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1.  Modification of Multiple Sclerosis Phenotypes by African Ancestry at HLA 
Archives of neurology  2009;66(2):226-233.
Background
In those with multiple sclerosis (MS), African American individuals have a more severe disease course, an older age at onset, and more often have clinical manifestations restricted to the optic nerves and spinal cord (opticospinal MS) than white persons.
Objective
To determine whether genetic variation influences clinical MS patterns.
Design
Retrospective multicenter cohort study.
Participants
Six hundred seventy-three African American and 717 white patients with MS.
Main Outcome Measures
Patients with MS were geno-typed for HLA-DRB1 and HLA-DQB1 alleles. The proportion of European ancestry at HLA was estimated by genotyping single-nucleotide polymorphisms with known significant frequency differences in West African and European populations. These genotypes were correlated with the opticospinal disease phenotype, disability measures, and age at onset.
Results
Subjects with DRB1*15 alleles were twice as likely to have typical MS rather than opticospinal MS (P = .001). Of the subjects with opticospinal MS or a history of recurrent transverse myelitis who were seropositive for anti–aquaporin 4 antibodies (approximately 5%), none carried DRB1*15 alleles (P = .008). Independently of DRB1* 15, African ancestry at HLA correlated with disability as measured by the Multiple Sclerosis Severity Score (P < .001) andriskof cane dependency (hazard ratio, 1.36; P < .001); DRB1*15 alleles were associated with a 2.1-year earlier age at onset (P < .001).
Conclusions
These data indicate that the role of HLA in MS is not limited to disease susceptibility but that genes embedded in this locus also influence clinical outcomes.
doi:10.1001/archneurol.2008.541
PMCID: PMC4334456  PMID: 19204159
2.  The Evaluation of Distal Symmetric Polyneuropathy: A Physician Survey of Clinical Practice 
Archives of neurology  2011;69(3):339-345.
Objective
To define current clinical practice in the evaluation of distal symmetric polyneuropathy (DSP).
Deisgn
Using a modified Dillman method, surveys were sent to 600 internists, 600 neurologists, and 45 neuromuscular specialists selected from the AMA Physician Masterfile. Survey questions pertained to which tests providers would order in the following three scenarios: 1) the initial evaluation of DSP, 2) additional tests if the initial evaluation was unrevealing, and 3) patients with diabetes. T-tests were used to compare the number of tests ordered by physician type and chi-square tests to compare proportions of tests ordered.
Setting
National survey of physicians
Participants
Internists and neurologists
Results
The response rate was 35%. Overall, many tests are ordered in the full evaluation of DSP (16.5 ± 7.2), and there is substantial variation within and between provider types. Internists planned to order fewer tests (14.5 ± 6.1) than neurologists (17.5 ± 7.9) (p<0.0001). Regarding the glucose tolerance test (GTT), substantial differences were found between physician types, with neurologists and neuromuscular specialists ordering this test more frequently than internists (28.6% and 72.3% versus 4.1%, respectively). A brain and/or spine MRI was ordered by 19.8% of internists and 12.9% of neurologists.
Conclusions
Practice intent for the evaluation of DSP is highly variable and differs widely from the supporting evidence. A high yield test, the GTT, is rarely utilized; whereas, MRIs are likely over-utilized in this disorder of peripheral nerves. Research that defines the optimal evaluation of DSP has the potential to result in more efficient care.
doi:10.1001/archneurol.2011.1735
PMCID: PMC4254745  PMID: 22083798
3.  Preservation of Neurons of the Nucleus Basalis in Subcortical Ischemic Vascular Disease 
Archives of neurology  2012;69(7):879-886.
Object
To compare loss of neurons in the nucleus basalis of Meynert (NB) in subcortical ischemic vascular disease (SIVD) to normal controls, Alzheimer’s disease (AD), and cases with mixed AD/SIVD pathology.
Design
Autopsied cases drawn from a longitudinal observational study with SIVD, AD and normal aging.
Subjects
Pathologically defined SIVD (n = 16), AD (n = 20), mixed pathology (n = 10), and age- and education-matched normal control (n = 17) groups were studied.
Main Outcome measures
NB neuronal cell counts in each group and their correlation with the extent of MRI white matter lesions (WML) and Clinical Dementia Rating (CDR) scores closest to death.
Results
No significant loss of neurons was found in SIVD compared to age-matched controls in contrast to AD and mixed groups, where there was significant neuronal loss. A significant inverse correlation between NB neurons and CDR scores was found in AD, but not in the SIVD and mixed groups. NB cell counts were not correlated with either the extent of white matter lesions or cortical gray matter volume in SIVD or AD groups.
