Monday, June 10, 2013

Fixed-dose dextromethorphan and quinidine is effective in the treatment of pseudobulbar affect due to neurodegenerative conditions: a case series


ENS 2013 (Barcelona, Spain)
Monday June 10, 2013



Click on poster (below) to download:


OBJECTIVE: 
To describe patient-reported response of pseudobulbar affect (PBA) secondary to stroke and Alzheimer’s disease (AD) to oral twice daily fixed dose combination of dextromethorphan 20 mg and quinidine 10 mg (DM/Q).

METHODS: Retrospective chart review at a single neurology clinic of 13 patients with AD (9 men, 4 women) and 17 patients with stroke (7 men, 10 women).

RESULTS:
All 13 patients with AD and PBA who were treated with DM/Q reported an improvement in their PBA frequency and/or severity, with 8 patients rating it as “mild” and 5 rating it as “major.” One patient discontinued therapy after 5 months due to financial concerns. Mean age at time of diagnosis with AD was 59 years (median = 58 years) and the length of time from AD diagnosis to PBA onset was 12 months (range=1–26). Prior to initiating DM/Q, the mean number of weekly PBA episodes was 19 (median=17), which were rated as mild by 2 patients, moderate by 5 patients and severe by 6 patients. Mean lag from PBA onset to DM/Q initiation was 17 months (median=8, range=1–53).

Most of the 17 patients with stroke and PBA who were treated with DM/Q reported an improvement in their PBA frequency and/or severity, with 3 patients rating it as “mild” and 10 rating it as “major.” Four patients discontinued DM/Q due to no reported change (all of those without an improvement had mild PBA). Mean and median age at time of diagnosis with stroke was 57 years, and the length of time from stroke diagnosis to PBA onset was 10 months (range=1–24). Prior to initiating DM/Q, the mean number of weekly PBA episodes was 14 (median=10), which were rated as mild by 7 patients, moderate by 7 patients and severe by 10 patients. Mean lag from PBA onset to DM/Q initiation was 21 months (median = 9 months, range = 1 – 84 months).

CONCLUSIONS: 
This real-word case series confirms the efficacy of DM/Q in the treatment of PBA regardless of underlying neurologic condition. DM/Q has previously been demonstrated to be safe and effective in the treatment of PBA secondary to multiple sclerosis and amyotrophic lateral sclerosis. In 2010, the U.S. Food and Drug Administration approved DM/Q for PBA regardless of the underlying neurologic condition due to the “clear distinctness of the primary pathology” of both of the conditions studied.  Ongoing controlled studies in special populations, in addition to real-world case series suggest the appropriateness of using DM/Q in the treatment of PBA regardless of the underlying neurologic condition.

- Dr. Daniel Kantor, MD
  Medical Director
  Neurologique

  info@neurologique.org
  www.neurologique.org

Thursday, June 6, 2013

Once Daily Gastroretentive Gabapentin Formulation for Episodic Migraine Prophylaxis: The First Case Report

Presented at the International Headache Congress, hosted by the International Headache Society and the American Headache Society (June 27 - 30, 2013 in Boston, MA):



Once Daily Gastroretentive Gabapentin Formulation for Episodic Migraine Prophylaxis: The First Case Report

Daniel Kantor, MD

Objectives:  
To report the use of a once daily gastroretentive gabapentin (G-GR) formulation for the prophylaxis of episodic migraine.

Background:  
Gabapentin is a calcium channel α2δ ligand that increases γ-aminobutyric acid (GABA) concentrations in the brain; it has been hypothesized to play a role in migraine prophylaxis. However, according to the 2012 updated evidence-based guideline report of the Quality Standards Subcommittee of the American Academy of Neurology and American Headache Society, the evidence is conflicting or inadequate to support or refute the use of gabapentin for migraine prevention (Level U recommendation). There are known side effects and limitations to the use of immediate release gabapentin (G-IR), and the conflicting data may be due to the difficulty in patients attaining and sustaining optimal dosages (due to side effects and frequency of administration). Gralise® is a once daily G-GR formulation approved by the U.S. Food and Drug Administration (FDA) for the management of postherpetic neuralgia (PHN); PHN patients seem to respond to G-GR without the same burden of side effects that limit dose titration of G-IR. We hypothesized that G-GR may play a beneficial role in the prophylaxis of episodic migraine.

