Abstracts
117 RE-KINECT: Real-World Dyskinesia Screening Study and Registry in Patients Taking Antipsychotic Agents: Interim Baseline Burden of Illness Results
- Andrew Cutler, Stanley Caroff, Caroline Tanner, William R. Lenderking, Karen Yeomans, Huda Shalhoub, Véronique Pagé, Chuck Yonan
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- 15 June 2018, p. 74
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Background
Tardive dyskinesia (TD) is associated with prolonged exposure to dopamine receptor blockers including antipsychotics. This registry describes the prevalence and impact of involuntary movements (possible TD) in a real-world population of patients taking antipsychotics.
MethodsRE-KINECT (NCT03062033) aims to enroll 1,000 patients from 70 US psychiatric practices. Adults with ≥3 months lifetime exposure to antipsychotic(s) and ≥1 psychiatric disorder are eligible for two-tier screening: informal observation, and then clinician observation of abnormal involuntary movements in general body regions (head/face, neck/trunk, upper/lower limbs) and confirmation of possible TD. Based on clinician assessment, patients are assigned to Cohort 1 or Cohort 2 (without or with abnormal involuntary movements, respectively). In both cohorts, the following baseline assessments are included: clinician’s assessment of clinical psychiatric severity, patient perceived health‐related quality of life (EuroQOL 5-Dimensions), social burden/disability questionnaire (Sheehan Disability Scale), and 12-month retrospective chart review ofmedical and treatment history. Cohort 2 also participate in 12-month longitudinal evaluation. Interim baseline data are available from four sites.
ResultsBaseline data are currently available for 116 patients—mean age, 49.6 years; female, 60.3%; schizophrenia/schizoaffective disorder, 32.8%; at least 1 mood disorder, 84.5%, and 10.4 years mean cumulative lifetime exposure to antipsychotic(s). The most concerning health condition for both cohorts is their mental health (69.0%), followed by physical activity and nutrition (33.6%). 32.8% of subjects had clinician confirmation of possible TD.
ConclusionThis novel registry aims to evaluate the real-world potential impact/burden of TD. Preliminary analyses suggest that TD is common in patients with schizophrenia and mood disorders taking antipsychotics. Further analyses will explore the burden of illness in this population.
Funding AcknowledgementsThis study was funded by Neurocrine Biosciences, Inc.
118 Demographics and Real World Healthcare Cost and Utilization for Patients With Probable Tardive Dyskinesia
- Michael Polson, Chuck Yonan, Ted Williams
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- 15 June 2018, p. 75
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Background
Tardive dyskinesia (TD) is a movement disorder associated with prolonged exposure to antipsychotics. The current study was designed to describe demographics and comorbidities for patients with a dyskinesia diagnosis as probable TD (cohort 1), patients likely to have undiagnosed/uncoded TD (cohort 2), and a control population.
MethodsThis retrospective study analyzed Medicaid claims data from July 2013-March 2017. For a pool of patients with a history of 3 months or more of taking an antipsychotic, three cohorts were evaluated: cohort 1 (ICD-9/10 codes for dyskinesia); cohort 2 (propensity score matching to cohort 1); and cohort 3 (patients withschizophrenia, major depressive disorder [MDD], and/or bipolar disorder [BD] and history of ≤2 antipsychotic medications). Outcomes included patient characteristics, Charlson Comorbity Index (CCI) and healthcare utilization (pre-and post [12-month] period).
ResultsCohort sizes and characteristics were: cohort 1 (n=1,887; female, 68%; mean age, 42 years; MDD, 17%; BD, 48%); cohort 2 (n=1,572; female, 58%; mean age, 39 years; MDD, 22%; BD, 48%); cohort 3 (n=25,949; female, 67%; mean age, 40 years; MDD, 11%; BD, 49%). Cohorts 1 and 2 had higher comorbidity burden than cohort 3 (mean pre-index CCIs: 0.68, 0.79, and 0.47, respectively; p<0.001 for each cohort). After 12 months, mean per member per year healthcare costs were higher in cohort 1 and2 compared to cohort 3 ($21,293, $18,988, and $11,522, respectively), as were mean claims per member per year (185, 138, and 109, respectively).
ConclusionIn the study population, patients likely suffering from TD, ICD-9/10 code-confirmed or unconfirmed, have a higher overall comorbidity burden and healthcareutilization than those who probably do not have TD.
Funding AcknowledgementsThis study was funded by Neurocrine Biosciences, Inc.
119 Refraction Focus Hallucination: The Role of Increased Excitation at Thalamus in Complex Visual Hallucination
- Chunhui Yang, Jasir T. Nayati, Khurram Janjua, Asma Ahmed, Angela Rekhi, Alan R. Hirsch
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- Published online by Cambridge University Press:
- 15 June 2018, pp. 75-76
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Study Objective(s)
The pathogenesis of complex visual hallucination in patients without visual lesions, appearing with eyes open and resolving with eyes closed, has been described to be associated with increased excitation at the lateral geniculate nucleus (LGN) and pulvinar of the thalamus (Winton-Brown, 2016). This reduces thefidelity of retinogeniculate transmissions and enhances aberrant projections to the visual cortex. Loss of the central sensory filtering function of the pulvinar increases “signal to noise ratio” in visual transmission. While visual hallucinations have been reported to disappear on eye closure (Manford, 1998), visual aberration with correction with refractionfollowed by focusing on actual visual images and visual hallucinations has not heretofore been reported. Such a case is presented.
MethodCase study: This 28-year-old, myopic, right-handed man, at 5 years of age began hallucinating vivid images of people. The visual hallucinations were triggered only with his eye open. He was myopic and without visual correction, his visual sphere would be blurred. The visual hallucinations were also blurred without visual correction. With refraction, the hallucinations became clearly in focus. He would close his eyes and the visual hallucinations disappeared but would reappear in the same position upon opening his eyes. For over 20 years, he experienced about 100 hallucinations a day. Electroencephalography (EEG) revealed continuous spikes and slow waves in bilateral temporal lobes, consistent with temporal lobe status epilepticus. After treatment with diphenylhydantoin the frequency and duration of the hallucinations markedly decreased to a second epoch every other day. However, the characteristic of the hallucinations remained the same (people).
ResultsThis phenomenon may involve epilepsy induced excitation of the thalamus. This then acts to reduce the fidelity of retinogeniculate transmission and increase “signal to noise ratio” in visual transmission. This may contribute to complex visual hallucinations with eyes open. The hallucinated figures becoming clearer with eyeglasses provides support that this complex hallucination arises in the pathway from retina-LGN-cortex, not from stored visual associated cortex of top-down cortical release.
ConclusionsGiven the above, those with visual hallucinations should be queried as to the influence of refraction on the clarity of hallucination.
FundingNo funding.
