over time. The other group included the much rarer atypical parkinsonian disorders (APDs), including multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), with features signaling early autonomous, pyramidal, or cortical involvement, poor motor response to levodopa, and a much more rapid functional decline and higher mortality than usually seen in PD.1




Language, meaning, and localization: Last year's words, next year's words

2017-03-06T12:45:27-08:00

Neurologic practice is deeply rooted in the ideal of localization. Some would argue that neurology arose in the mid-18th century from the study of language localization, regarded as a uniquely human function. The classic aphasias, those described by Broca and Wernicke, were believed to represent exemplars of lesion-symptom mapping, but many features of language-onset dementias went unexplained by conventional aphasiology.2 The description of aphasia syndromes in neurodegenerative diseases has largely overturned the static conceptualization of a brain language postcode.3 While incremental and cumulative, these neural network–based conceptual changes have proven critical for elucidating the neural basis of communication, both in healthy speakers and those with neurologic disease. Greater understanding of the interconnectedness and functionality of language regions remains particularly important clinically, such as for decision-making around epilepsy or oncology surgery, and can assist in providing prognostic information for affected individuals and their families.




Early case fatality in intracerebral hemorrhage: Sophistication of care, application globally

2017-03-06T12:45:27-08:00

Acute spontaneous (nontraumatic) intracerebral haemorrhage (ICH), presumed due to cerebral small vessel disease, remains a serious and difficult-to-treat form of stroke.1 The 1-month case fatality of ICH is around 40%, with half of the deaths occurring in the first few days after onset.1,2 This outlook has remained largely unchanged during the last decades.3 The consistently high case fatality, in combination with the diverse etiologies of ICH, may have hampered development of acute evidence-based management strategies.2 Similarly, despite improved management of vascular risk factors including hypertension, the overall ICH incidence is stable, possibly due to the aging of the population and the more widespread use of antithrombotic drugs, such as for atrial fibrillation.3 To consolidate epidemiologic knowledge about early case-fatality trends of ICH in the last decades and identify clinical needs in the acute setting, well-designed prospective population-based studies are needed.




David A. Drachman, MD (1932-2016)

2017-03-06T12:45:27-08:00

With the passing of Dr. David A. Drachman on December 5, 2016, at age 84, we have lost one of our major academic clinicians in neurology. At the time of his death, he was Professor and Chair Emeritus of the Department of Neurology at the University of Massachusetts Medical School in Worcester, a department he founded in 1977 and led for 25 years.




Blood-based NfL: A biomarker for differential diagnosis of parkinsonian disorder

2017-03-06T12:45:27-08:00

Objective: To determine if blood neurofilament light chain (NfL) protein can discriminate between Parkinson disease (PD) and atypical parkinsonian disorders (APD) with equally high diagnostic accuracy as CSF NfL, and can therefore improve the diagnostic workup of parkinsonian disorders. Methods: The study included 3 independent prospective cohorts: the Lund (n = 278) and London (n = 117) cohorts, comprising healthy controls and patients with PD, progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), as well as an early disease cohort (n = 109) of patients with PD, PSP, MSA, or CBS with disease duration ≤3 years. Blood NfL concentration was measured using an ultrasensitive single molecule array (Simoa) method, and the diagnostic accuracy to distinguish PD from APD was investigated. Results: We found strong correlations between blood and CSF concentrations of NfL ( ≥ 0.73–0.84, p ≤ 0.001). Blood NfL was increased in patients with MSA, PSP, and CBS (i.e., all APD groups) when compared to patients with PD as well as healthy controls in all cohorts (p < 0.001). Furthermore, in the Lund cohort, blood NfL could accurately distinguish PD from APD (area under the curve [AUC] 0.91) with similar results in both the London cohort (AUC 0.85) and the early disease cohort (AUC 0.81). Conclusions: Quantification of blood NfL concentration can be used to distinguish PD from APD. Blood-based NfL might consequently be included in the diagnostic workup of patients with parkinsonian symptoms in both primary care and specialized clinics. Classification of evidence: This study provides Class III evidence that blood NfL levels discriminate between PD and APD. [...]