Conclusions
These findings inveigh against primary loss of cholinergic neurons in SIVD, but do not rule out the possibility of secondary cholinergic deficits due to disruptions of cholinergic projections to cerebral cortex.
doi:10.1001/archneurol.2011.2874
PMCID: PMC4184885  PMID: 22393167
4.  Natalizumab and Progressive Multifocal Leukoencephalopathy: What are the causal factors? Can it be avoided? 
Archives of neurology  2010;67(8):923-930.
Natalizumab (Tysabri®) was the first monoclonal antibody approved for the treatment of relapsing forms of multiple sclerosis (MS). After its initial approval, three patients undergoing natalizumab therapy in combination with other immunoregulatory and immunosuppressive agents were diagnosed with progressive multifocal leukoencephalopathy (PML). The agent was later re-approved, and its use restricted to monotherapy in patients with relapsing forms of MS. Over the past year, five additional cases of PML were reported in MS patients receiving natalizumab monotherapy. Thus, there is currently no convincing evidence that natalizumab-associated PML is restricted to combination therapy with other disease modifying or immunosuppressive agents.
The initial section of this review focuses on the scientific rationale for natalizumab in MS treatment. In the second part, our understanding of PML will be outlined. Thirdly, recent results on altered immune surveillance under natalizumab treatment are reviewed. In the forth section, the link of viral reactivation and very late activation antigen 4 (VLA-4) antagonism will be discussed. Finally, this review will address the potential impact of our current knowledge on the use of natalizumab in clinical practice.
doi:10.1001/archneurol.2010.161
PMCID: PMC4157908  PMID: 20697042
5.  Adult-Onset Vanishing White Matter Disease Due to a Novel EIF2B3 Mutation 
Archives of neurology  2012;69(6):765-768.
Objective
To report a novel mutation in the gene EIF2B3 responsible for a late-onset form of vanishing white matter disease.
Design
Case report.
Setting
University teaching hospital.
Patient
A 29-year-old pregnant woman with a history of premature ovarian failure and hemiplegic migraines presented with a 10-week history of progressive confusion and headaches. Magnetic resonance imaging of the brain revealed a diffuse leukoencephalopathy.
Results
Sequencing of the exons and intron boundaries of EIF2B3 uncovered 2 missense mutations: c.260C>T (p.Ala87Val) and c.272G>A (p.Arg91His). To our knowledge, the latter missense mutation has never been previously reported.
Conclusion
This is the second report of adult-onset vanishing white matter disease due to mutations in EIF2B3 and the first report of the c.272G>A (p.Arg91His) missense mutation.
doi:10.1001/archneurol.2011.1942
PMCID: PMC4154510  PMID: 22312164
6.  Novel Infantile-Onset Leukoencephalopathy With High Lactate Level and Slow Improvement 
Archives of neurology  2012;69(6):718-722.
Objective
To describe a novel pattern of magnetic resonance imaging (MRI) abnormalities as well as the associated clinical and laboratory findings.
Design
The MRIs of more than 3000 patients with an unclassified leukoencephalopathy were systematically reviewed. Clinical and laboratory data were retrospectively collected.
Setting
University hospital.
Patients
Seven patients (3 male) shared similar MRI abnormalities and clinical features.
Main Outcome Measures
Pattern of MRI abnormalities and clinical and laboratory findings.
Results
The MRIs showed signal abnormalities of the deep cerebral white matter, corpus callosum, thalamus, basal ganglia, brainstem, and cerebellar white matter between the ages of 9 months and 2 years. On follow-up, abnormalities gradually improved. Clinical regression occurred in the second half-year of life with spasticity and loss of milestones. From the second year on, clinical improvement occurred. So far, no second episode of regression has happened. Lactate levels were elevated during clinical regression.
Conclusion
These patients represent a single novel leukoencephalopathy, probably caused by a mitochondrial defect.
doi:10.1001/archneurol.2011.1048
PMCID: PMC4154514  PMID: 22312165
7.  A Randomized, Placebo-Controlled Trial of Latrepirdine in Huntington Disease 
Archives of neurology  2010;67(2):154-160.
Objectives
To evaluate the safety and tolerability of latrepirdine in Huntington disease (HD) and explore its effects on cognition, behavior, and motor symptoms.
Design
Double-blind, randomized, placebo-controlled trial.
Setting
Multicenter outpatient trial.