120 Fragile X Syndrome Sharing Similar Neural Network Abnormalities as ADHD
- Chunhui Yang, Carolyn Beebe Smith, Guoqiang Xing, Sandeep Gaonkar
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- 15 June 2018, p. 76
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Title
Fragile X syndrome sharing similar neural network abnormalities as ADHD
Study Objective(s)The Fragile X syndrome (FXS) phenotype typically involves a variety of psychiatric symptoms, including features of autism, attention deficit/hyperactivity disorder (ADHD), anxiety, and aggression. Studies have shown that ADHD is characterized by multiple functional and structural neural network abnormalities including fronto-striatal, fronto-parieto-temporal, fronto-cerebellar and fronto-limbic networks (Rubia, 2014; Norman, 2017). Studies have shown that ADHD is characterized by a delay in structural brain maturation (Rubia, 2007). Absence of the FMR1 gene product Fragile X mental retardation protein (FMRP) results in FXS, an inherited form of mental retardation. FMRP is an RNA binding protein functioning as a nucleocytoplasmic shuttling. In a knockout mouse model of FXS (Fmr1 null), Qin, et al showed regionally selective effects on cerebral metabolic rates for glucose (rCMRglc) (Qin, 2002) and rates of cerebral protein synthesis (Qin, 2005). In the present study, we asked if there is a relationship between brain regions most vulnerable to the effects of the absence of FMRP in the Fmr1 null mouse, and if the distribution consistent with the structural and functional brain abnormalities in ADHD. We also asked if there is a difference between males and females in the regional distributions and the levels of the FXR mRNAs.
MethodWe used 35S-labeled probes specific for the mRNAs to perform in situ hybridization on brains from male (n=4) and female (n=4) mice at 6 months of age. Flowing hybridization, brain sections were exposed to X-ray film and optical density were measured in nine brain regions on autoradiograms of sections hybridized to the probe.
ResultsThe highest levels of expression we observed were in the cerebellum, granular layers of the hippocampus. Levels of expression were also high in CA1 pyramidal neurons of hippocampus, amygdala and granule layer of olfactory bulb. We found intermediate levels in the anterior hypothalamus and in cingulate and frontal cortex. Low levels of expression were found in thalamus and caudate. The distribution for the probe was similar in male and female mice, but we found a tendency for male mice to have higher levels than females.
Funding AcknowledgementsNo funding.
121 Enhancing Emotional Wellness With Smartphone Apps in Early Psychosis
- Dale D’Mello
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- 15 June 2018, pp. 76-77
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Introduction
There is wide consensus that the combination of psychopharmacology and psychotherapy is superior to either approach used alone, in managing depressive, anxiety and psychotic disorders. Completing homework assignments are prerequisite for successful outcomes in psychotherapy. The convergence of digital computer technology and consumer self-empowerment have generated a bewildering array of mental health applications for smartphones and other mobile devices. The purpose of the present poster is to review available apps of interest for patients with early psychosis.
MethodA search was recently conducted of the stores on the iOS and Android platforms, seeking apps for mood, anxiety, psychotic and cognitive disorders. Reviews of digital technology resources provided by the International Mental Health Research Organization (IMHRO) at www.psyberguide.org were consulted. Criteria for inclusion included: (1) popularity measured by greater than 10,000 downloads (2) a score of 3.5 or higher on the Mobile Apps Rating System (MARS) and (3) acquisition cost less than $1. Consumer reviews were scanned. A total of 7 apps were culled from an expanding universe of thousands. This included top-rated apps in each of three symptom domains: depression, anxiety and cognitive disorders. Ranked in order of MARS rating the leading depression apps were “Depression CBT Self-Help Guide” and “eCBT Mood”. The most popular anxiety apps were “Stop Panic & Anxiety” and “Headspace”. The top apps for cognitive enhancement training were “Brain HQ” and “Fit Brains Focus”. In addition, the suicide prevention app “My3” was included because of its life saving potential. Consumers have rated the reviewed apps favorably. Conclusion: Smartphone apps are achieving wide acceptance in self-management of common psychiatric disorders. Clinicians need to become familiar with these adjunctive therapeutic tools, and integrate them in brief psychopharmacology visits.
Funding AcknowledgementsNo funding.
122 Use of Pimavanserin in Patients With Parkinson’s Disease Psychosis: Subgroup Analysis of Efficacy and Safety in Patients With and Without Cognitive Impairment
- Daniel Weintraub, James Norton, Bruce Coate, Candace Andersson, Doral Fredericks, Clive Ballard
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- 15 June 2018, p. 77
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Objective
A planned subgroup analysis of a phase 3 study was performed to evaluate the efficacy and safety of pimavanserin (PIM) in Parkinson’s disease psychosis (PDP) patients withglobal cognitive impairment.
BackgroundPDP is frequent, distressing, a leading cause of institutionalization, complicates PD management and is linked to increased morbidity, incident dementia and mortality. PIM, a selective serotonin receptor (5-HT2A) inverse agonist/antagonist, is newly FDA-approved for the treatment of hallucinations and delusions associated with PDP.
MethodsIn Study 020, a 6-week FDA registration study, 199 patients with baseline Mini-Mental State Examination (MMSE) score ≥21, moderate-severe psychosis, and on stable PD meds, were randomized to PIM (34 mg/day) or placebo (PBO) for 6 weeks. This subgroup analysis evaluates efficacy and safety between two groups: those with MMSE total score ≥21 but <25 (cognitively impaired; equivalent to Montreal Cognitive Assessment [MoCA] score 15-19) and those with score ≥25 (cognitively normal; equivalent to MoCA score 20-30). Safety assessments were performed on the full safety dataset (i.e., three 6-week placebo-controlled studies) including 614 subjects (PIM=382, PBO=231).
ResultsOverall, patients in the PIM group experienced a statistically significant improvement in SAPS-PD scores from baseline to Day 43 compared with PBO (-5.79 vs. -2.73; p=0.001). In the subgroup analysis stratifying by baseline MMSE score, the change from baseline to Day 43 compared with PBO in the cognitively-impaired group (N=50) was numerically larger (-7.11 vs. -0.47; p=0.002). In the full safety dataset examining cognitively impaired patients, there were no between-group (PIM vs. PBO) differences in any treatment-emergent adverse event (TEAE) (57.6% vs. 56.1%) or serious TEAE (6.8% vs. 5.3%). The most common TEAEs occurring at ≥5% in either group were fall (7.4% vs.10.5%), confusional state (6.5% vs.1.8%), and orthostatic hypotension (0.0% vs. 8.8%).
ConclusionsIn this subgroup analysis of PDP patients, the treatment effect of PIM on SAPS-PD was larger in the cognitively-impaired group, with similar TEAE and serious TEAE rates. These results hold promise for cognitively-impaired patients that will be further elucidated in future studies.
Funding AcknowledgementsClinical study was funded by ACADIA Pharmaceuticals Inc.