Phase I/II multicenter ketogenic diet study for adult superrefractory status epilepticus

2017-03-06T12:45:27-08:00

Objective: To investigate the feasibility, safety, and efficacy of a ketogenic diet (KD) for superrefractory status epilepticus (SRSE) in adults. Methods: We performed a prospective multicenter study of patients 18 to 80 years of age with SRSE treated with a KD treatment algorithm. The primary outcome measure was significant urine and serum ketone body production as a biomarker of feasibility. Secondary measures included resolution of SRSE, disposition at discharge, KD-related side effects, and long-term outcomes. Results: Twenty-four adults were screened for participation at 5 medical centers, and 15 were enrolled and treated with a classic KD via gastrostomy tube for SRSE. Median age was 47 years (interquartile range [IQR] 30 years), and 5 (33%) were male. Median number of antiseizure drugs used before KD was 8 (IQR 7), and median duration of SRSE before KD initiation was 10 days (IQR 7 days). KD treatment delays resulted from intravenous propofol use, ileus, and initial care received at a nonparticipating center. All patients achieved ketosis in a median of 2 days (IQR 1 day) on KD. Fourteen patients completed KD treatment, and SRSE resolved in 11 (79%; 73% of all patients enrolled). Side effects included metabolic acidosis, hyperlipidemia, constipation, hypoglycemia, hyponatremia, and weight loss. Five patients (33%) ultimately died. Conclusions: KD is feasible in adults with SRSE and may be safe and effective. Comparative safety and efficacy must be established with randomized placebo-controlled trials. Classification of evidence: This study provides Class IV evidence that in adults with SRSE, a KD is effective in inducing ketosis. [...]



Variability of fasting plasma glucose increased risks of diabetic polyneuropathy in T2DM

2017-03-06T12:45:27-08:00

Objective:

To examine whether variations in fasting plasma glucose (FPG), as measured by the coefficient of variation (CV), is a predictor of diabetic polyneuropathy (DPN) risk, considering glycated hemoglobin (HbA1c) and other traditional risk factors.

Methods:

Type 2 diabetic patients enrolled in the National Diabetes Care Management Program were ≥30 years of age and free of DPN (n = 36,152). They were enrolled in 2002–2004 and were monitored until 2011. The related factors were analyzed using Cox proportional hazards regression models.

Results:

During an average 7.23 years of follow-up, a total of 7,219 incident cases of DPN were identified, with a crude incidence rate of 27.62/1,000 person-years (25.83 for men and 29.31 for women). After multivariate adjustment, both FPG-CV and HbA1c were significant predictors of DPN, with corresponding hazard ratios of 1.14 (95% confidence interval [CI] 1.05–1.23) and 1.15 (95% CI 1.06–1.24) for FPG-CV in the fourth to fifth quintiles and 1.13 (95% CI 1.07–1.20) for HbA1c ≥7%. This finding maintained consistency after excluding potential confounders in the sensitivity analysis, further validating the results.

Conclusions:

FPG-CV and HbA1c ≥7% were potent predictors of DPN in type 2 diabetic patients. The associations among HbA1c, glycemic variability, and DPN suggest a linked pathophysiologic mechanism, which may play a crucial role in clinical risk assessments.




Increased default-mode network centrality in cognitively impaired multiple sclerosis patients

2017-03-06T12:45:27-08:00

Objective: To investigate how changes in functional network hierarchy determine cognitive impairment in multiple sclerosis (MS). Methods: A cohort consisting of 332 patients with MS (age 48.1 ± 11.0 years, symptom duration 14.6 ± 8.4 years) and 96 healthy controls (HCs; age 45.9 ± 10.4 years) underwent structural MRI, fMRI, and extensive neuropsychological testing. Patients were divided into 3 groups: cognitively impaired (CI; n = 87), mildly cognitively impaired (MCI; n = 65), and cognitively preserved (CP; n = 180). The functional importance of brain regions was quantified with degree centrality, the average strength of the functional connections of a brain region with the rest of the brain, and eigenvector centrality, which adds to this concept by adding additional weight to connections with brain hubs because these are known to be especially important. Centrality values were calculated for each gray matter voxel based on resting-state fMRI data, registered to standard space. Group differences were assessed with a cluster-wise permutation-based method corrected for age, sex, and education. Results: CI patients demonstrated widespread centrality increases compared to both HCs and CP patients, mainly in regions making up the default-mode network. Centrality decreases were similar in all patient groups compared to HCs, mainly in occipital and sensorimotor areas. Results were robust across centrality measures. Conclusions: Patients with MS with cognitive impairment show hallmark alterations in functional network hierarchy with increased relative importance (centrality) of the default-mode network. [...]