Participants
Ninety-one participants with mild to moderate HD enrolled at 17 US and UK centers from July 18, 2007, through July 16, 2008.
Intervention
Latrepirdine, 20 mg 3 times daily (n=46), or matching placebo (n=45) for a 90-day treatment period.
Main Outcome Measures
The primary outcome variable was tolerability, defined as the ability to complete the study at the assigned drug dosage. Secondary outcome variables included score changes from baseline to day 90 on the Unified Huntington's Disease Rating Scale (UHDRS), the Mini-Mental State Examination (MMSE), and the Alzheimer Disease Assessment Scale–cognitive subscale (ADAS-cog).
Results
Latrepirdine was well tolerated (87% of the patients given latrepirdine completed the study vs 82% in the placebo group), and adverse event rates were comparable in the 2 groups (70% in the latrepirdine group and 80% in the placebo group). Treatment with latrepirdine resulted in improved mean MMSE scores compared with stable performance in the placebo group (treatment effect, 0.97 points; 95% confidence interval, 0.10-1.85; P=.03). No significant treatment effects were seen on the UHDRS or the ADAS-cog.
Conclusions
Short-term administration of latrepirdine is well tolerated in patients with HD and may have a beneficial effect on cognition. Further investigation of latrepirdine is warranted in this population with HD.
doi:10.1001/archneurol.2009.334
PMCID: PMC4134015  PMID: 20142523
8.  A Renaissance for Antisense Oligonucleotide Drugs in Neurology 
Archives of neurology  2009;66(1):32-38.
Antisense oligonucleotides are short nucleic acid sequences designed for use as small-molecule drugs. They recognize and bind to specific messenger RNA (mRNA) or pre-mRNA sequences to create small double-stranded regions of the target mRNA that alter mRNA splicing patterns or inhibit protein translation. Antisense approaches have been actively pursued as a form of molecular medicine for more than 20 years, but only one has been translated to a marketed drug (intraocular human immunodeficiency virus treatment). Two recent advances foreshadow a change in clinical applications of antisense strategies. First is the development of synthetic DNA analogues that show outstanding stability and sequence specificity yet little or no binding to modulator proteins. Second is the publication of impressive preclinical and clinical data using antisense in an exon-skipping strategy to increase dystrophin production in Duchenne muscular dystrophy. As long-standing barriers are successfully circumvented, attention turns toward scale-up of production, long-term toxicity studies, and the challenges to traditional drug regulatory attitudes presented by tightly targeted sequence-specific drugs.
doi:10.1001/archneurol.2008.540
PMCID: PMC4111150  PMID: 19139297
9.  Subjective cognition and amyloid deposition imaging: a Pittsburgh Compound B positron emission tomography study in normal elderly individuals 
Archives of Neurology  2012;69(2):223-229.
Background
Subjective cognitive impairment (SCI) as an early clinical manifestation in Alzheimer disease (AD) is a central and highly debated question.
Objective
To study the relationship between subjective cognition and the neuropathological hallmark of AD, amyloid-beta (Aβ) deposition, imaged with [11C]-Pittsburg compound B (PiB) - positron emission tomography (PET), in normal elderly individuals.
Design
Cross-sectional analysis.
Subjects
Forty-eight cognitively normal elderly subjects (11 with high PiB uptake and 28 with low PiB uptake) were included. All underwent clinical and neuropsychological evaluations and MRI and PET scanning.
Results
High PiB subjects showed significantly lower performance than low PiB subjects on an episodic memory measure, and were less confident about their general memory abilities when required to evaluate themselves relative to other people of the same age. High and low PiB groups did not differ on the accuracy of their cognitive self-reports compare to objective cognitive performance. General memory self-reports from the whole group were significantly correlated to regional PiB uptake in the right medial prefrontal cortex (PFC)/anterior cingulate cortex (ACC) and in the right precuneus/posterior cingulate cortex (PCC). Reduced confidence about memory abilities was associated with greater PiB in these brain regions. All results are independent of demographic variables and depressive affects.