Methods: 
Case report.

Results:  
A 36-year-old woman with a 15-year history of episodic migraines without aura (frequency 7 migraines/month, intensity 4-6/10) presented to a headache specialist; her body-mass index (BMI) was 27 kg/m2. In the past, she had attempted topiramate (up to a dose of 200 mg/day), which was discontinued secondary to cognitive side effects and propranolol 80 mg three times a day, which was discontinued due to hypotension. She refused to attempt antidepressants for migraine prophylaxis due to her concerns regarding the potential for neuropsychiatric side effects. G-GR was initiated at 300 mg with her evening meal, and it was titrated up over 2 weeks to 1800 mg with her evening meal. The patient denied any side effects and within the first month of treatment, her migraine frequency reduced to 3 migraines/month (average intensity 3/10). By the third month of treatment, her migraine frequency had reduced to 1–2 migraines/month (average intensity 2-3/10). 6 months after initiation of G-GR, her migraine frequency remains at 1 migraine/month (average intensity 2/10). The patient denies any treatment-emergent side effects and is satisfied with her migraine prophylaxis


Conclusions:  
This case report suggests that G-GR should be further studied in case series, prospective open-label studies and, eventually, randomized double-blind placebo controlled trials for the prophylaxis of episodic migraines. Our patient may respond even further with escalating doses of G-GR beyond 1800 mg a day, and perhaps with administration with the morning, rather than evening, meal or even twice a day (with breakfast and dinner) dosing. However, dosing deviations from that approved for PHN may have the disadvantage of increased side effects. Dose finding trials, including serial measurement of serum gabapentin, will be invaluable in helping to elucidate the potential role of G-GR in the prophylaxis of episodic migraines.


Selected References:

Argoff, Chen C and Cowles VE. Clinical development of a once-daily gastroretentive formulation of gabapentin for treatment of postherpetic neuralgia: an overview. Expert Opin Drug Deliv 2012;9(9):1147-60.

Mathew NT, Rapoport A, Saper J, et al. Efficacy of gabapentin in migraine prophylaxis. Headache 2001;41:119–128.

Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000;55: 754–762.

Silberstein SD. Preventive migraine treatment. Neurologic Clinics 2009;27:429-43.

Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: Pharmacologic treatment for episodic migraine prevention in adults. Neurology 2012;78:1337-1345.


Chronic Migraine (CM) Patients Should Be Screened For Pseudobulbar Affect (PBA)

Presented at the International Headache Congress, hosted by the International Headache Society and the American Headache Society (June 27 - 30, 2013 in Boston, MA):



Chronic Migraine (CM) Patients Should Be Screened For Pseudobulbar Affect (PBA)

Daniel Kantor, MD


Objectives:

To report a case series of pseudobulbar affect (PBA) in patients with chronic migraine (CM).

Background:

Pseudobulbar affect (PBA) is an under-recognized neurologic condition characterized by uncontrollable, inappropriate outbursts of laughing and/or crying that are incongruous or disproportionate to the patient’s emotional state; PBA occurs secondary to a variety of neurologic conditions, but it has not previously been reported in patients with chronic migraine (CM).  CM shares many pathophysiological features with other diseases affecting the central nervous system, yet it was not included in the recent point-prevalence epidemiological data from the PBA Registry Series (PRISM) of 5,290 neurologic patients. PBA is screened for using the Center for Neurologic Studies – Lability Scale (CNS-LS), the first self-report measure of PBA to be established and validated; it consists of subscales for laughter (4 items) and for crying (3 items), with each item scored on a 5-point scale (1 = applies never; 5 = applies most of the time) for a total score ranging from 7 (no symptoms) to 35 (maximum). In the clinical trials leading to the FDA approval of fixed dose combination dextromethorphan/quinidine (DM/Q) for the treatment of PBA, more patients treated with placebo had headache than patients treated with DM/Q (15.6% vs 14.0%). This led to our use of DM/Q for the treatment of headache; we previously reported a patient with >20 year history of refractory chronic migraine who responded dramatically (reduction of headache frequency and severity) to DM/Q. It is unclear, however, whether the therapeutic effect of DM/Q in CM is due to its efficacy in PBA.

