Evidence-based guideline: Treatment of tardive syndromes

Objective: To make evidence-based recommendations regarding management of tardive syndromes (TDS), including tardive dyskinesias (TDD), by addressing 5 questions: 1) Is withdrawal of dopamine receptor blocking agents (DRBAs) an effective TDS treatment? 2) Does switching from typical to atypical DRBAs reduce TDS symptoms? 3) What is the efficacy of pharmacologic agents in treating TDS? 4) Do patients with TDS benefit from chemodenervation with botulinum toxin? 5) Do patients with TDS benefit from surgical therapy?

Methods: PsycINFO, Ovid MEDLINE, EMBASE, Web of Science, and Cochrane were searched (1966–2011). Articles were classified according to a 4-tiered evidence-rating scheme; recommendations were tied to the evidence.

Results and recommendations: Clonazepam probably improves TDD and ginkgo biloba probably improves TDS (both Level B); both should be considered as treatment. Risperidone may improve TDS but cannot be recommended as treatment because neuroleptics may cause TDS despite masking symptoms. Amantadine and tetrabenazine might be considered as TDS treatment (Level C). Diltiazem should not be considered as TDD treatment (Level B); galantamine and eicosapentaenoic acid may not be considered as treatment (Level C). Data are insufficient to support or refute use of acetazolamide, bromocriptine, thiamine, baclofen, vitamin E, vitamin B₆, selegiline, clozapine, olanzapine, melatonin, nifedipine, fluperlapine, sulpiride, flupenthixol, thiopropazate, haloperidol, levetiracetam, quetiapine, ziprasidone, sertindole, aripiprazole, buspirone, yi-gan san, biperiden discontinuation, botulinum toxin type A, electroconvulsive therapy, α-methyldopa, reserpine, and pallidal deep brain stimulation as TDS treatments (Level U). Data are insufficient to support or refute TDS treatment by withdrawing causative agents or switching from typical to atypical DRBA (Level U).

Report of the Guideline Development Subcommittee of the American Academy of Neurology- News from AAN

Discovering neurological signs: poly hill sign in FSHD patients

The sign, which was termed the “poly-hill sign” was considered positive when certain features were present. Over the superolateral border of neck, shoulder, and arm, from medial to lateral side, the following

were noted: 

(1) depression due to wasting of trapezius,

(2) a bulge due to jutting of the superior angle of the scapula, 

(3) second depression from the wasted trapezius,

(4) a bulge due to unusual bony prominence of the inferolaterally displaced acromio-clavicular joint,

(5) a depression due to wasting of the proximal one-fourth of the deltoid muscle fibers originating from the acromion processes,

(6) a bulge due to a slightly enlarged (in early stage) or relatively preserved (in late stage) distal threefourths of the deltoid muscle, 

(7) a depression due to wasted biceps muscle

(8) a bulge due to preserved bulk or hypertrophy of brachioradialis or extensor digitorum communis muscle. 

Bad news for AD patients

A Phase 3 Trial of Semagacestat for Treatment of Alzheimer's Disease

BACKGROUND

Alzheimer's disease is characterized by the presence of cortical amyloid-beta (Aβ) protein plaques, which result from the sequential action of β-secretase and γ-secretase on amyloid precursor protein. Semagacestat is a small-molecule γ-secretase inhibitor that was developed as a potential treatment for Alzheimer's disease.

METHODS

We conducted a double-blind, placebo-controlled trial in which 1537 patients with probable Alzheimer's disease underwent randomization to receive 100 mg of semagacestat, 140 mg of semagacestat, or placebo daily. Changes in cognition from baseline to week 76 were assessed with the use of the cognitive subscale of the Alzheimer's Disease Assessment Scale for cognition (ADAS-cog), on which scores range from 0 to 70 and higher scores indicate greater cognitive impairment, and changes in functioning were assessed with the Alzheimer's Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) scale, on which scores range from 0 to 78 and higher scores indicate better functioning. A mixed-model repeated-measures analysis was used.