Conclusions
Our findings suggest that a decrease of self-confidence about memory abilities in cognitively normal elderly subjects is related to the neuropathological hallmark of AD measured with PiB-PET imaging. The relevance of SCI in the early stages of the AD pathological process is addressed.
doi:10.1001/archneurol.2011.666
PMCID: PMC4004919  PMID: 22332189
Aged; Aged, 80 and over; Aging; physiology; Amyloid beta-Peptides; metabolism; Aniline Compounds; Biological Markers; Cerebral Cortex; radionuclide imaging; Cognition; physiology; Cognition Disorders; metabolism; psychology; radionuclide imaging; Cohort Studies; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Memory; physiology; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Prefrontal Cortex; radionuclide imaging; Radiopharmaceuticals; Reference Values; Thiazoles; subjective cognition; normal aging; Alzheimer's disease (AD); amyloid-beta (Aβ); [11C]-Pittsburgh compound B (PiB) - positron emission tomography (PET)
10.  Investigation of C9orf72 in 4 Neurodegenerative Disorders 
Archives of neurology  2012;69(12):1583-1590.
Objective
To estimate the allele frequency of C9orf72 (G4C2) repeats in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer disease (AD), and Parkinson disease (PD).
Design
The number of repeats was estimated by a 2-step genotyping strategy. For expansion carriers, we sequenced the repeat flanking regions and obtained APOE genotypes and MAPT H1/H2 haplotypes.
Setting
Hospitals specializing in neurodegenerative disorders.
Subjects
We analyzed 520 patients with FTLD, 389 patients with ALS, 424 patients with AD, 289 patients with PD, 602 controls, 18 families, and 29 patients with PD with the LRRK2 G2019S mutation.
Main Outcome Measure
The expansion frequency.
Results
Based on a prior cutoff (>30 repeats), the expansion was detected in 9.3% of patients with ALS, 5.2% of patients with FTLD, and 0.7% of patients with PD but not in controls or patients with AD. It was significantly associated with family history of ALS or FTLD and age at onset of FTLD. Phenotype variation (ALS vs FTLD) was not associated with MAPT, APOE, or variability in the repeat flanking regions. Two patients with PD were carriers of 39 and 32 repeats with questionable pathological significance, since the 39-repeat allele does not segregate with PD. No expansion or intermediate alleles (20–29 repeats) were found among the G2019S carriers and AD cases with TAR DNA-binding protein 43–positive inclusions. Surprisingly, the frequency of the 10-repeat allele was marginally increased in all 4 neurodegenerative diseases compared with controls, indicating the presence of an unknown risk variation in the C9orf72 locus.
Conclusions
The C9orf72 expansion is a common cause of ALS and FTLD, but not of AD or PD. Our study raises concern about a reliable cutoff for the pathological repeat number, which is important in the utility of genetic screening.
doi:10.1001/archneurol.2012.2016
PMCID: PMC4005900  PMID: 22964832
11.  Spreading Depolarization 
Archives of neurology  2010;68(1):31-36.
A neurysmal subarachnoid hemorrhage (SAH) is a devastating disease with a high mortality and morbidity rate. Gradual improvements have been made in the reduction of mortality rates associated with the disease during the last 30 years. However, delayed cerebral ischemia (DCI), the major delayed complication of SAH, remains a significant contributor to mortality and morbidity despite substantial research and clinical efforts. During the last several years, the predominant role of cerebral vasospasm, the long-accepted etiologic factor behind DCI, has been questioned. It is now becoming increasingly clear that the pathophysiology underlying DCI is multifactorial. Cortical spreading depression is emerging as a likely factor in this complex web of pathologic changes after SAH. Understanding its role after SAH and its relationship with the other pathologic processes such as vasospasm, microcirculatory dysfunction, and microemboli will be vital to the development of new therapeutic approaches to reduce DCI and improve the clinical outcome of the disease.
doi:10.1001/archneurol.2010.226
PMCID: PMC3998646  PMID: 20837823
12.  Age-Dependent Structural Connectivity Effects in Fragile X Premutation 
Archives of neurology  2012;69(4):482-489.
Objective
To examine the effects of premutation alleles on major brain fiber tracts in males.
Design
Cross-sectional study performed in 2007–2009.
Setting
Institutional practice.
Patients
Fifteen younger (18–45 years old) carriers, 11 older (>45 years old) unaffected carriers, and 15 older carriers with fragile X–associated tremor/ataxia syndrome, together with 19 younger and 15 older controls matched by age and educational level.
Main Outcome Measures
Diffusion tensor imaging was performed on all study participants. Eleven fiber tracts important for motor, social, emotional, and cognitive functions were reconstructed and quantified. Complementary tract-based spatial statistical analyses were performed in core white matter.