123 Adjunctive Brexpiprazole in Patients With MDD and Symptoms of Anxiety: Results From Post-Hoc Analyses of Three Placebo-Controlled Studies
- Emmanuelle Weiller, Anna-Greta Nylander, Catherine Weiss, Peter Zhang, Mary Hobart
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- Published online by Cambridge University Press:
- 15 June 2018, pp. 77-78
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Study objectives
Symptoms of anxiety are prevalent in Major Depressive Disorder (MDD) and are associated with greater illness severity, suicidality, impaired functioning and poor response to antidepressant treatment (ADT). In MDD, anxiety symptoms can be assessed as ‘anxious distress’ (new DSM-5 specifier) or ‘anxious depression’ (score ≥7 on the HAM-D anxiety/somatization factor). Brexpiprazole is a serotonin–dopamine activity modulator that is a partial agonist at 5-HT1A and dopamine D2 receptors, and an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors – all at similar potency. Brexpiprazole is approved in the US for treatment ofschizophrenia, and as adjunctive treatment in MDD. The objective of this post-hoc analysis was to assess the efficacy of brexpiprazole as adjunct to ADT in patients with MDDand anxiety symptoms, using these two definitions of anxiety.
MethodsData were pooled from three randomized, double-blind, placebo-controlled studies with similar designs (Pyxis – NCT01360645; Polaris – NCT01360632; Sirius – NCT02196506). In each study, patients with MDD and an inadequate response to 1–3 ADTs received single-blind ADT for 8 weeks. Patients with inadequate response throughout this prospective phase were randomized to receive either ADT+brexpiprazole (2mg in Pyxis and Sirius; 1mg or 3 mg in Polaris) or ADT+placebo for 6 weeks. Proxies used to categorize patients as having ‘anxious distress’ included a score of ≥2 on the following symptoms at randomization: tension (MADRS item 3 score ≥3); restlessness (IDS item 24 score ≥2); concentration (MADRS item 6 score ≥3); or apprehension (HAM-D item 10 score ≥3). Scores on the items of the HAM-D anxiety/somatization factor at randomization (baseline) were used to identify patients with ‘anxious depression’. Efficacy was assessed as the change in MADRS total score from baseline to Week 6. Statistical analysis used a Mixed Model Repeated Measure approach using pooled brexpiprazole doses.
ResultsAfter 8 weeks of prospective ADT monotherapy, 57.6% (n=797/1,383) of patients met the criteria for anxious distress, and 48.5% (n=671/1,383) for anxious depression. The mean MADRS total score was 29.0 for patients with anxious distress in the adjunctive brexpiprazole (n=462) group and 29.1 in the placebo (n=327) group; while those with anxious depression were 28.9 (brexpiprazole; n=384) and 28.6 (placebo; n=282). Compared to those receiving placebo, patients with both anxious distress and anxious depression who received adjunctive brexpiprazole showed a greater improvement in MADRS total score (LS mean difference -2.38, p=0.0001 and -1.68, p=0.012, respectively). These improvements, compared to placebo, were similar to those in patients who had not met the criteria for anxious distress (-1.40, p=0.023) or anxious depression (-2.17, p<0.001).
ConclusionAdjunctive brexpiprazole may be efficacious in reducing depressive symptoms both in patients with or without symptoms of anxiety.
Funding AcknowledgementsThe studies were funded by H. Lundbeck A/S and Otsuka Pharmaceutical Development & Commercialization, Inc.
124 Epochs of Anosmia and Ageusia in Multiple Sclerosis: Chemosensory Uhthoff’s Phenomenon
- Davinder Dhillon, Jasir T Nayati, Priya Batta, Alan R. Hirsch
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- 15 June 2018, pp. 78-79
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Study Objective
To reveal that while long duration of anosmia and ageusia has been seen with Multiple Sclerosis (MS) [Doty 1997], repetitive shorter epochs ofanosmia and ageusia has not heretofore been presented.
MethodsCase Study: A 39 year old right-handed male, with a history of MS, presents with six years MS concurrent with epochs of anosmia and ageusia. The anosmia andageusia present concurrently, preventing him from smelling and tasting his meal. At baseline, he is able to smell and taste coffee, peppermint, gum, sweet and salty foods, rating his smell and taste at 70% normal. However, during the epochal events, he reports the inability to smell and taste white rice, shrimp, meat, butter, carrots, onions, spinach, and sour foods. He states that these episodes occur approximately ten times a week, last for two hours, and rates his smell and taste from 0-10% during these events.
ResultsAbnormalities Neurological Examination: Cranial Nerve (CN) Examination: CN II: bilateral pale discs. CN III, IV, VI: bilateral ptosis. CN IX, X: decreased gag reflex bilaterally. Motor Examination: Drift Test: positive left pronator drift, with right adductor digiti minimi sign and right cerebellar spooning. Sensory Examination: Ipswich Touch Test: decreased in left lower extremity. Temperature: decreased in left lower extremity. Rydel-Seiffer Vibratory Test: bilateral upper extremities 5 and bilateral lower extremities 3. Tandem Gait: unstable. Cerebellar Examination: Holmes Rebound Phenomena: positive with left greater than right. Reflexes: 1+ bilateral upper extremities, absent bilateral lower extremities. Neuropsychiatric Examination: Animal Fluency Test: 15 (abnormal). Clock Drawing Test: 3 (abnormal). Center for Neurologic Study Lability Scale: 16 (pseudobulbar affect).
ConclusionPrimary olfactory dysfunction with secondary inhibition of retronasal smell and perceived taste [Gruss 2015] can be an etiology. Such an olfactory dysfunction may reflect variation in nasal mucosal engorgement due to normal variability of the olfactory cycle [Eccles 1978]. This phenomenon is an unlikely due to the short duration ofepochs.
The cause of anosmia and ageusia in this patient suggests a central lesion involved in the processing of both smell and taste. Transient rapid symptoms associated with temperature change, as in Uhthoff’s phenomenon seen in MS, can manifest with deficiency in special senses including visual field loss [Davis 2010]. Such also may be the origin for the chemosensory loss seen here. While this phenomenon may be induced by hot baths, more subtle temperature changes may also induce such symptoms [Romani 2000]. Given that olfactory threshold changes have been demonstrated in acute inflammatory changes in MS, such a temperature related etiology is more likely to manifest [Lutterotti 2011]. MS patients should be screened for chemosensory dysfunction, and those with chemosensory dysfunction should be assessed for demyelinating disease.
Funding AcknowledgementsSmell and Taste Treatment and Research Foundation
125 Short Duration Monoballismus
- Davinder Dhillon, Priya Batta, Alan R. Hirsch
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- 15 June 2018, pp. 79-80
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Study Objective
While monoballismus has been reported to be associated with hemorrhagic lesions in the subthalamic nucleus (Ohnishi, 2009) and multiple sclerosis (MS) (Rosa, 2011), the duration has been reported to be at least six days (Soysal, 2012). A patient with epochs of monoballismus lasting for 45 minutes is presented.