RESULTS

The trial was terminated before completion on the basis of a recommendation by the data and safety monitoring board. At termination, there were 189 patients in the group receiving placebo, 153 patients in the group receiving 100 mg of semagacestat, and 121 patients in the group receiving 140 mg of semagacestat. The ADAS-cog scores worsened in all three groups (mean change, 6.4 points in the placebo group, 7.5 points in the group receiving 100 mg of the study drug, and 7.8 points in the group receiving 140 mg; P=0.15 and P=0.07, respectively, for the comparison with placebo). The ADCS-ADL scores also worsened in all groups (mean change at week 76, −9.0 points in the placebo group, −10.5 points in the 100-mg group, and −12.6 points in the 140-mg group; P=0.14 and P<0.001, respectively, for the comparison with placebo). Patients treated with semagacestat lost more weight and had more skin cancers and infections, treatment discontinuations due to adverse events, and serious adverse events (P<0.001 for all comparisons with placebo). Laboratory abnormalities included reduced levels of lymphocytes, T cells, immunoglobulins, albumin, total protein, and uric acid and elevated levels of eosinophils, monocytes, and cholesterol; the urine pH was also elevated.

CONCLUSIONS

As compared with placebo, semagacestat did not improve cognitive status, and patients receiving the higher dose had significant worsening of functional ability. Semagacestat was associated with more adverse events, including skin cancers and infections. 

N Engl J Med 2013; 369:341-350July 25, 2013DOI: 10.1056/NEJMoa1210951

Altered splicing of ATP6AP2 causes X-linked parkinsonism with spasticity (XPDS)

Abstract

We report a novel gene for a parkinsonian disorder. X-linked parkinsonism with spasticity (XPDS) presents either as typical adult onset Parkinson's disease or earlier onset spasticity followed by parkinsonism. We previously mapped the XPDS gene to a 28 Mb region on Xp11.2–X13.3. Exome sequencing of one affected individual identified five rare variants in this region, of which none was missense, nonsense or frame shift. Using patient-derived cells, we tested the effect of these variants on expression/splicing of the relevant genes. A synonymous variant in ATP6AP2, c.345C>T (p.S115S), markedly increased exon 4 skipping, resulting in the overexpression of a minor splice isoform that produces a protein with internal deletion of 32 amino acids in up to 50% of the total pool, with concomitant reduction of isoforms containing exon 4. ATP6AP2 is an essential accessory component of the vacuolar ATPase required for lysosomal degradative functions and autophagy, a pathway frequently affected in Parkinson's disease. Reduction of the full-size ATP6AP2 transcript in XPDS cells and decreased level of ATP6AP2 protein in XPDS brain may compromise V-ATPase function, as seen with siRNA knockdown in HEK293 cells, and may ultimately be responsible for the pathology. Another synonymous mutation in the same exon, c.321C>T (p.D107D), has a similar molecular defect of exon inclusion and causes X-linked mental retardation Hedera type (MRXSH). Mutations in XPDS and MRXSH alter binding sites for different splicing factors, which may explain the marked differences in age of onset and manifestations.

Hum. Mol. Genet. (2013) 22 (16): 3259-3268 doi:10.1093/hmg/ddt180

Discovering strange diseases: CCPD

OBJECTIVES:

 We aimed to identify the target antigens  or combined central and peripheral demyelination (CCPD).

METHODS:

We screened target antigens by immunohistochemistry and immunoblotting using peripheral nerve tissues to identify target antigens recognized by serum antibodies from selected CCPD and chronic inflammatory demyelinatingpolyradiculoneuropathy (CIDP) cases. We then measured the level of antibody to the relevant antigen in 7 patients with CCPD, 16 patients with CIDP, 20 patients with multiple sclerosis, 20 patients with Guillain-Barré syndrome, 21 patients with other neuropathies, and 23 healthy controls (HC) by ELISA and cell-based assays using HEK293 cells.