Results
In the younger carriers, premutation status was associated with a greater age-related connectivity decline in the extreme capsule. Among older carriers, unaffected individuals did not display structural alterations, whereas the affected carriers showed connectivity loss in 5 fiber tracts and exhibited greater age-related connectivity decline in all 11 tracts compared with the controls. In addition, 9 fiber tracts showed significantly higher variability relative to the controls, and symptom severity explained the variability in 6 measurements from the superior cerebellar peduncle, corpus callosum, and cingulum.
Conclusions
The findings revealed widespread alterations in structural connectivity associated with fragile X–associated tremor/ataxia syndrome and preserved or subtle changes in structural connectivity in unaffected carriers. Diffusion tensor imaging is sensitive to pathologic changes in the white matter associated with this neurodegenerative disorder.
Wang et al examine the effects of premutation alleles on major brain fiber tracts in males, who are at risk of developing fragile X-associated tremor/ataxia syndrome and may manifest subtle cognitive, social, and emotional disturbances before clinical involvement.
doi:10.1001/archneurol.2011.2023
PMCID: PMC3979438  PMID: 22491193
13.  Continued High Prevalence and Adverse Clinical Impact of Human Immunodeficiency Virus–Associated Sensory Neuropathy in the Era of Combination Antiretroviral Therapy 
Archives of neurology  2010;67(5):552-558.
Objective
To provide updated estimates of the prevalence and clinical impact of human immunodeficiency virus−associated sensory neuropathy (HIV-SN) and neuropathic pain due to HIV-SN in the combination antiretroviral therapy (CART) era.
Design
Prospective, cross-sectional analysis. Clinical correlates for HIV-SN and neuropathic pain, including age, exposure to CART, CD4 levels, plasma viral load, hepatitis C virus infection, and alcohol use disorders, were evaluated in univariate and multivariate models.
Setting
Six US academic medical centers.
Patients
One thousand five hundred thirty-nine HIV-infected individuals enrolled in the CNS (Central Nervous System) HIV Anti-Retroviral Therapy Effects Research study.
Main Outcome Measures
The presence of HIV-SN, defined by 1 or more clinical signs (diminished vibration or sharp sensation in the legs and feet; reduced ankle reflexes) in a distal, symmetrical pattern. Neuropathic pain was defined as aching, stabbing, or burning in a similar distribution. The effect on quality of life was assessed with the Medical Outcomes Study HIV Health Survey.
Results
We found HIV-SN in 881 participants. Of these, 38.0% reported neuropathic pain. Neuropathic pain was significantly associated with disability in daily activities, unemployment, and reduced quality of life. Risk factors for HIV-SN after adjustment were advancing age (odds ratio, 2.1 [95%confidence interval, 1.8–2.5] per 10 years), lower CD4 nadir (1.2 [1.1–1.2] per 100-cell decrease), current CART use (1.6 [1.3–2.8]), and past “D-drug” use (specific dideoxynucleoside analogue antiretrovirals) (2.0 [1.3–2.6]). Risk factors for neuropathic pain were past D-drug use and higher CD4 nadir.
Conclusions
Neuropathic pain and HIV-SN remain prevalent, causing substantial disability and reduced quality of life even with successful CART. The clinical correlates of HIV-SN have changed with the evolution of treatment. These findings argue for redoubled efforts to determine HIV-SN pathogenesis and the development of symptomatic and neuroregenerative therapies.
doi:10.1001/archneurol.2010.76
PMCID: PMC3924778  PMID: 20457954
14.  A purpose “driven” life: Is it potentially neuroprotective? 
Archives of neurology  2010;67(8):1010-1011.
doi:10.1001/archneurol.2010.170
PMCID: PMC3918477  PMID: 20697053
15.  Acute Severe Animal Model of Muscle-Specific Kinase Myasthenia: Combined Postsynaptic and Presynaptic Changes 
Archives of neurology  2011;69(4):453-460.
Objective
To determine the pathogenesis of anti-muscle-specific kinase (MuSK) myasthenia, a newly described severe form of myasthenia gravis associated with MuSK antibodies, characterized by focal muscle weakness and wasting, and absence of acetylcholine receptor antibodies; also to determine whether antibodies to MuSK, a crucial protein in the formation of the neuromuscular junction (NMJ) during development, can induce disease in the mature NMJ.
Design/Methods
Lewis rats were immunized with a single injection of a newly discovered splicing variant of MuSK, MuSK 60, which has been demonstrated to be expressed primarily in the mature NMJ. Animals were assessed clinically, serologically and by repetitive stimulation of median nerve. Muscle tissue was examined immunohistochemically and by electron microscopy.