MethodsCase Study: A 57 year old right handed female with attention deficit hereditary disorder predominantly inattentive on amphetamine sulphate, presented with two years of memory loss. For instance, after ordering food in restaurants, by the time the food arrives, she could not recall what she ordered. At the onset of this symptom, she noted three epochs of her left arm jerking for 45 minutes. The jerking would begin with low amplitude and low frequency and rapidly progress to the forearm and arm of greater magnitude and low frequency. With her right hand she would try to hold down her left arm without success. There was no associated paresis, sensory phenomena, headaches, dizziness, presyncope, loss of consciousness, or strong emotions. She admitted to frequent jamais vu.
ResultsAbnormalities: Neurological Examination: Mental Status Examination: Memory: Immediate Recall: 5 digits forward and 2 digits backwards. Cranial Nerve (CN) Examination: CN I: Alcohol Sniff Test 8 (hyposmia). CN XII: tongue tremor on protrusion. Motor Examination: Drift Test: positive right pronator drift. Gait Examination: Tandem Gait: unstable. Reflexes: 0-1 throughout. Neuropsychiatric Examination: Go-No-Go Test: 6/6 (normal). Animal Fluency Test: 15 (normal). Clock Drawing Test: 3 (abnormal). Center for Neurologic Study Lability Scale: 16 (pseudobulbar affect). Other: MRI with and without infusion: normal.
ConclusionTransient tonic-clonic movements of one limb have been described with focal epilepsy associated with diabetic non-ketotic hyperglycemia (Grant, 1985). A metabolic abnormality such as transient hypoglycemia or hyperkalemia can cause a focal dystonia (Soysal, 2012), which theoretically could manifest with monoballismus. This could be a somatic manifestation of underlying conflict, conversion disorder, or as a result of a physical manifestation of panic attack with hyperventilation and tetany (Mihai, 2008). This may be the first manifestation of a generalized cerebral disorder associated with chorea or ballismus such as Wilson’s disease, or Huntington’s Chorea (Mihai, 2008). It is possible that this is a variant of Alien Hand Syndrome with parietal lobe involvement (Shrestha, 2015). But this is unlikely given the absence of hemineglect or hemiagnosia. It is possible that amphetamines may have induced a monochorea. Chronic amphetamine use has been demonstrated to cause chorea (Klawans, 1974) and it theoretically could have caused ballismus movements in this case. In patients who present with short duration monoballismus, evaluation for subthalamic nuclei function, seizure disorders and other origins of ballismus are warranted.
Funding AcknowledgementsSmell & Taste Treatment and Research Foundation
127 Cardiovascular Safety Assessment of Deutetrabenazine in Healthy Volunteers and Implications for Patients With Huntington Disease or Tardive Dyskinesia
- Donna S. Cox, Micha Levi, Laura Rabinovich-Guilatt, David Truong, David Stamler
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- 15 June 2018, p. 80
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Introduction
Deutetrabenazine is approved for treating Huntington disease (HD) chorea and is being evaluated for tardive dyskinesia (TD).
ObjectiveTo assess the effect of deutetrabenazine on cardiac repolarization.
MethodsA QT interval study was performed to evaluate effects of deutetrabenazine 12 and 24 mg on cardiac repolarization, as assessed by time-matched change from baseline, placebo-adjusted, in Fridericia-corrected QT interval (ΔΔQTcF). Moxifloxacin (400 mg) and tetrabenazine (50 mg) were the positive control and comparator, respectively. An exposure–response analysis was developed from this study to predict maximal effects on QTcF at maximum recommended dosing based on CYP2D6 status, an approach consistent with regulatory guidance at predicting QT interval effects.
ResultsMaximal ΔΔQTcF between the least-squares mean (90% two-sided confidence interval) of deutetrabenazine 12 and 24 mg (n=45 in each group) were 2.8 (0.7–4.8) ms and 4.5 (2.4–6.5) ms, respectively. The ΔΔQTcF increase with tetrabenazine (n=45) was 7.6 (5.6–9.5) ms. Assay sensitivity was verified with moxifloxacin (n=47), which produced a maximal effect on ΔΔQTcF of 14.0 (11.9–16.0) ms. A linear model was developed that described a correlation between plasma concentrations from pivotal HD andTD trials (n=101) and QT interval prolongation. Using that model and the individual predicted Cmax for HD and TD patients, the placebo-adjusted change from baseline inQTcF for deutetrabenazine at maximal recommended daily doses was found to be 5.4 (2.5–9.5) ms.
ConclusionsPatients receiving the maximal recommended doses of deutetrabenazine are predicted to have a QTcF increase below the level of regulatory concern.
Presented at: Psych Congress; September 16–19, 2017; New Orleans, Louisiana, USA.
Funding AcknowledgementsThis study was funded by Teva Pharmaceutical Industries, Petach Tikva, Israel
128 Effect of DR/ER-MPH on Early Morning and Late Afternoon/Evening Functioning in Children With ADHD: Analysis of PREMB-R Items From a Phase 3 Trial
- Steven R. Pliszka, Valerie K. Arnold, Andrea Marraffino, Norberto J. DeSousa, Bev Incledon, F. Randy Sallee, Timothy E. Wilens, Jeffrey H. Newcorn
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- 15 June 2018, pp. 80-81
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Objective
In a phase 3 trial of children with ADHD, DR/ER-MPH (formerly HLD200), a delayed-release and extended-release methylphenidate, improved ADHD symptoms and reduced at-home early morning and late afternoon/evening functional impairments versus placebo, as measured by the validated Parent Rating of Evening andMorning Behaviors-Revised, Morning (PREMB-R AM) and Evening (PREMB-R PM) subscales. This post hoc analysis evaluated the effect of DR/ER-MPH versus placebo onindividual PREMB-R AM/PM item scores.
MethodData were analyzed from a pivotal, randomized, double-blind, multicenter, placebo-controlled, parallel-group, phase 3 trial of DR/ER-MPH in children (6-12 years) withADHD (NCT02520388). Using the 3-item PREMB-R AM and 8-item PREMB-R PM, both key secondary endpoints, investigators evaluated early morning and lateafternoon/evening functional impairment by scoring each item on a severity scale from 0 (none) to 3 (a lot). For post hoc analyses, treatment comparisons between DR/ER-MPH and placebo at endpoint were determined by using least squares mean changes from baseline on individual PREMB-R AM/PM items score derived from an analysis ofcovariance (ANCOVA) model with treatment as the main effect, and study center and baseline score as covariates.
