Nuedexta and its potential use for agitation in Alzheimer’s

Presenter: Deepa Panjeti-Moore

Clinical Question:

In a patient with Alzheimer’s disease-related agitation, does dextromethorphan hydrobromide-quinidine sulfate provide efficacy, safety, and tolerability.

Journal Club Article: 

Cummings, JL et al.  Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia: A Randomized Clinical Trial.  JAMA 2015 Sep 22-29;314(12):1242-54.

Methodology:

Phase 2 randomized, multicenter, double-blind, placebo-controlled trial using a sequential parallel comparison design with 2 consecutive 5-week treatment stages conducted August 2012-August 2014. Patients with probable Alzheimer disease, clinically significant agitation (Clinical Global Impressions-Severity agitation score ≥4), and a Mini-Mental State Examination score of 8 to 28 participated at 42 US study sites. Stable dosages of antidepressants, antipsychotics, hypnotics, and antidementia medications were allowed.

In stage 1, 220 patients were randomized in a 3:4 ratio to receive dextromethorphan-quinidine (n = 93) or placebo (n = 127). In stage 2, patients receiving dextromethorphan-quinidine continued; those receiving placebo were stratified by response and rerandomized in a 1:1 ratio to dextromethorphan-quinidine (n = 59) or placebo (n = 60).

The primary end point was change from baseline on the Neuropsychiatric Inventory (NPI)Agitation/Aggression domain (scale range, 0 [absence of symptoms] to 12 [symptoms occur daily and with marked severity]).

Study Conclusions:

In this preliminary 10-week phase 2 randomized clinical trial
of patients with probable Alzheimer disease, combination dextromethorphan-quinidine demonstrated clinically relevant efficacy for agitation and was generally well tolerated.

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Oral vs. Intravenous methylprednisolone for multiple sclerosis relapse

Presenter: Dr. Will Roche

Link to Presentation: https://prezi.com/ta-cnz1aobn6/copousep/?utm_campaign=share&utm_medium=copy

Clinical Question:

High doses of intravenous methylprednisolone are recommended to treat relapses in patients with multiple sclerosis, but can be inconvenient and expensive.  This RCT aims to assess whether oral administration of high-dose methylprednisolone was non-inferior to intravenous administration.

Journal Club Article:

Le Page, E et al.  Orval versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial.  Lancet. 2015 Sep 5;386(9997):937-9.

Methodology:

This multicentre, double-blind, randomised, controlled, non-inferiority trial was performed at 13 centers for multiple sclerosis in France. Patients aged 18–55 years were with relapsing-remitting multiple sclerosis were enrolled who reported a relapse within the previous 15 days that caused an increase of at least one point in one or more scores on the Kurtzke Functional System Scale. With use of a computer-generated randomisation list and in blocks of four, the study randomly assigned (1:1) patients to either oral or intravenous methylprednisolone, 1000 mg, once a day for 3 days. Patients, treating physicians and nurses, and data and outcome assessors were all masked to treatment allocation, which was achieved with the use of saline solution and placebo capsules. The primary endpoint was the proportion of patients who had improved by day 28 (decrease of at least one point in most affected score on Kurtzke Functional System Scale), without need for retreatment with corticosteroids, in the per-protocol population. The trial was powered to assess non-inferiority of oral compared with intravenous methylprednisolone with a predetermined non-inferiority margin of 15%.

Study Conclusions:

The study data support the use of oral methylprednisolone 1000 mg per day for 3 days to treat multiple sclerosis relapses. This finding could have implications for rapidity of access to treatment, patient comfort, and cost of the management of multiple sclerosis relapses. However, because oral administration is easier and cheaper, it might increase non-specialists’ use of this treatment in a more liberal way, without thorough consideration of the indication.

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Antiplatelet treatment vs. Anticoagulation for CADISS

Presenters: David T. Pearce, MD, Russell Powell, MD

Link to Presentation Powerpoint: Journal Club_CADISS

Clinical Question:

The Cervical Artery Dissection In Stroke Study (CADISS) was established to compare the effectiveness of antiplatelet drugs with anticoagulant drugs for the prevention of recurrent stroke in patients with carotid and vertebral dissection.

Journal Club Article:

CADISS trial investigators.  Antiplatelet treatment compared with anticoagulation treatment for cervical artery dissection (CADISS): a randomised trial.  Lancet Neurol. 2015 Apr;14(4):361-7.

Methodology:

The investigators conducted this randomized trial at hospitals with specialized stroke or neurology services (39 in the UK and seven in Australia). We included patients with extracranial carotid and vertebral dissection with onset of symptoms within the past 7 days. Patients were randomly assigned (1:1) by an automated telephone randomisation service to receive antiplatelet drugs or anticoagulant drugs (specific treatment decided by the local clinician) for 3 months. Patients and clinicians were not masked to allocation, but investigators assessing endpoints were. The primary endpoint was ipsilateral stroke or death in the intention-to-treat population.