Results
Animals immunized with 100ug of MuSK 60 develop severe progressive weakness, starting at day 16, with 100% mortality by day 27. The weakness is associated with high MuSK antibody titers, weight loss, axial muscle wasting and decrementing compound muscle action potentials. Light and electron microscopy demonstrate fragmented NMJs with varying degrees of postsynaptic muscle endplate destruction along with abnormal nerve terminals, lack of registration between endplates and nerve terminals, local axon sprouting and extrajunctional dispersion of cholinesterase activity.
Conclusions
These findings: 1) support the role of MuSK antibodies in the human disease; 2) demonstrate the role of MuSK, not only in the development of the NMJ, but also in the maintenance of the mature synapse; and 3) demonstrate involvement in this disease of both pre- and post-synaptic components of the NMJ.
doi:10.1001/archneurol.2011.2200
PMCID: PMC3915865  PMID: 22158720
16.  Inhibition of Interferon-beta Responses in Multiple Sclerosis Immune Cells Associated With High-Dose Statins 
Archives of neurology  2012;69(10):1303-1309.
Objective
To determine whether statins affect type 1 interferon responses in relapsing-remitting multiple sclerosis (RRMS).
Design
Study effects of atorvastatin on type 1 interferon responses in Jurkat cells, mononuclear cells (MNCs) from therapy-naive patients with RRMS in vitro, and MNCs from interferon-treated RRMS patients in vivo in 4 conditions: no drug, statin only, interferon-beta only, and statin added on to interferon-beta therapy.
Patients
The study examined clinically stable patients with RRMS: 21 therapy-naive patients and 14 patients receiving interferon-beta with a statin.
Interventions
Statin effects on in vitro and in vivo interferon-beta–induced STAT1 transcription factor activation, expression of interferon-stimulated proteins in MNCs, and serum type 1 interferon activity.
Results
In vitro, atorvastatin dose dependently inhibited expression of interferon-stimulated P-Y-STAT1 by 44% (P< .001), interferon regulatory factor 1 protein by 30% (P= .006), and myxovirus resistance 1 protein by 32% (P=.004) compared with no-statin control in MNCs from therapy-naive RRMS patients. In vivo, 9 of 10 patients who received high-dose statins (80 mg) had a significant reduction in interferon-beta therapy–induced serum interferon-α/β activity, whereas only 2 of 4 patients who received medium-dose statins (40 mg) had reductions. High-dose add-on statin therapy significantly blocked interferon-beta function, with less P-Y-STAT1 transcription factor activation, and reduced myxovirus resistance 1 protein and viperin protein production. Medium doses of statins did not change STAT1 activation.
Conclusions
High-dose add-on statin therapy significantly reduces interferon-beta function and type 1 interferon responses in RRMS patients. These data provide a putative mechanism for how statins could counteract the beneficial effects of interferon-beta and worsen disease.
doi:10.1001/archneurol.2012.465
PMCID: PMC3910505  PMID: 22801747
17.  Primary progressive aphasia and transient global amnesia 
Archives of neurology  2012;69(3):401-404.
Objective
To report three patients with history of transient global amnesia who developed primary progressive aphasia.
Patients
Three patients presenting to the Neurology clinic with language complaints
Setting
Tertiary care center
Results
We describe three patients with a history of transient global amnesia who were subsequently diagnosed with primary progressive aphasia. All patients had recurrent attacks of transient global amnesia. The diagnoses of primary progressive aphasia were supported by speech pathology evaluations, neuropsychometric testing and imaging findings. PET scans, for example, revealed left posterior frontal hypometabolism in one patient, predominately left temporal-parietal hypometabolism in another while single-photon emission computed tomography demonstrated decreased perfusion in the anterior left temporal and frontal lobe in the third.
Conclusions
There may be a relationship between recurrent transient global amnesia and the development of primary progressive aphasia.
doi:10.1001/archneurol.2011.1129
PMCID: PMC3904294  PMID: 22410450
18.  Multilevel Intramedullary Spinal Neurocysticercosis With Eosinophilic Meningitis 
Archives of neurology  2004;61(5):770-772.
Background
Cysticercal involvement of the spinal cord is a very rare form of neurocysticercosis. Intramedullary cysts are even less common.
Objective
To describe a novel presentation of multilevel intramedullary neurocysticercosis with eosinophilic meningitis.
Design
Case report.
Patient
A 35-year-old man with a history of cerebral neurocysticercosis who presented with both cauda equina and Brown-Sequard syndromes associated with cerebrospinal fluid findings of eosinophilic meningitis.