ResultsOf 163 children enrolled across 22 sites, 161 were included in the intent-to-treat population (DR/ER-MPH, n=81; placebo, n=80) and 138 completed the study. The mean DR/ER-MPH dose achieved after 3 weeks of treatment was 68.1 mg. Following 3 weeks of treatment, DR/ER-MPH significantly reduced mean individual item scores from baseline versus placebo on all PREMB-R AM items (all P≤0.002; “getting out of bed”, “getting ready”, and “arguing or struggling in the morning”). Additionally, DR/ER-MPH significantly reduced mean individual item scores from baseline on 5 out of 8 PREMB-R PM items (P<0.01 in 2 items [“sitting through dinner” and “playing quietly”] and P<0.05 in 3 items [“inattentive/distractible”, “transitioning between activities”, and “settling down/getting ready for bed”]). There was a trend towards a reduction on 2 other items of the PREMB-R PM (P<0.09). Distributions of the ratings for each item will be presented. No serious TEAEs were reported; TEAEs were consistent withmethylphenidate.
ConclusionsPost hoc analyses revealed that DR/ER-MPH significantly reduced all PREMB-R AM item scores, including “getting out of bed”, and many PREMB-R PM items, including “getting ready for bed” in children with ADHD. These findings are worth further exploration.
Funding AcknowledgementsIronshore Pharmaceuticals & Development, Inc.
129 Effect of DR/ER-MPH on Caregiver-Reported ADHD Symptom Improvement in Children With ADHD and Caregiver Strain: Results From a Phase 3 Trial
- Steven R. Pliszka, Valerie K. Arnold, Andrea Marraffino, Norberto J. DeSousa, Bev Incledon, F. Randy Sallee, Timothy E. Wilens, Jeffrey H. Newcorn
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- 15 June 2018, p. 81
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Objective
Evening-dosed DR/ER-MPH (formerly HLD200), a delayed-release and extended-release methylphenidate, was designed to provide efficacy upon awakening and through the evening. The objective was to evaluate whether treatment with DR/ER-MPH in children with attention-deficit/hyperactivity disorder (ADHD): (1) improves caregiver-rated ADHD symptoms, and (2) reduces caregiver strain, versus placebo.
MethodCaregiver-rated ADHD symptoms (Conners’ Global Index–Parent [CGI-P]) and caregiver strain (Caregiver Strain Questionnaire [CGSQ]) were assessed as secondary endpoints following 3 weeks of treatment in a randomized, double-blind, multicenter, placebo-controlled, parallel-group, phase 3 trial of DR/ER-MPH in children (6-12 years) with ADHD (NCT02520388). Using the 10-item CGI-P, parents rated their child’s ADHD symptoms on a 4-point scale (0=never/seldom; 3=very often/frequently). Caregivers also rated the impact of caring for a child with emotional and behavioral challenges on the 21-item CGSQ (5-point scale: 1=not at all; 5=very much). A reduction on individual item and total scores for both measures indicated an improvement.
ResultsOf 163 children enrolled across 22 sites, 161 were included in the intent-to-treat population (DR/ER-MPH, n=81; placebo, n=80) and 138 completed the study. The mean DR/ER-MPH dose after 3 weeks of treatment was 68.1 mg. Mean CGI-P scores at baseline and CGSQ scores at screening (ie, before washout of prior ADHD therapy) were comparable for both DR/ER-MPH (CGI-P: 22.8, CGSQ: 54.5) and placebo (CGI-P: 21.8; CGSQ: 54.9) groups. After 3 weeks of treatment, caregivers of children onDR/ER-MPH reported significant reductions in CGI-P scores versus those on placebo (least-squares [LS] mean: 12.3 vs 17.4; P<0.001). Additionally, there was a significant reduction in CGSQ scores after 3 weeks of treatment with DR/ER-MPH versus placebo (LS mean: 41.2 vs 49.1; P<0.001). Post hoc analyses on the effect of DR/ER-MPHversus placebo on individual items of CGI-P and CGSQ, and the two subscales of CGI-P will be presented. No serious TEAEs were reported and all TEAEs were consistent with those of MPH.
ConclusionsCaregivers reported significant improvements in their child’s ADHD symptoms and these improvements coincided with reductions in caregiver strain after 3 weeks of treatment on evening-dosed DR/ER-MPH versus placebo.
Funding AcknowledgementsIronshore Pharmaceuticals & Development, Inc.
130 Consistent Efficacy of DR/ER-MPH on Early Morning Functioning in Children With ADHD: Analysis of BSFQ Item Ratings From a Pivotal Phase 3 Trial
- Timothy E. Wilens, Steven R. Pliszka, Valerie K. Arnold, Andrea Marraffino, Norberto J. DeSousa, Bev Incledon, F. Randy Sallee, Jeffrey H. Newcorn
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- 15 June 2018, p. 82
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Objective
In a phase 3 trial of children with attention-deficit/hyperactivity disorder (ADHD), DR/ER-MPH (formerly HLD200), a delayed-release and extended-release methylphenidate, improved ADHD symptoms and reduced at-home early morning and late afternoon/evening functional impairment versus placebo. The validated Before School Functioning Questionnaire (BSFQ), a key secondary endpoint, was used to measure early morning functional (EMF) impairment. This post hoc analysis evaluated the effect of DR/ER-MPH versus placebo on individual BSFQ item scores from baseline.
MethodData were analyzed from a pivotal, randomized, double-blind, multicenter, placebo-controlled, parallel-group, phase 3 trial of DR/ER-MPH in children (6-12 years) withADHD (NCT02520388). Using the 20-item BSFQ, investigators evaluated EMF impairment by scoring each item on a severity scale of 0 to 3, with 0 denoting “no impairment” and 3 denoting “severe impairment”. For post hoc analyses, treatment comparisons between DR/ER-MPH and placebo at endpoint were determined by using least squares mean changes from baseline on individual BSFQ items score derived from an analysis of covariance (ANCOVA) model with treatment as the main effect, and study center and baseline score as covariates.
ResultsOf 163 children enrolled across 22 sites, 161 were included in the intent-to-treat population (DR/ER-MPH, n=81; placebo, n=80) and 138 completed the study. The mean DR/ER-MPH dose achieved after 3 weeks of treatment was 68.1 mg. Following 3 weeks of treatment, DR/ER-MPH significantly reduced mean BSFQ item scores frombaseline on 18 out of 20 items versus placebo (P<0.001 in 8 items [listening, following directions, attention, forgetfulness, talkativeness, silliness, time awareness, getting to school]; P<0.01 in 7 items [overall organization, being quiet, distraction, interrupt/blurt out, breakfast, hygiene, independence]; P<0.05 in 3 items [procrastination, hyperactivity, awaiting turn]). Only “dressing” and “misplacing/losing items” showed no significant between-group differences (P=0.171 and P=0.175, respectively). Distributions of the severity ratings for each item will be presented. No serious TEAEs were reported; TEAEs were consistent with methylphenidate.