RESULTS:

At the initial screening, sera from 2 patients with CCPD showed cross-like binding to sciatic nerve sections at fixed intervals, with nearly perfect colocalization with neurofascin immunostaining at the node and paranode. ELISA with recombinant neurofascin revealed significantly higher mean optical density values in the CCPD group than in other disease groups and HC. Anti-neurofascin antibody positivity rates were 86% in patients with CCPD, 10% in patients with multiple sclerosis, 25% in patients with CIDP, 15% in patients with Guillain-Barré syndrome, and 0% in patients with other neuropathies and HC. The cell-based assay detected serum anti-neurofascin antibody in 5 of 7 patients with CCPD; all others were negative. CSF samples examined from 2 patients with CCPD were both positive. In anti-neurofascin antibody-positiveCCPD patients, including those with a limited response to corticosteroids, IV immunoglobulin or plasma exchange alleviated the symptoms.

CONCLUSION:

Anti-neurofascin antibody is frequently present in patients with CCPD. Recognition of this antibody may be important, because patients with CCPD who are antibody positive respond well to IV immunoglobulin or plasma exchange.

Neurology July 2013

Unusual Clinical and Molecular-Pathological Profile of Gerstmann-Sträussler-Scheinker Disease Associated With a Novel PRNP Mutation (V176G)

Importance  Here we describe the unusual clinical and molecular-neuropathological profile of a case of Gerstmann-Sträussler-Scheinker disease associated with a novel prion protein (PRNP) gene mutation.

Observations  This case report from the Australian National Creutzfeldt-Jakob Disease Registry concerns a 61-year-old British-born woman with no history of neurodegenerative disorder in first-degree relatives. Rapidly progressive dementia, altered behavior, and cerebellar ataxia dominated the clinical picture in the period immediately following minor elective surgery, with death 1 month later in an akinetic-mute state. Brain histopathological examination revealed neuronal loss, scant foci of spongiform change, and diffuse multicentric amyloid plaques, selectively immunoreactive for prion protein, within the cerebral and cerebellar cortices and deep gray matter. Tau immune-reactive neurofibrillary tangles and neuritic threads were present in the cerebral cortex. PRNPsequencing demonstrated a valine to glycine mutation at codon 176, with valine homozygosity at polymorphic codon 129. Western-blot analysis of frozen brain tissue displayed a nonclassic protease-resistant prion protein banding pattern, with a prominent approximately 8-kDa protease-resistant fragment.

Conclusions and Relevance  Reported is a proband with a novel PRNP mutation associated with neuropathologically confirmed Gerstmann-Sträussler-Scheinker disease displaying a somewhat unusual constellation of clinicopathological features, which overall subserve to further broaden an already diverse phenotypic spectrum.

JAMA Neurol. 2013;():-. doi:10.1001/jamaneurol.2013.165.

Genes Influencing Rate of Cognitive Decline in AD Identified

Alzheimer's Association International Conference (AAIC) 2013. Poster P4-007. Presented July 12, 2013.

Alzheimer's disease is characterized by progressive decline in cognitive functioning, especially in memory but also executive functioning (including planning, attention and problem solving) and global cognition. Each person may experience Alzheimer's differently, and there are considerable differences in rates of decline between affected individuals.

"If we can understand more about the genetic basis of this variability in rate of decline, it could help illuminate the biological pathways involved in disease progression," said Richard Sherva, Ph.D., research assistant professor in the department of Biomedical Genetics at Boston University School of Medicine. "It also could inform the development of therapies to slow the progression of disease."

Sherva and colleagues are utilizing research funds awarded by the Alzheimer's Association to study the genetics of the rate of Alzheimer's-related cognitive decline in a large population from a completed clinical trial. By expanding their work into a multi-institutional consortium (known as Genetic Architecture of Rate of Alzheimer's Decline, or GENAROAD, led by Drs. Robert Green and Paul Crane), they have amassed a relatively large sample of Alzheimer's cases with the longitudinal data necessary to study the topic in depth.

At AAIC 2013, Sherva reported genome wide association studies (GWAS) from participants in multiple research studies including the Alzheimer's Disease Neuroimaging Initiative (n=301), National Alzheimer's Coordinating Centers (n=865), Religious Orders Study/Rush Memory and Aging Project (n=323), and AddNeuroMed study (n=123). The combined GWAS identified at least four genetic variants strongly associated with rate of decline in Alzheimer's, including SPON1, MANB4A, KCNJ14, MAP3K1 and HIBADH.