Results
Magnetic resonance imaging confirmed the multilevel intramedullary cord lesions. The patientwas treated medically with dexamethasone and albendazole and had a good recovery.
Conclusion
Intramedullary neurocysticercosis should be considered as a potentially treatable cause of multilevel spinal lesions with subacute meningitis.
doi:10.1001/archneur.61.5.770
PMCID: PMC3902854  PMID: 15148157
19.  Antibodies to Low Density Lipoprotein Receptor-Related Protein 4 in Seronegative Myasthenia Gravis 
Archives of neurology  2011;69(4):434-435.
doi:10.1001/archneurol.2011.2855
PMCID: PMC3903387  PMID: 22158717
20.  Disparate Diseases Due to Copycat Copy Number Variations 
Archives of neurology  2009;66(9):1158-1159.
doi:10.1001/archneurol.2009.197
PMCID: PMC3903580  PMID: 19752307
21.  MPV17 Mutations Causing Adult-Onset Multisystemic Disorder With Multiple Mitochondrial DNA Deletions 
Archives of neurology  2012;69(12):1648-1651.
Objective
To identify the cause of an adult-onset multisystemic disease with multiple deletions of mitochondrial DNA (mtDNA).
Design
Case report.
Setting
University hospitals.
Patient
A 65-year-old man with axonal sensorimotor peripheral neuropathy, ptosis, ophthalmoparesis, diabetes mellitus, exercise intolerance, steatohepatopathy, depression, parkinsonism, and gastrointestinal dysmotility.
Results
Skeletal muscle biopsy revealed ragged-red and cytochrome-c oxidase–deficient fibers, and Southern blot analysis showed multiple mtDNA deletions. No deletions were detected in fibroblasts, and the results of quantitative polymerase chain reaction showed that the amount of mtDNA was normal in both muscle and fibroblasts. Exome sequencing using a mitochondrial library revealed compound heterozygous MPV17 mutations (p.LysMet88-89MetLeu and p.Leu143*), a novel cause of mtDNA multiple deletions.
Conclusions
In addition to causing juvenile-onset disorders with mtDNA depletion, MPV17 mutations can cause adult-onset multisystemic disease with multiple mtDNA deletions.
doi:10.1001/archneurol.2012.405
PMCID: PMC3894685  PMID: 22964873
22.  Spinal Muscular Atrophy 
Archives of neurology  2011;68(8):10.1001/archneurol.2011.74.
Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by loss of motor neurons in the anterior horn of the spinal cord and resultant weakness. The most common form of SMA, accounting for 95% of cases, is autosomal recessive proximal SMA associated with mutations in the survival of motor neurons (SMN1) gene. Relentless progress during the past 15 years in the understanding of the molecular genetics and pathophysiology of SMA has resulted in a unique opportunity for rational, effective therapeutic trials. The goal of SMA therapy is to increase the expression levels of the SMN protein in the correct cells at the right time. With this target in sight, investigators can now effectively screen potential therapies in vitro, test them in accurate, reliable animal models, move promising agents forward to clinical trials, and accurately diagnose patients at an early or presymptomatic stage of disease. A major challenge for the SMA community will be to prioritize and develop the most promising therapies in an efficient, timely, and safe manner with the guidance of the appropriate regulatory agencies. This review will take a historical perspective to highlight important milestones on the road to developing effective therapies for SMA.
doi:10.1001/archneurol.2011.74
PMCID: PMC3860273  PMID: 21482919
23.  “Unequivocally Abnormal” vs “Usual” Signs and Symptoms for Proficient Diagnosis of Diabetic Polyneuropathy 
Archives of neurology  2012;69(12):1609-1614.
Objective
To repeat the Clinical vs Neurophysiology (Cl vs N Phys) trial using “unequivocally abnormal” signs and symptoms (Trial 2) compared with the earlier trial (Trial 1), which used “usual” signs and symptoms.
Design
Standard and referenced nerve conduction abnormalities were used in both Trials 1 and 2 as the standard criterion indicative of diabetic sensorimotor poly-neuropathy. Physician proficiency (accuracy among evaluators) was compared between Trials 1 and 2.
Setting
Academic medical centers in Canada, Denmark, England, and the United States.
Participants
Thirteen expert neuromuscular physicians. One expert was replaced in Trial 2.