Neurofilament as a blood marker for diagnosis and monitoring of primary progressive aphasias

2017-03-06T12:45:27-08:00

Objective: To assess the utility of serum neurofilament for diagnosis and monitoring of primary progressive aphasia (PPA) variants. Methods: We investigated neurofilament light chain (NF-L) levels in blood of 99 patients with PPA (40 with nonfluent variant PPA [nfvPPA], 38 with semantic variant PPA [svPPA], 21 with logopenic variant PPA [lvPPA]) and compared diagnostic performance with that reached by CSF NF-L, phosphorylated neurofilament heavy chain (pNF-H), β-amyloid (Aβ1-42), tau, and phosphorylated tau. The longitudinal change of blood NF-L levels was measured and analyzed for correlation with functional decline and brain atrophy. Results: Serum NF-L is increased in PPA compared to controls and discriminates between nfvPPA/svPPA and lvPPA with 81% sensitivity and 67% specificity (cutoff 31 pg/mL). CSF NF-L, pNF-H, tau, phosphorylated tau, and Aβ1-42 achieved similar performance, and pNF-H was the only marker for discrimination of nfvPPA from svPPA/lvPPA. In most patients with nfvPPA and svPPA, but not lvPPA, serum NF-L increased within follow-up. The increase correlated with functional decline and progression of atrophy of the left frontal lobe of all patients with PPAs and the right middle frontal gyrus of patients with nfvPPA and svPPA. Conclusions: Blood level of NF-L can aid the differential diagnosis of PPA variants, especially in combination with CSF pNF-H. Because serum NF-L correlates with functional decline and atrophy in the disease course, it qualifies as an objective disease status marker. Extended follow-up studies with cases of known neuropathology are imperative. Classification of evidence: This st[...]



Lesion localization of speech comprehension deficits in chronic aphasia

2017-03-06T12:45:27-08:00

Objective:

Voxel-based lesion-symptom mapping (VLSM) was used to localize impairments specific to multiword (phrase and sentence) spoken language comprehension.

Methods:

Participants were 51 right-handed patients with chronic left hemisphere stroke. They performed an auditory description naming (ADN) task requiring comprehension of a verbal description, an auditory sentence comprehension (ASC) task, and a picture naming (PN) task. Lesions were mapped using high-resolution MRI. VLSM analyses identified the lesion correlates of ADN and ASC impairment, first with no control measures, then adding PN impairment as a covariate to control for cognitive and language processes not specific to spoken language.

Results:

ADN and ASC deficits were associated with lesions in a distributed frontal-temporal parietal language network. When PN impairment was included as a covariate, both ADN and ASC deficits were specifically correlated with damage localized to the mid-to-posterior portion of the middle temporal gyrus (MTG).

Conclusions:

Damage to the mid-to-posterior MTG is associated with an inability to integrate multiword utterances during comprehension of spoken language. Impairment of this integration process likely underlies the speech comprehension deficits characteristic of Wernicke aphasia.




Early life risk factors for cerebrovascular disease: A systematic review and meta-analysis

2017-03-06T12:45:27-08:00

Objective:

Cerebrovascular disease (CVD) causes subclinical brain vascular lesions detected using neuroimaging and childhood factors may increase later CVD risk.

Methods:

We searched MEDLINE, PsycINFO, and EMBASE, and meta-analyzed all available evidence on childhood (premorbid) IQ, socioeconomic status (SES), education, and subclinical CVD in later life. Overall odds ratios (OR), mean difference or correlation, and 95% confidence intervals (CIs) were calculated using random effects methods.

Results:

We identified 30 relevant studies (n = 22,890). Lower childhood IQ and lower childhood SES were associated with more white matter hyperintensities (WMH) (IQ: n = 1,512, r = –0.07, 95% CI –0.12 to –0.02, p = 0.007; SES: n = 243, deep WMH r = –0.18, periventricular WMH r = –0.146). Fewer years of education were associated with several CVD markers (n = 15,439, OR = 1.17, 95% CI 1.05 to 1.31, p = 0.003). No studies assessed early life factors combined.

Conclusions:

Childhood IQ, SES, and education are associated with increased risk of CVD on neuroimaging in later life. Further studies are required to provide further evidence and thereby inform policy.