Study Conclusions:

  • No significant difference between the two groups
  • Trend to more strokes in the anti-platelet group, although one SAH in anti-coag, TIAs no difference
  • Incidence of recurrent strokes lower than previously reported
  • Feasibility of Phase III will require large enrollment and will be difficult
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Acute ischemic stroke and intraarterial treatment within 6 hours of onset

Presenters: Jennifer Choi & Melanie Winningham

Link to Presentation Powerpoint: Journal Club

Clinical Question:

Is intraarterial treatment plus usual care more effective than usual care alone in patients with a proximal arterial occlusion in the anterior cerebral circulation when treated intraarterially within 6 hours of symptom onset?

Journal club article:

Berkhemer, et al.  A randomized trial of intraarterial treatment for acute ischemic stroke.  N Engl J Med. 2015 Jan 1;372(1):11-20.

Methodology:

The study randomly assigned eligible patients to either intraarterial treatment plus usual care or usual care alone. Eligible patients had a proximal arterial occlusion in the anterior cerebral circulation that was confirmed on vessel imaging and that could be treated intraarterially within 6 hours after symptom onset. The primary outcome was the modified Rankin scale score at 90 days; this categorical scale measures functional outcome, with scores ranging from 0 (no symptoms) to 6 (death). The treatment effect was estimated with ordinal logistic regression as a common odds ratio, adjusted for prespecified prognostic factors. The adjusted common odds ratio measured the likelihood that intraarterial treatment would lead to lower modified Rankin scores, as compared with usual care alone (shift analysis).

Study conclusions:

In patients with acute ischemic stroke caused by a proximal intracranial occlusion of the anterior circulation, intraarterial treatment administered within 6 hours after stroke onset was effective and safe. (Funded by the Dutch Heart Foundation and others; MR CLEAN Netherlands Trial Registry number, NTR1804, and Current Controlled Trials number, ISRCTN10888758.)

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Childhood absence epilepsy: monotherapy outcomes

Journal Club Article:   Glauser, TA et al.  Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy: initial monotherapy outcomes at 12 months.  Epilepsia. 2013 Jan;54(1):141-55.

Summary: Purpose was to determine the optimal initial monotherapy for children with newly diagnosed childhood absence epilepsy, based on 12 months of double-blind therapy.

Methods: A double-blind, randomized controlled clinical trial.

Significance: As initial monotherapy, the superior effectiveness of ethosuximide and valproic acid compared to lamotrigine in controlling seizures without intolerable adverse events noted at 16-20 persisted at 12 months.  The vaproic acid cohort experienced a higher rate of adverse events leading to drug discontinuation as well as significant negative effects on attentional measures that were not seen in the ethosuximide cohort.

Calculate the Number Needed to Treat (NNT):

  • Ethosuximide –vs- Lamotrigine (NNT=5, OR=3.07)
  • Ethosuximide –vs- Valproic Acid (NNT=63, OR=1.06)
  • Valproic Acid –vs- Lamotrigine (NNT=5, OR=3)
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Sudden unexpected death in epilepsy: critical appraisal of systematic review

Sept. 30th, 2014 Journal Club Featured Article:

Thurman DJ, Hesdorffer DC, French JA.  Sudden unexpected death in epilepsy: Assessing the public health burden.  Epilepsia. 2014 Oct; 55(10): 1479-1485.

Summary of Article:

The limitations of the review suggest that the review’s estimate of the incidence of SUDEP in the general population is probably conservative and likely to be revised upward with future studies incorporating methods with more complete case ascertainment. In any event, it is clear from this analysis that the public health burden of SUDEP is substantial and deserves greater attention from clinicians and the medical research community. The estimated annual number of U.S. deaths from SUDEP—2,750—exceeds the corresponding number of deaths attributed to SIDS, of which 2,063 were reported in 2010.[29] For more than two decades, SIDS has received a great deal of attention from clinicians, researchers, and public health professionals, who through public education have achieved substantial reductions in its occurrence. SUDEP deserves the same attention. And in relation to other neurologic disorders, the relative importance of SUDEP is underscored by the years of potential life lost to it, a more complete measure of public health burden than mortality alone.