"We found that the genes that influence rate of decline are largely different that those that influence Alzheimer's risk in general but are genes involved in pathways related to Alzheimer's risk," Sherva said. "The most interesting gene we identified is called SPON1, which has functions related to beta-amyloid generation and also regulates brain cell connectivity."

Development and validation of a clinical guideline for diagnosing blepharospasm

Objective: To design and validate a clinical diagnostic guideline for aiding physicians in confirming or refuting suspected blepharospasm.

Methods: The guideline was developed and validated in a 3-step procedure: 1) identification of clinical items related to the phenomenology of blepharospasm, 2) assessment of the relevance of each item to the diagnosis of blepharospasm, and 3) evaluation of the reliability and diagnostic sensitivity/specificity of the selected clinical items.

Results: Of 19 clinical items initially identified, 7 were admitted by content validity analysis to further assessment. Both neurologists and ophthalmologists achieved satisfactory interobserver agreement for all 7 items, including “involuntary eyelid narrowing/closure due to orbicularis oculi spasms,” “bilateral spasms,” “synchronous spasms,” “stereotyped spasm pattern,” “sensory trick,” “inability to voluntarily suppress the spasms,” and “blink count at rest.” Each selected item yielded unsatisfactory accuracy in discriminating patients with blepharospasm from healthy subjects and patients with other eyelid disturbances. Combining the selected items, however, improved diagnostic sensitivity/specificity. The best combination, yielding 93% sensitivity and 90% specificity, was an algorithm starting with the item “stereotyped, bilateral, and synchronous orbicularis oculi spasms inducing eyelid narrowing/closure” and followed by recognition of “sensory trick” or, alternatively, “increased blinking.”

Conclusion: This study provides an accurate and valid clinical guideline for diagnosing blepharospasm. Use of this guideline would make it easier for providers to recognize dystonia in clinical and research settings.

Neurology July 16, 2013 vol. 81 no. 3 236-240

discovering strange diseases: PRRT2 mutations and paroxysmal disorders

In the past year, mutations in the PRRT2 gene have been identified in patients with paroxysmal kinesigenic dyskinesia and other paroxysmal disorders. We conducted a review of the literature on PRRT2 mutation-associated disorders. Our objectives were to describe the wide clinical spectrum associated with PRRT2 mutations, and to present the current hypotheses on the underlying pathophysiology.PRRT2 mutations are associated with a wide range of clinical syndromes: the various paroxysmal dyskinesias, infantile seizures, paroxysmal torticollis, migraine, hemiplegic migraine, episodic ataxia and even intellectual disability in the homozygous state. The PRRT2protein, through its interaction with SNAP-25, could play a role in synaptic regulation in the cortex and the basal ganglia. The pathogenesis may be caused by PRRT2 loss of function, which may induce synaptic deregulation and neuronal hyperexcitability. However, this does not explain the phenotypic variability, which is likely modulated by environmental factors, modifier genes or age-dependent expression. The clinical spectrum of PRRT2 mutations has expanded among paroxysmal disorders and beyond. Unraveling the molecular pathways linking the genetic defect to its clinical expression will be crucial for the diagnosis and treatment of these disorders.

European Journal of Neurology Volume 20, Issue 6, pages 872–878, June 2013

Vasopressin, Steroids, and Epinephrine and Neurologically Favorable Survival After In-Hospital Cardiac Arrest A Randomized Clinical Trial

Importance  Among patients with cardiac arrest, preliminary data have shown improved return of spontaneous circulation and survival to hospital discharge with the vasopressin-steroids-epinephrine (VSE) combination.

Objective  To determine whether combined vasopressin-epinephrine during cardiopulmonary resuscitation (CPR) and corticosteroid supplementation during and after CPR improve survival to hospital discharge with a Cerebral Performance Category (CPC) score of 1 or 2 in vasopressor-requiring, in-hospital cardiac arrest.

Design, Setting, and Participants  Randomized, double-blind, placebo-controlled, parallel-group trial performed from September 1, 2008, to October 1, 2010, in 3 Greek tertiary care centers (2400 beds) with 268 consecutive patients with cardiac arrest requiring epinephrine according to resuscitation guidelines (from 364 patients assessed for eligibility).