Temporal trends in early case-fatality rates in patients with intracerebral hemorrhage

2017-03-06T12:45:27-08:00

Objective: To assess whether temporal trends in very early (within 48 hours) case-fatality rates may differ from those occurring between 48 hours and 30 days in patients with spontaneous intracerebral hemorrhage (ICH). Methods: All cases of ICH that occurred in Dijon, France (151,000 inhabitants), were prospectively collected between 1985 and 2011, using a population-based registry. Time trends in 30-day case fatality were analyzed in 3 periods: 1985–1993, 1994–2002, and 2003–2011. Cox regression models were used to evaluate associations between time periods and case fatality within 48 hours and between 48 hours and 30 days, after adjustments for demographics, risk factors, severity, and ICH location. Results: A total of 531 ICH cases were recorded (mean age 72.9 ± 15.8, 52.7% women). Thirty-day case fatality gradually decreased with time from 40.9% in 1985–1993 to 33.5% 1994–2002 and to 29.6% in 2003–2011 (adjusted hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.47–1.07, p = 0.106, for 1994–2002, and adjusted HR 0.49, 95% CI 0.32–0.73, p < 0.001, for 2003–2011). Over the whole study period, 43.6% of 1-month deaths occurred within the first 48 hours following ICH onset. There was no temporal change in case fatality occurring within the first 48 hours but a decrease in deaths occurring between 48 hours and 30 days was observed with time (HR 0.53, 95% CI 0.31–0.90, p = 0.02, for 1994–2002, and HR 0.32, 95% CI 0.32–0.55, p < 0.01, for 2003–2011, compared [...]



Genetic testing in ALS: A survey of current practices

2017-03-06T12:45:27-08:00

Objective: To determine the degree of consensus among clinicians on the clinical use of genetic testing in amyotrophic lateral sclerosis (ALS) and the factors that determine decision-making. Methods: ALS researchers worldwide were invited to participate in a detailed online survey to determine their attitudes and practices relating to genetic testing. Results: Responses from 167 clinicians from 21 different countries were analyzed. The majority of respondents (73.3%) do not consider that there is a consensus definition of familial ALS (FALS). Fifty-seven percent consider a family history of frontotemporal dementia and 48.5% the presence of a known ALS genetic mutation as sufficient for a diagnosis of FALS. Most respondents (90.2%) offer genetic testing to patients they define as having FALS and 49.4% to patients with sporadic ALS. Four main genes (SOD1, C9orf72, TARDBP, and FUS) are commonly tested. A total of 55.2% of respondents would seek genetic testing if they had personally received a diagnosis of ALS. Forty-two percent never offer presymptomatic testing to family members of patients with FALS. Responses varied between ALS specialists and nonspecialists and based on the number of new patients seen per year. Conclusions: There is a lack of consensus among clinicians as to the definition of FALS. Substantial variation exists in attitude and practices related to genetic testing of patients and presymptomatic testing of their relatives across geographic regions and between experienced specialists in ALS and nonspecialists. [...]



Munchausen syndrome by genetics: Next-generation challenges for clinicians

2017-03-06T12:45:27-08:00

Sixty-five years ago, Richard Asher1 was the first to describe, in The Lancet, a pattern of self-harm characterized by fabricated histories, symptoms, and signs of illness. Asher named this condition Munchausen syndrome after the famous Baron Münchhausen, a literary character loosely based on the German nobleman Hieronymus Karl Friedrich Freiherr von Münchhausen, a model of a shameless but cunning liar toying with reality and exaggeration. Munchausen syndrome frequently involves movement disorders2 difficult to distinguish from organic disease. Here, we describe the novel constellation of a factitious disorder presenting as a supposedly genetically confirmed hereditary disease manifesting with abnormal movements. As genetic testing plays a rapidly increasing role in diagnostics in all areas of medicine including rare and unusual conditions3,4 and is typically considered gold standard without further scrutiny, it is important to alert physicians to the possibility of manipulation of genetic testing reports by the patient in the context of somatoform disorders.