Methods:

Retrospective analysis of 5 consecutive chronic migraine (CM) patients, all of whom completed both the CNS-LS to screen for PBA symptoms and the Beck Depression Inventory -II (BDI-II) to screen for depression. The CNS-LS subscores for laughing and crying were also analyzed separately, as was the crying specific question of the BDI-II.


Results:

All 5 CM patients were women, between the age of 40 and 65 years (mean/median age = 50 years). The mean number of headache days per month was 26 and 4 patients met criteria for PBA (CNS-LS≥13), while the other patient had a CNS-LS = 12. Mean CNS-LS was 15 and median was 14. Mean BDI-II was 15 and median was 13. There appeared to be some correlation (Pearson coefficient, 0.54) between CNS-LS and BDI-II scores, but depression alone did not explain the presence of PBA. 

Conclusions:

PBA has not previously been described in patients with chronic migraine (without other underlying neurologic conditions, such as multiple sclerosis, amyotrophic lateral sclerosis, stroke, traumatic brain injury, parkinson’s diseases or Alzheimer’s dementia). This case series suggests that PBA (in addition to depression) should be screened for in patients with CM. Further research should be conducted to estimate the prevalence of PBA in CM patients and to ascertain whether the response of CM to DM/Q is independent of the effect of DM/Q on PBA.



References:
Kantor D. Dextromethorphan Plus Quinidine For Headache Prophylaxis: The First Case Report. Poster presented at: 137th Annual Meeting of the American Neurological Association; 2012 Oct 9-12; Boston, MA.

Moore SR, Gresham LS, Bromberg MB, et al.  A Self Report Measure of Affective Liability. J Neruol Neurosurg Psychol 1997;63:89-93.

Pioro EP, Brooks BR, Cummings J, et al; Safety, Tolerability, and Efficacy Results Trial of AVP-923 in PBA Investigators. Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect. Ann Neurol. 2010; 68:693-702

Smith RA, Berg JE, Pope LE, Callahan JD, Wynn D, Thisted RA. Validation of the CNS emotional lability scale for pseudobulbar affect (pathological laughing and crying) in multiple sclerosis patients. Mult Scler. 2004;10:1-7.

Thursday, April 25, 2013

Treating Orally Earlier

News:
Top-line results of the TOPIC (Teriflunomide Versus Placebo in Patients With First Clinical Symptom of Multiple Sclerosis) trial were release today, April 25, 2013 and I had the opportunity to interview Dr. Aaron E. Miller (Medical Director, The Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai Medical Center) about the study, its results and his major takeaway messages.


Aubagio (teriflunomide) becomes the first and only oral medication for MS (multiple sclerosis) that also reduces the risk of conversion from a single demyelinating attack (clinically isolated syndrome or CIS)  to a second attack (MS) -- a place previously held only by the self injectable medications.

TOPIC was similar in design to the other CIS trials -- see the study design at: http://www.clinicaltrials.gov/ct2/show/NCT00622700?term=topic+teriflunomide&rank=1

There were no unexpected safety or tolerability concerns and the dose response was consistent to what has been seen in trials of Aubagio for MS (TEMSO, TOWER and TENERE). Patients receiving Aubagio 14 mg orally daily had a 43% reduction n the risk of conversion to clinically definite MS (CDMS) compared to placebo (fake pill), over the two-year study period (p=0.0087), while those receiving 7 mg orally daily has a 37% reduction in the risk of conversion to CDMS compared to placebo.
 
Dr. Miller concluded that it is "important to treat early before a definitive diagnosis of MS can be made."
  

- Dr. Daniel Kantor, MD
  Medical Director 
  Neurologique 

   info@neurologique.org 
   www.neurologique.org

Wednesday, March 27, 2013

BiG News for MS: 3rd oral disease modifying drug gains FDA Approval

Breaking News:

Tecfidera (BG00012) is FDA approved for relapsing forms of MS

In 1992 we had 0 medications FDA approved for the reduction of relapses and/or disability. Since the Betaseron/Betaferon (Interferon beta-1b under the skin every other day) lottery in 1993, Tecfidera (dimethyl fumarate) becomes the 10th branded MS disease modifying agent approved for use by the FDA (U.S. Food and Drug Administration) and 3rd oral MS DMA/DMD/DMT (disease modifying agent/drug/therapy).

Tecfidera (BG12) is taken orally twice a day to try to prevent MS relapses and disability. Like every medication, it is not right for everyone.