ConclusionsPost hoc analyses revealed that DR/ER-MPH significantly reduced 18 out of 20 individual BSFQ item scores versus placebo in children with ADHD. These findings are worth further exploration.
Funding AcknowledgementsIronshore Pharmaceuticals & Development, Inc.
132 Effects of Valbenazine on Depression and Suicidality in Adults With Tardive Dyskinesia: Pooled Results of 3 Double-Blind, Placebo-Controlled Trials
- Gary Remington, Dao Thai-Cuarto, Joshua Burke, Scott Siegert, Grace S. Liang
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- Published online by Cambridge University Press:
- 15 June 2018, pp. 82-83
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Study Objectives
Valbenazine (INGREZZA; VBZ) is a novel and highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor that is approved for the treatment of tardive dyskinesia (TD) in adults. The randomized, double-blind, placebo (PBO)-controlled trials of VBZ evaluated the treatment of TD in patients with a primary psychiatric diagnosis (schizophrenia/schizoaffective disorder or mood disorder) while on concomitant psychiatric medications to manage these disorders. Since treatment-emergent depression and suicidal ideation/behavior are important clinical concerns in psychiatric patient populations, data from these trials were analyzed to assess the effectsof once-daily VBZ on depression and suicidality.
MethodsData were pooled from three 6-week trials: KINECT (NCT01688037), KINECT 2 (NCT01733121), KINECT 3 (NCT02274558). Outcome data were analyzed in the safety population by pooled VBZ doses (40 mg, 80 mg) and PBO. Outcomes of interest included: treatment-emergent adverse events (TEAEs) related to depression or suicidality; mean score change from baseline to Week 6 in the Calgary Depression Scale for Schizophrenia (CDSS, for participants with schizophrenia/schizoaffective disorder) or the Montgomery-Åsberg Depression Rating Scale (MADRS, for participants with mood disorder); and, worsening from baseline in Columbia-Suicide Severity Rating Scale (C-SSRS) suicidal ideation scores. All outcomes were analyzed descriptively.
ResultsThere were 400 total participants in the pooled safety population; 286 participants had schizophrenia/schizoaffective disorder (40 mg, n=82; 80 mg, n=70; PBO, n=134) and 114 had a mood disorder (40 mg, n=28; 80 mg, n=42; PBO, n=44). Over one-third of participants had a lifetime history of suicidal ideation or behavior (40 mg, 45%; 80 mg, 39%; PBO, 37%). Few participants had a depression- or suicide-related TEAE, with no apparent differences between VBZ and PBO: suicidal ideation (40 mg, 3.6%; 80 mg, 0.9%; PBO, 2.2%); depression (40 mg, 0%; 80 mg, 1.8%; PBO, 1.1%); depressive symptom (40 mg, 0.9%; 80 mg, 0%; PBO, 0.6%); suicide attempt (40 mg, 0%; 80 mg, 0.9%; PBO, 0%). Mean changes from baseline to Week 6 in depression scale scores were generally small and similar across treatment groups: CDSS total score (40 mg, -0.5; 80 mg, -0.6; PBO, -0.3); MADRS total score (40 mg, -0.2; 80 mg, -1.7; PBO, 0.6). Few participants had a shift from no suicidal ideation at baseline (C-SSRS score=0) to any suicidal ideation during treatment (C-SSRS score=1-5): 40 mg, 3.9% (4/103); 80 mg, 0.9% (1/111); PBO, 2.9% (5/174).
ConclusionData from 3 double-blind, placebo-controlled trials indicate that once-daily VBZ treatment was not associated with a worsening in depression-related symptoms or an increased risk of suicidal ideation or behavior.
Funding AcknowledgementsThis study was funded by Neurocrine Biosciences, Inc.
133 Cognitive Impairment Following Overdose on Lamotrigine
- Geetha Chandrashekar, David Ash, Garima Singh
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- 15 June 2018, pp. 83-84
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Objective
To generate hypotheses, accumulate scientific data about rare presentations, and serve as a major educational tool.
MethodThis is a retrospective case report of a patient in inpatient unit.
IntroductionLamotrigine is a mood stabilizer with unique mechanisms of action. At therapeutic levels, it has been reported that Lamotrigine is neuroprotective and improves cognition. In this case, we present a patient who suffered significant cognitive slowing following overdose on Lamotrigine.
CaseA 17yo white male with a diagnosis of Autism spectrum disorder and Bipolar disorder type 1 was admitted for bizarre behavior and profound cognitive impairment. His past psychiatric history was significant for two suicide attempts - first by overdose on baby aspirin and second by overdose on Lamotrigine, both of which had occurred about six months prior to his presentation and had each required an inpatient hospitalization. His family reported that since his overdose on Lamotrigine, he had been withdrawn, aloof, and appeared depressed. His school teachers had noticed significant decline in his memory, attention and concentration, and there had been noticeable impairment in his ability to follow commands or complete a task. On assessment, he was noted to have significant psychomotor slowing, latency in speech and thought blocking. At the time of his presentation, he was on Lithium 300mg BID. A careful review of his previous medical records revealed that he had been on a combination of Seroquel, Lamotrigine and Lithium prior to his overdose attempt on Lamotrigine. During this hospitalization, Seroquel was restarted. Patient tolerated the medication well. There were no safety concerns and he was deemed safe to discharge under 24hr supervision of his family. He has since been followed up in clinic. Although he continues to have some cognitive slowing, overall, he has demonstrated slow but steady improvement.
DiscussionLamotrigine acts by blocking voltage sensitive sodium channels. It also reduces release of glutamate, a major excitatory neurotransmitter in the central nervous system. Glutamate modulates synaptic plasticity, a property thought to be vital for memory and learning. While too much glutamate causes over activation of NMDA receptors resulting in increased intracellular oxidative stress and eventually apoptosis, too little glutamate may lead to decreased glutamate mediated postsynaptic excitation of neural cells and thus impacting memory formation, learning and cognition. At therapeutic levels (2.5- 15mcg/ml), it has been reported that Lamotrigine is neuroprotective and improves cognition. At the time of overdose, our patient had a Lamotrigine level of 21.5mcg/ml. There is limited literature on cognitive effect of supra-thrapeutic levels of Lamotrigine. As such, a causal relationship cannot be determined from a single care report. Also in differentials to consider are schizophrenia and seizures from lamotrigine withdrawal.
Funding AcknowledgementsNo funding.
134 Improvements in Clinical Global Impression of Change With Deutetrabenazine Treatment in Tardive Dyskinesia From the ARM-TD and AIM-TD Studies
- Hubert H. Fernandez, Mat D. Davis, Stewart A. Factor, Robert A. Hauser, L. Fredrik Jarskog, Joohi Jimenez-Shahed, Rajeev Kumar, Stanislaw Ochudlo, William G. Ondo, Karen E. Anderson
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- 15 June 2018, p. 84
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Introduction
Tardive dyskinesia (TD) is an involuntary movement disorder that is often irreversible, can affect any body region, and can be debilitating. In the ARM-TDand AIM-TD studies, deutetrabenazine treatment demonstrated statistically and clinically significant reductions in Abnormal Involuntary Movement Scale (AIMS) scores at Week 12 compared with placebo (primary endpoint).