Interventions  Patients received either vasopressin (20 IU/CPR cycle) plus epinephrine (1 mg/CPR cycle; cycle duration approximately 3 minutes) (VSE group, n = 130) or saline placebo plus epinephrine (1 mg/CPR cycle; cycle duration approximately 3 minutes) (control group, n = 138) for the first 5 CPR cycles after randomization, followed by additional epinephrine if needed. During the first CPR cycle after randomization, patients in the VSE group received methylprednisolone (40 mg) and patients in the control group received saline placebo. Shock after resuscitation was treated with stress-dose hydrocortisone (300 mg daily for 7 days maximum and gradual taper) (VSE group, n = 76) or saline placebo (control group, n = 73).

Main Outcomes and Measures  Return of spontaneous circulation (ROSC) for 20 minutes or longer and survival to hospital discharge with a CPC score of 1 or 2.

Results  Follow-up was completed in all resuscitated patients. Patients in the VSE group vs patients in the control group had higher probability for ROSC of 20 minutes or longer (109/130 [83.9%] vs 91/138 [65.9%]; odds ratio [OR], 2.98; 95% CI, 1.39-6.40; P = .005) and survival to hospital discharge with CPC score of 1 or 2 (18/130 [13.9%] vs 7/138 [5.1%]; OR, 3.28; 95% CI, 1.17-9.20; P = .02). Patients in the VSE group with postresuscitation shock vs corresponding patients in the control group had higher probability for survival to hospital discharge with CPC scores of 1 or 2 (16/76 [21.1%] vs 6/73 [8.2%]; OR, 3.74; 95% CI, 1.20-11.62; P = .02), improved hemodynamics and central venous oxygen saturation, and less organ dysfunction. Adverse event rates were similar in the 2 groups.

Conclusion and Relevance  Among patients with cardiac arrest requiring vasopressors, combined vasopressin-epinephrine and methylprednisolone during CPR and stress-dose hydrocortisone in postresuscitation shock, compared with epinephrine/saline placebo, resulted in improved survival to hospital discharge with favorable neurological status.

JAMA. 2013;310(3):270-279. doi:10.1001/jama.2013.7832.

Mutations in COQ2 in Familial and Sporadic Multiple-System Atrophy

BACKGROUND

Multiple-system atrophy is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Although multiple-system atrophy is widely considered to be a nongenetic disorder, we previously identified multiplex families with this disease, which indicates the involvement of genetic components.

METHODS

In combination with linkage analysis, we performed whole-genome sequencing of a sample obtained from a member of a multiplex family in whom multiple-system atrophy had been diagnosed on autopsy. We also performed mutational analysis of samples from members of five other multiplex families and from a Japanese series (363 patients and two sets of controls, one of 520 persons and one of 2383 persons), a European series (223 patients and 315 controls), and a North American series (172 patients and 294 controls). On the basis of these analyses, we used a yeast complementation assay and measured enzyme activity of parahydroxybenzoate-polyprenyl transferase. This enzyme is encoded by the gene COQ2 and is essential for the biosynthesis of coenzyme Q10. Levels of coenzyme Q10 in lymphoblastoid cells and brain tissue were measured on high-performance liquid chromatography.

RESULTS

We identified a homozygous mutation (M78V-V343A/M78V-V343A) and compound heterozygous mutations (R337X/V343A) in COQ2 in two multiplex families. Furthermore, we found that a common variant (V343A) and multiple rare variants in COQ2, all of which are functionally impaired, are associated with sporadic multiple-system atrophy. The V343A variant was exclusively observed in the Japanese population.

CONCLUSIONS

Functionally impaired variants of COQ2 were associated with an increased risk of multiple-system atrophy in multiplex families and patients with sporadic disease, providing evidence of a role of impaired COQ2 activities in the pathogenesis of this disease. (Funded by the Japan Society for the Promotion of Science and others.)