Critical Appraisal:

Prepared by Matt Agan, PGY-2   &   Joash Lazarus, PGY-4:  Journal Club 9-30

Guidelines for Critical Appraisal:

Critical appraisal of systematic reviews

[Abalos et al, Critical appraisal of systematic reviews: the WHO Reproductive Health Library, No. 4, Geneva, The World Health Organization, 2001 (WHO/RHR/01.6)]

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Bimonthly professor rounds clinical case

Clinical Summary:

41 y/o F with PMH newly-diagnosed DM who presented with horizontal diplopia x 3 months and ptosis that developed shortly thereafter. She was evaluated by an outpatient neurologist, who diagnosed her with myasthenia gravis. Anti-AchR and MUSK antibodies were negative. She was started on Mestinon and did not respond. Over the next two months, she developed progressive weakness with difficulty breathing and fatigueability in arms>legs, problems with speech and swallowing, as well as difficulty coughing. In July, she visited family in New York, who noticed significant dyspnea, weakness, and bilateral facial droop. When she returned from her trip, she saw her outpatient neurologist, who discontinued Mestinon and referred her to neuro-ophthalmology. In neuro-ophthalmology clinic, she was noted to have bulbar weakness and respiratory distress, and she was referred to the ER.

On admission, she was afebrile with normal blood pressure. Her heart rate was 105, and she was tachypneic but with O2 saturation  99% on room air taking shallow breaths. She was able to count to 20 in a single breath. Her cardiovascular exam was normal.

Cranial nerve exam was significant for conjugate vertical gaze palsy, gaze-evoked horizontal nystagmus, bilateral ptosis, bilateral upper and lower facial weakness, hypophonic voice with absent cough, and weakness with bilateral tongue movement. Motor exam was significant for 2/5 neck flexion and 5/5 strength in her extremities with fatigueable weakness in her arms. Sensory and coordination exams were normal. Reflexes were 3+ throughout with upgoing toes bilaterally.

Admission chemistry showed sodium 133, Cl 93, gap 12, glucose 244, LFTs WNL. CBC showed no leukocytosis, and H/H 16.2/47.1. U/A showed glucosuria, ketonuria, large leukocyte esterase, 12 WBCs, and 20 squamous cells. Beta-hcg was negative.

She was admitted to the neuro floor and had the following workup:

ESR 46, CRP 7.63

Blood and urine cultures negative

-RPR non-reactive

Borrelia Burgdorferi negative

HIV negative

CSF: 2-3 WBCs, 220-250 RBCs without xanthochromia, Protein 39, and glucose 118. Bacterial culture negative. CMV, VZV, HSV, EBV negative. Cytology and flow cytometry negative.

Negative serum antibody studies: Acetyl receptor binding and striational, ANNA1, ANNA2, ANNA3, Anti-glial nuclear, Anti-collapsin, Anti-Purkinje Cytoplasm 1 and 2 and TR, Anti-Ampiphysin, Anti-P/Q type calcium channel, Anti-N type calcium channel, Anti-ganglionic neuron Ach-R, Anti-Voltage gated K channel, ANCA, Anti-dsDNA, Anti-Tissue Transglutaminase, Anti-Centromere, Anti-Smith, Anti-RNP, Anti-SCL70, Anti-SSB, Anti-JO1, Anti-CCP, Anti-GQ1B

Positive serum antibody studies: Anti-SSA/RO (IgG titer 91), Anti-Thyroid Peroxidase (titer 75), Anti-glutamic acid decarboxylase (titer 69.8), Anti-thyroglobulin antibody (titer 116.8), Anti-ma2 (Anti-Ta)

Cortisol, FSH, LH, ACTH, PRL, TSH levels all WNL.

Negative Tumor Markers: alpha-fetoprotein, CEA, and CA 125 all negative.

Positive Tumor Markers: Elevated CA GI 19 9 (level = 49)

MRI brain and C-spine with and without contrast: WNL

CT C/A/P, MRI pelvis, bilateral breast sonogram, whole body PET: No evidence of malignancy

She developed respiratory failure within a few days of admission, for which she was transferred to the ICU and intubated. Her hospital course has been complicated by PNA. She received IVIG, PLEX x 5, and IV steroids without response, and she is currently being treated with Rituxan with a working diagnosis of Anti-GAD65, Anti-Ma2 antibody mediated autoimmune bulbar encephalitis.

 Reference:

Dalmau J, Graus F, Villarejo A, Posner JB, Blumenthal D, Thiessen B, Saiz A, Meneses P, Rosenfeld MR.  Clinical analysis of anti-Ma2-associated encephalitis.  Brain. 2004 Aug;127(Pt 8):1831-44.

Article Summary: Increasing experience indicates that anti-Ma2-associated encephalitis differs from classical paraneoplastic limbic or brainstem encephalitis, and therefore may be unrecognized. To facilitate its diagnosis we report a comprehensive clinical analysis of 38 patients with anti-Ma2 encephalitis.

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