11C-PBR28 PET detects translocator protein in a patient with astrocytoma and Alzheimer disease

2017-03-06T12:45:27-08:00

A 66-year-old woman with probable Alzheimer disease (AD) enrolled in National Institute of Mental Health protocols 09-M-0198 and 08-M-0066. The protocols were approved by the Combined Neurosciences Institutional Review Board, and the patient gave informed consent before entering the study. Brian MRI showed diffuse atrophy and a small T2 hyperintensity in the right posterior temporal region (0.4 x 1.4 cm) interpreted as nonspecific gliosis (figure). 18Fluorodeoxyglucose PET revealed bilateral temporo-parietal hypometabolism (with no hypermetabolism in the area of the T2 hyperintensity) and 11C-Pittsburgh compound B PET imaging showed fibrillar β-amyloid retention, both consistent with AD pathophysiology. PET imaging with 11C-PBR28, a radioligand for the 18 kDa translocator protein (TSPO), was performed to measure microglial activation. Diffuse 11C-PBR28 binding was found in gray matter, with a small focus of increased binding colocalized to the T2 hyperintensity. 11C-PR28 binding was 19% greater in the T2 hyperintensity than in an identical volume in contralateral brain (figure).




Tumefactive demyelination following treatment for relapsing multiple sclerosis with alemtuzumab

2017-03-06T12:45:27-08:00

Alemtuzumab, a humanized anti-CD52 monoclonal antibody that results in profound depletion and repopulation of mature lymphocytes, is a highly efficacious therapy for active, relapsing-remitting multiple sclerosis (RRMS). In 2 phase 3 clinical trials of alemtuzumab, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) I and II, 14% and 23% of patients treated with alemtuzumab had a clinical relapse within the first 12 months, respectively.1,2




Editors' Note

2017-03-06T12:45:27-08:00

Editors' Note: In WriteClick this week, Drs. Kunchok et al. report an additional patient with chronic low-grade leptomeningeal lymphoma, adding to the case described by Gazzola et al. in "Primary marginal zone lymphoma of the CNS presenting as a diffuse leptomeningeal process."




Letter re: Primary marginal zone lymphoma of the CNS presenting as a diffuse leptomeningeal process

2017-03-06T12:45:27-08:00

Similar to Gazzola et al.,1 we treated a patient with primary marginal zone leptomeningeal lymphoma. A 58-year-old man presented with headaches, papilledema, and confusion on a background of left face/arm paresthesias for 3 years, attributed to migraine. CT brain scan showed sulcal-pattern right frontal hyperdensity, suspicious for subarachnoid blood, but normal size ventricles. Catheter arteriogram was normal. MRI showed frontal, basal, and spinal leptomeningeal enhancement. Lumbar punctures showed persistently elevated CSF pressure (>30 cm H2O) and protein (3.95 g/L) with monoclonal B lymphocytes and reactive T cell. Leptomeningeal biopsy showed a low-grade B cell neoplasm. Biopsy flow cytometry showed CD19, CD20, CD22, and FMC7-positive, kappa light-chain restricted B cells interpreted as low-grade marginal zone lymphoma. The patient was given high-dose methotrexate, rituximab IV, and intrathecal methotrexate for 6 weeks without clear response, then intrathecal rituximab plus methotrexate, with some improvement in CSF and MRI abnormalities. Our patient similarly had 2–3 years of intermittent cortical symptoms, then confusion and neuroimaging suggested subarachnoid hemorrhage. In addition, our patient also developed pseudotumor cerebri,2 probably due to very high CSF protein, and had incomplete response to chemotherapy. He completed a course of low-dose (2 Gy x 2) craniospinal radioth[...]



Author response: Primary marginal zone lymphoma of the CNS presenting as a diffuse leptomeningeal process

2017-03-06T12:45:27-08:00

Dr. Kunchok et al. describe a patient similar to our reported patient,1 ultimately diagnosed with low-grade, primary leptomeningeal, marginal zone B cell lymphoma. As illustrated in both cases, the malignancy can initially masquerade as a subarachnoid hemorrhage on neuroimaging. However, additional features, including an indolent clinical course, presence of cortical symptoms, and extracranial (spinal) leptomeningeal enhancement, should expand the differential diagnosis. In the patient reported by Kunchok et al., the presence of higher protein levels with elevated intracranial pressure and spinal leptomeningeal enhancement are notable findings that suggest a more advanced disease state compared to that of our patient. Whether these clinical features are simply related to longer-standing disease or to a more aggressive lymphoma variant is unclear. It is also worth noting that this patient had an incomplete response to chemotherapy and progressed to craniospinal radiotherapy. Continued reporting of this rare primary CNS malignancy will hopefully lead not only to increased awareness of its existence, but to more robust evidence-based treatment protocols.