N Engl J Med 2013; 369:233-244July 18, 2013DOI: 10.1056/NEJMoa1212115

Neocortical interneurons

The cerebral cortex contains 2 types of neurons: principal (mostly pyramidal) neurons, which constitute approximately 80% of the total population, and local interneurons, which constitute approximately 20% of the total population, with some species variation. Pyramidal cells are excitatory glutamatergic neurons that participate in cortico-cortical connections or project to subcortical areas. Local interneurons utilize γ-aminobutyric acid (GABA) as their primary neurotransmitter and participate in local circuits in the cerebral cortex. Normal sensory perception, attention, and planning and execution of behaviors depend on interactions among canonical neocortical circuits involving excitatory and inhibitory neurons. Cortical interneurons have a fundamental role in shaping cortical circuits and controlling neocortical network interactions. These interneurons form functionally distinct networks that are temporally coordinated by electrical coupling via gap junctions, and establish GABAergic synapses not only with pyramidal neurons but also among each other. Via these interactions, GABAergic interneurons control the timing of pyramidal cell firing, generation of cortical rhythms, organization of sensory fields, and cortical plasticity. Impaired activity of neocortical inhibitory interneurons has been associated with several neurologic and psychiatric disorders, including epilepsy, mental retardation, schizophrenia, and autism. There are many comprehensive reviews on GABAergic interneuron heterogeneity, development, plasticity, function in shaping cortical activity, and involvement in disease.

Neurology July 16, 2013 vol. 81 no. 3 273-280

Development and validation of a clinical guideline for diagnosing blepharospasm.

Neurology. 2013 Jun 14. [Epub ahead of print]

Abstract

OBJECTIVE:

To design and validate a clinical diagnostic guideline for aiding physicians in confirming or refuting suspected blepharospasm.

METHODS:

The guideline was developed and validated in a 3-step procedure: 1) identification of clinical items related to the phenomenology of blepharospasm, 2) assessment of the relevance of each item to the diagnosis of blepharospasm, and 3) evaluation of the reliability and diagnostic sensitivity/specificity of the selected clinical items.

RESULTS:

Of 19 clinical items initially identified, 7 were admitted by content validity analysis to further assessment. Both neurologists and ophthalmologists achieved satisfactory interobserver agreement for all 7 items, including "involuntary eyelid narrowing/closure due to orbicularis oculi spasms," "bilateral spasms," "synchronous spasms," "stereotyped spasm pattern," "sensory trick," "inability to voluntarily suppress the spasms," and "blink count at rest." Each selected item yielded unsatisfactory accuracy in discriminating patients with blepharospasm from healthy subjects and patients with other eyelid disturbances. Combining the selected items, however, improved diagnostic sensitivity/specificity. The best combination, yielding 93% sensitivity and 90% specificity, was an algorithm starting with the item "stereotyped, bilateral, and synchronous orbicularis oculi spasms inducing eyelid narrowing/closure" and followed by recognition of "sensory trick" or, alternatively, "increased blinking." CONCLUSION: This study provides an accurate and valid clinical guideline for diagnosing blepharospasm. Use of this guideline would make it easier for providers to recognize dystonia in clinical and research settings

breaking news: The International Classification of Headache Disorders, 3rd edition (beta version), pdf version

http://www.ihs-classification.org/_downloads/mixed/International-Headache-Classification-III-ICHD-III-2013-Beta.pdf