Results
The marked overreporting, especially of signs, in Trial 1 was avoided in Trial 2. Reproducibility of diagnosis between days 1 and 2 was significantly (P=.005) better in Trial 2. The correlation of the following clinical scores with composite nerve conduction measures spanning the range of normality and abnormality was improved in Trial 2: pinprick sensation (P = .03), decreased reflexes (P = .06), touch-pressure sensation (P=.06), and the sum of symptoms (P=.06).
Conclusions
The simple pretrial decision to use unequivocally abnormal signs and symptoms—taking age, sex, and physical variables into account—in making clinical judgments for the diagnosis of diabetic sensorimotor polyneuropathy (Trial 2) improves physician proficiency compared with use of usual elicitation of signs and symptoms (Trial 1); both compare to confirmed nerve conduction abnormality.
doi:10.1001/archneurol.2012.1481
PMCID: PMC3570730  PMID: 22986424
24.  Regional white matter hyperintensity volume, not hippocampal atrophy, predicts incident Alzheimer’s disease in the community 
Archives of neurology  2012;69(12):1621-1627.
Background
New onset Alzheimer’s disease (AD) is often attributed to degenerative changes in the hippocampus. However, the contribution of regionally distributed small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH) on MRI, remains unclear.
Objective
To determine whether regional WMH and hippocampal volume predict incident AD in an epidemiological study.
Design
A longitudinal community-based epidemiological study of older adults from northern Manhattan.
Setting
The Washington Heights/Inwood Columbia Aging Project
Participants
Between 2005 and 2007, 717 non-demented participants received MRI scans. An average of 40.28 (SD=9.77) months later, 503 returned for follow-up clinical examination and 46 met criteria for incident dementia (45 with AD). Regional WMH and relative hippocampal volumes were derived. Three Cox proportional hazards models were run to predict incident dementia, controlling for relevant variables. The first included all WMH measurements; the second included relative hippocampal volume; and the third combined the two measurements.
Main outcome measures
Incident Alzheimer’s disease.
Results
White matter hyperintensity volume in the parietal lobe predicted time to incident dementia (HR=1.194, p=0.031). Relative hippocampal volume did not predict incident dementia when considered alone (HR=0.419, p=0.768) or with the WMH measures included in the model (HR=0.302, p=0.701). Including hippocampal volume in the model did not notably alter the predictive utility of parietal lobe WMH (HR=1.197, p=0.049).
Conclusion
The findings highlight the regional specificity of the association of WMH with AD. It is not clear whether parietal WMH solely represent a marker for cerebrovascular burden or point to distinct injury compared to other regions. Future work should elucidate pathogenic mechanisms linking WMH and AD pathology.
doi:10.1001/archneurol.2012.1527
PMCID: PMC3597387  PMID: 22945686
Alzheimer’s disease; MRI; cerebrovascular disease; hippocampus
25.  Observational Study of Spinal Muscular Atrophy Type 2 and 3 
Archives of neurology  2011;68(6):10.1001/archneurol.2010.373.
Objective
To characterize the short-term course of spinal muscular atrophy (SMA) in a genetically and clinically well-defined cohort of patients with SMA.
Design
A comprehensive multicenter, longitudinal, observational study.
Setting
The Pediatric Neuromuscular Clinical Research Network for SMA, a consortium of clinical investigators at 3 clinical sites.
Participants
Sixty-five participants with SMA types 2 and 3, aged 20 months to 45 years, were prospectively evaluated.
Intervention
We collected demographic and medical history information and determined the SMN2 copy number.
Main Outcome Measures
Clinical outcomes included measures of motor function (Gross Motor Function Measure and expanded Hammersmith Functional Motor Scale), pulmonary function (forced vital capacity), and muscle strength (myometry). Participants were evaluated every 2 months for the initial 6 months and every 3 months for the subsequent 6 months. We evaluated change over 12 months for all clinical outcomes and examined potential correlates of change over time including age, sex, SMA type, ambulatory status, SMN2 copy number, medication use, and baseline function.
Results
There were no significant changes over 12 months in motor function, pulmonary function, and muscle strength measures. There was evidence of motor function gain in ambulatory patients, especially in those children younger than 5 years. Scoliosis surgery during the observation period led to a subsequent decline in motor function.
Conclusions
Our results confirm previous clinical reports suggesting that SMA types 2 and 3 represent chronic phenotypes that have relatively stable clinical courses. We did not detect any measurable clinical disease progression in SMA types 2 and 3 over 12 months, suggesting that clinical trials will have to be designed to measure improvement rather than stabilization of disease progression.
doi:10.1001/archneurol.2010.373
PMCID: PMC3839315  PMID: 21320981

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