ObjectiveTo evaluate the efficacy of deutetrabenazine, as measured by the Clinical Global Impression of Change (CGIC) scale, in patients with TD from the pooled ARM-TDand AIM-TD (24 and 36 mg/day doses) data sets, as compared with the pooled placebo cohort.
MethodsARM-TD and AIM-TD were 12-week, randomized, double-blind, placebo-controlled studies that evaluated the safety and efficacy of deutetrabenazine for thetreatment of TD. The key secondary endpoint of each study was the proportion of patients “much improved” or “very much improved” (treatment success) at Week 12 on theCGIC.
ResultsAt Week 12, the odds of treatment success among patients treated with deutetrabenazine (n=152) was more than double that of patients given placebo (n=107; odds ratio: 2.12; P=0.005). In a categorical analysis of CGIC ratings, patients treated with deutetrabenazine showed greater improvement than patients given placebo (P=0.003). Patients treated with deutetrabenazine also had a significantly better treatment response than those given placebo (least-squares mean CGIC score treatment difference: –0.4; P=0.006).
ConclusionsDeutetrabenazine treatment led to statistically and clinically significant improvements in TD symptoms based on the CGIC result, suggesting that clinicians were able to recognize the benefit in patients treated with deutetrabenazine.
Presented at: The International Congress of Parkinson’s Disease and Movement Disorders; June 4–8, 2017; Vancouver, British Columbia, Canada.
Funding AcknowledgementsThese studies were funded by Teva Pharmaceutical Industries, Petach Tikva, Israel.
135 Use of Pimavanserin in Combination With Selective Serotonin Reuptake Inhibitors (SSRIs)
- James Norton, Doral Fredericks, Kathy Chi-Burris, Randy Owen
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- 15 June 2018, pp. 84-85
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Study Objective
Psychosis is common in Parkinson’s disease (PD) and increases in both frequency and severity with disease duration. It is associated withincreased morbidity/mortality, complicates management of motor symptoms and often leads to long-term care placement. Pimavanserin is a selective 5-HT2A inverse agonist/antagonist approved in the U.S. for treatment of hallucinations and delusions associated with Parkinson’s disease psychosis (PDP). Depression affects up to 60% ofPD patients and is frequently treated with SSRIs/SNRIs. Data suggest the potential for a synergistic effect between 5 HT2A receptor inverse agonist/antagonists and SSRIs insubjects with neuropsychiatric disease. This post-hoc analysis evaluated a subgroup of subjects from the pimavanserin clinical program to determine if there was any difference in antipsychotic response between the subjects receiving pimavanserin in combination with an SSRI versus those without.
MethodA pooled analysis of two 6-week randomized, double-blind, placebo-controlled Phase 3 studies was conducted to assess the overall treatment effect of pimavanserin34 mg. The outside-North America region in Study 012 was not included due to a difference in methodology in the assessment of the primary endpoint. Subjects in both the 020 and 012 studies received 42 days of treatment. The mITT population included 268 subjects; with 135 in the pimavanserin group. The full safety dataset included 433 subjects; with 202 in the pimavanserin group. Of the 268 subjects in the mITT population, a total of 77 received concomitant therapy with SSRIs. A subgroup analysis was conducted to determine if there was any difference in response among the subjects receiving concomitant SSRIs.
ResultsOverall, pimavanserin demonstrated a -6.21-point improvement in psychosis at Week 6 as measured by the PD-adapted Scale for Assessment of Positive Symptoms (primary change from baseline analysis [MMRM]). The treatment difference was 2.87 points over placebo (p<0.001) and was clinically meaningful. Both subgroups (pimavanserin +/- SSRI) demonstrated a statistically significant improvement over placebo. Among subjects taking concomitant SSRIs, the decrease in psychosis symptoms was more prominent for both pimavanserin and placebo-treated subjects (-8.33 points and -4.01 points, respectively) compared to the 189 subjects not taking SSRIs (-5.36 points and -3.01 points, respectively); the treatment difference was of greater magnitude in the concomitant SSRI treated group (-4.32 vs. -2.34). A total of 10% (4/40) and 7.4% (12/162) of pimavanserin treated subjects, with and without SSRIs, respectively, discontinued because of adverse reactions.
ConclusionsThe results of this analysis further support findings that the combination of selective 5-HT2A agonist/antagonists and SSRIs may have additive beneficial effects, suggesting a possible enhancement of antipsychotic effect in subjects treated with concomitant SSRIs.
Funding AcknowledgementsClinical study was funded by ACADIA Pharmaceuticals Inc.
136 CerefolinNAC Therapy-Induced Dizziness
- Jasir T. Nayati, Alan R. Hirsch
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- 15 June 2018, pp. 85-86
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Study Objective
CerefolinNAC (CFLN-NAC) contains L-methylfolate (6 mg), methylcobalamin (2 mg), and N-acetylcysteine [NAC] (600 mg) [Pamlab 2017]. Dizziness and lightheadedness have not heretofore been described with use of CFLN-NAC.
MethodsCase Study: A 64 year old right-handed female was started on CFLN-NAC for smell and taste issues. Over a three day period, she experienced a gradual increase in dizziness. This was a non-vertiginous lightheadedness, so severe that she was unable to walk, and would lie down the entire day to alleviate the dizziness. It was associated with nausea, but without any vomiting or falls. The dizziness would come and go, last for several hours, and was 9/10 in severity.
She admits to a past history of epochs of vertigo. The vertigo occurred three times with nausea and vomiting 13 years, 11 years, and 4 years prior to presentation. She also developed a constant, bilateral, high-pitched tinnitus 14 years prior to presentation, which obstructs her hearing. It is level 3/10 in intensity during the night and in the quiet. There were no alleviating or aggravating factors. Acupuncture was without effect, and she denies any ear pain. After ceasing CFLN-NAC for three days, a gradual reduction of dizziness to baseline ensued.
ResultsAbnormalities in Physical Examination: General: Decreased blink frequency and hypokinesia. Cranial Nerve III, IV, VI: Saccadization of horizontal eye movements. Motor Examination: Tone: 1+ cogwheel rigidity in both upper extremities, left more than right. Drift Test: Bilateral Abductor Digiti Minimi sign with cerebellar spooning. Reflexes: Absent quadriceps femoris and Achilles bilaterally. Positive Hoffman reflex bilaterally. Neuropsychiatric Testing: Go-No-Go Test: 6/6 (normal). Animal Fluency Test: 19 (normal). Reliable Digit Span: 10 (normal). Clock Drawing Test: 4 (normal). Center for Neurologic Study Lability Scale: 10 (normal). Other: Audiometry and Fiberoptic Endoscopy: normal. MRI of the brain with and without contrast was normal.