and here is pdf format 

Breaking News: ICHD-3 beta is published. Use it immediately

http://217.174.249.183/upload/Common1/CHA%20editorial-JO-Jun%2013.pdf

Discovering strange diseases: Cerebral–Renal Salt Wasting

Cerebral or the preferred term, renal salt wasting (RSW), remains an unresolved syndrome that has historically evolved from being considered nonexistent to acceptance as a distinct clinical syndrome. Yet, differences over its prevalence continue. Many with RSW are diagnosed and treated for SIADH, which has diametrically opposite therapeutic goals from RSW, that is, to water-restrict in SIADH and administer salt and water in RSW. The major obstacles to differentiating SIADH from RSW are the overlapping of significant findings and clinical associations of both syndromes and our inability to assess the volume status of these patients, being volume-depleted in RSW and expanded in SIADH. In this chapter, we (1) redefine RSW, (2) review the pathophysiology of RSW, (3) review relevant volume studies, which prove RSW to be much more common than SIADH in neurosurgical patients, (4) review the complexities of differentiating RSW from SIADH, focusing on how a previously increased FEurate normalizes in SIADH as compared to being persistently increased in RSW after correction of hyponatremia, (5) review the emerging importance of determining fractional excretion (FE) of urate, which surpasses serum urate in the evaluation of hyponatremic conditions, (6) increased FEurate in the presence of normonatremia is suggestive of RSW, (7, 8) A normal FEurate in nonedematous hyponatremia is highly suggestive of reset osmostat, (9) present an algorithm that uses FEurate as central to the evaluation of the hyponatremic patient, (10). demonstrate the presence of a natriuretic factor in RSW that has different characteristics from A/BNP (11) advocate changing cerebral salt wasting to RSW based on reports of RSW occurring in patients without clinical cerebral disease and eliminating reset osmostat as a subtype of SIADH based on a normal FEurate and the predictability of ADH response to changes in serum osmolality, and (12) awareness, that symptoms with potentially serious complications are associated with hyponatremia, creates a therapeutic urgency to improve methods of differentiating RSW from SIADH.

Hyponatremia 2013, pp 65-85

Brain network connectivity assessed using graph theory in frontotemporal dementia

1. Federica Agosta, MD, PhD, 
2. Sara Sala, PhD, 
3. Paola Valsasina, MSc, 
4. Alessandro Meani, MSc, 
5. Elisa Canu, MSc,
6. Giuseppe Magnani, MD, 
7. Stefano F. Cappa, MD, 
8. Elisa Scola, MD, 
9. Piero Quatto, PhD, 
10. Mark A. Horsfield, PhD, 
11. Andrea Falini, MD, 
12. Giancarlo Comi, MD and 
13. Massimo Filippi, MD

ABSTRACT

Objective: To investigate whether brain functional network connectivity is disrupted in patients with the behavioral variant of frontotemporal dementia (bvFTD).

Methods: Graph theoretical analysis was applied to resting state functional MRI data from 18 patients with probable bvFTD and 50 healthy individuals. Functional connectivity between 90 cortical and subcortical brain regions was estimated using bivariate correlation analysis and thresholded to construct a set of undirected graphs. Correlations between network properties and cognitive variables were tested.

Results: Global topologic organization of the functional brain network in bvFTD was significantly disrupted as indicated by reduced mean network degree, clustering coefficient, and global efficiency and increased characteristic path length and assortativity relative to normal subjects. Compared to controls, bvFTD data showed retention of major “hub” regions in the medial parietal, temporal, and occipital lobes, but cortical hubs were not noted in the frontal lobes. Medial and dorsal frontal regions, left caudate nucleus, left insular cortices, and some regions of the temporal, parietal, and occipital lobes showed decreased nodal centrality. BvFTD patients showed the greatest decrease in inter-regional connectivity between the frontal and occipital regions, and the insular cortices and occipital, temporal, subcortical, and frontal regions. In bvFTD, altered global network properties correlated with executive dysfunction.

Conclusions: Global and local functional networks are altered in bvFTD, suggesting a loss of efficiency in information exchange between both distant and close brain areas. Altered brain regions are located in structures that are closely associated with neuropathologic changes in bvFTD. Aberrant topology of the functional brain networks in bvFTD appears to underlie cognitive deficits in these patients.

Neurology July 9, 2013 vol. 81 no. 2 134-143

Cerebral hyperperfusion syndrome

Cerebral hyperperfusion syndrome: a novel presentation of internal carotid artery dissection

Cervical artery dissection (CeAD) occurs preferentially in the middle-aged, and its annual incidence rate is 2.6 to 3.0 per 100,000. Manifestations of internal carotid artery dissection (ICAD) include ischemic stroke and TIA (>70% of patients), headache, neck pain, Horner syndrome, cranial nerve palsy, pulsatile tinnitus, and, rarely, subarachnoid hemorrhage. Cerebral hyperperfusion syndrome is known to occur after carotid artery revascularization procedures and it is thought to result from the combination of several factors that impair cerebral vascular autoregulatory mechanisms.
Neurology, July 3 2013