ConclusionNone of the individual components in CFLN-NAC have been reported to precipitate dizziness [Pamlab 2017]. The non-vertiginous nature of the dizziness makes it unlikely to be due to vestibular involvement, raising the spectre of this drug having an impact on the autonomic nervous system. While a nocebo effect could be in action, this is unlikely since dizziness was not presented as a potential side effect on initiation of the medication. In addition, methylcobalamin can cause hyperviscosity syndrome, but due to an absence of visual disturbances and altered mental status, it is also improbable. The relatively rapid onset with initiation and resolution upon discontinuation of this medication strongly suggests that it is not a coincidence, rather an origin for the dizziness. Those who are treated with CFLN-NAC should be queried as to new onset dizziness. For those already dizzy, one should consider other treatment options.
Funding AcknowledgementsSmell and Taste Treatment and Research Foundation
137 Menstrual Synchrony of Burning Mouth Syndrome
- Jasir T. Nayati, Alan R. Hirsch
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- 15 June 2018, p. 86
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Study Objective
Burning mouth syndrome (BMS) is characterized by oral mucosal burning sensations, with normal clinical and laboratory results. Menstrual synchrony of migraines and epilepsy have been discussed; however, menstrual synchrony of BMS has not heretofore been described.
MethodsCase Study: A 29 year old right-handed female exhibited intermittent BMS symptoms, one month after suffering a left parietal infarction. She describes the pain as a burningsensation, localized to the bilateral and anterior aspects of her tongue. It lasts for four days, starts three days prior to her menses, and occurs twice a month. She is unable to correlate any patterns or triggers that may cause to exacerbate her BMS. She denies any taste disturbances, hot-flashes, night sweats, and perspiration.
ResultsAbnormalities during neurological examination were noted. Cranial nerves (CN) III, IV, and VI showed bilateral lateral first degree end-gaze unsustained nystagmus. CN IX and X showed decreased bilateral gag reflex. A right pronator drift with a right abductor digiti minimi sign was seen in the motor examination. The cerebellar examination was positive for bilateral dysmetria during the Finger-To-Nose examination, and exhibited Holmes rebound phenomena, right more than left. Sensory examination showed decreased light touch in the lower extremities, right more than left. Hoffman reflex was bilaterally positive. Mental status examinations demonstrated poor similarity interpretation and calculation ability. Her neuropsychiatric testing was normal, and included the Go-No-Go and Animal Fluency Testing. MRI of the brain exhibited gliosis/laminar necrosis in the left inferior parietal lobe, and an 8mm descent of cerebellar tonsils below the foramen magnum.
ConclusionThe potential mechanism for catamenial BMS is manyfold. Estrogen and progesterone both have nociceptive properties. Premenstrual drop or reduction of estrogen and progesterone may act to disinhibit pain [Vincent 2008], with pain modulation being more effective during the ovulatory phase (high estrogen and low progesterone) [Rezaii 2012]. Depression in the presence of Late Luteal Phase Dysphoric Disorder may function to exacerbate the perception of underlying pain throughout the body, including the mouth and tongue. Decrease in estrogen and progesterone levels may also alter salivary output and composition. This may allow baseline reduction of proprioceptive input on the tongue, thus acting through Melzack and Wall’s Gate Control Theory of Pain to disinhibit small C fibers, which is perceived as burning pain [Melzack 1978]. Along with menses, olfactory ability drops, and food preferences are often reported to change [Keller 2013]. A decrease in estrogen and progesterone can also enhance trigeminal nerve sensitivity [Martin 2007], which exacerbates pain. This may indirectly influence or be associated with her BMS. Such observations justifies a trial of hormonal agents for therapy of BMS.
Funding AcknowledgementsSmell and Taste Treatment and Research Foundation
138 Gait Ignition Failure Syndrome Secondary to Spinal Stenosis
- Jasir T. Nayati, Angela Rekhi, Alan R. Hirsch
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- 15 June 2018, pp. 86-87
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Case Objective
Gait ignition failure syndrome, where immobility occurs only upon initiation of ambulation and normal gait ensues once entrained, has been reported with frontal lobe and midbrain locomotor region pathology. However, gait ignition failure syndrome secondary to lumbosacral spinal stenosis has not heretofore been described.
MethodsCase Study: A 65-year-old right-handed woman underwent a right frontal parasagittal arteriovenous malformation embolization 25 years prior to presentation. After a fall resulting in a T12 and L1 compression fracture, two kyphoplasties were performed. After the second kyphoplasty, one year prior to presentation, she developed new onset of gait ignition failure, left anterior thigh pain, lower back pain at L5 with radiation to both hips, and bilateral lower extremity weakness. The gait difficulty duration correlates to the duration she is in a seated position. Upon standing, she is unable to move her legs and exhibits basophobia, feeling she may fall due to weakness and she is unable to lift up her left foot to initiate gait, as if it is glued to the floor. She is able to initiate gait after one minute, but has an unsteady scissors-gait for the first few steps. Afterwards, her gaitreturns to baseline. Anteroflexion was noted to eliminate her back and leg pain.
ResultsGait examination shows inability to initiate gait after standing, feeling as if frozen. However, she demonstrated scissors-gait after 30 seconds for 3-5 steps, which gradually improved to baseline. Her quadriceps femoris reflex was absent on the right, 3+ on the left. Her Achilles reflex was absent on left. MRI indicated spinal stenosis with broad based osteophytes at T9-T12 and bilateral neural foraminal stenosis at L1-S1. Exercise therapy designed for spinal stenosis was initiated, and resulted in elimination of gaitignition failure.
ConclusionGait ignition failure syndrome may not be necessarily due to frontal or midbrain dysfunction, but can be secondary to lumbosacral impairment. In this patient, dysfunctional arachnoid villi in the lumbosacral nerve roots may have led to transient increases in pressure throughout the neural axis, including the brain, and associated NPH-like symptoms, such as magnetic gait. Seeing that posture affects epidural pressure in lumbar spinal stenosis, with a decrease pressure in response to anteroflexion and reduced pain [Takahashi 1995], one can postulate that this may be a mechanism affecting the patient. Furthermore, since her symptoms are episodic and directly associated with the duration of time she is seated, one may deduce gait ignition failure to be a manifestation of cerebrospinal fluid or intracranial pressure changes influenced by posture. In addition, symptom resolution via exercise therapy strongly suggests that gait apraxia can also be a manifestation of lumbosacral dysfunction. Therefore, those with gait ignitionfailure syndrome warrant evaluation for lumbosacral pathology.
Funding AcknowledgementsSmell and Taste Treatment and Research Foundation.