If you are interested in Tecfidera or any of the MS DMDs (Aubagio, Avonex, Betaseron, Copaxone, Extavia, Gilenya, Novantrone, Rebif, Tysabri), talk to your neurologist.
 
- Dr. Daniel Kantor, MD
  Medical Director
  Neurologique

  info@neurologique.org
  www.neurologique.org

Wednesday, March 20, 2013

Sports related concussion guidelines interview

Dr. Kantor interviews Dr. Giza, the lead author on the new AAN concussion guidelines.

When in doubt, sit them out!



-  Daniel Kantor, MD
   Medical Director
   Neurologique

   President
   Florida Society of Neurology

   Chair
   Subcommittee on Concussion
   Sports Medicine Advisory Committee
   Florida High School Athletics Association

   info@neurologique.org
   www.neurologique.org

Monday, March 18, 2013

New Concussion Guidelines

Sports related concussions are traumatic brain injuries.

Today (03/18/2013), the American Academy of Neurology (AAN) released updated concussion guidelines.

According to the guideline:

• Among the sports in the studies evaluated, risk of concussion is greatest in football and rugby,
followed by hockey and soccer. The risk of concussion for young women and girls is greatest in
soccer and basketball.

• An athlete who has a history of one or more concussions is at greater risk for being diagnosed
with another concussion.

• The first 10 days after a concussion appears to be the period of greatest risk for being diagnosed
with another concussion.

• There is no clear evidence that one type of football helmet can better protect against concussion
over another kind of helmet. Helmets should fit properly and be well maintained.

• Licensed health professionals trained in treating concussion should look for ongoing symptoms
(especially headache and fogginess), history of concussions and younger age in the athlete. Each
of these factors has been linked to a longer recovery after a concussion.

• Risk factors linked to chronic neurobehavioral impairment in professional athletes include prior
concussion, longer exposure to the sport and having the ApoE4 gene.

• Concussion is a clinical diagnosis. Symptom checklists, the Standardized Assessment of
Concussion (SAC), neuropsychological testing (paper-and-pencil and computerized) and the
Balance Error Scoring System may be helpful tools in diagnosing and managing concussions but
should not be used alone for making a diagnosis.


Signs and symptoms of a concussion include:

• Headache and sensitivity to light and sound

• Changes to reaction time, balance and coordination

• Changes in memory, judgment, speech and sleep

• Loss of consciousness or a “blackout” (happens in less than 10 percent of cases)

The guideline states that while an athlete should immediately be removed from play following a
concussion, there is currently insufficient evidence to support absolute rest after concussion. Activities that do not worsen symptoms and do not pose a risk of repeat concussion may be part of concussion management.

The guideline is endorsed by the National Football League Players Association, the American Football Coaches Association, the Child Neurology Society, the National Association of Emergency Medical Service Physicians, the National Association of School Psychologists, the National Athletic Trainers Association and the Neurocritical Care Society.


When in doubt, sit them out!



- Daniel Kantor, MD
  Medical Director
  Neurologique

   President
   Florida Society of Neurology

   Chair
   Subcommittee on Concussion
   Sports Medicine Advisory Committee
   Florida High School Athletics Association

   info@neurologique.org
   www.neurologique.org

Saturday, October 6, 2012

Initiating a low dose class Ia anti-arrhythmic(dextromethorphan/quinidine) in fingolimod-treated patients may be safeand effective: The first case series



ECTRIMS 2012 (Lyon, France)
Poster 529: Thursday, October 11, 2012, 15:30 - 17:00 




Click on poster (below) to download:




Background:
Recent safety concerns regarding the risk for bradyarrhythmia with fingolimod has resulted in U.S. Food and Drug Administration (FDA) changes to the package insert (PI) for the only oral MS disease modifying drug. Previously the PI listed no contraindications, while the 04/2012 version lists treatment with Class Ia anti-arrhythmic drugs among the new contraindications. Fixed dose dextromethorphan/quinidine (DM/Q) is FDA approved for the treatment of pseudobulbar affect (PBA), which is increasingly recognized as a common MS symptom. Quinidine at very low doses (10 mg twice a day) blocks CYP2D6 metabolism of DM, thus allowing this NMDA receptor antagonist and sigma-1 agonist to enter the central nervous system and exert its therapeutic effect. Qunidine causes dose-dependant QTc (corrected Q-T interval) prolongation, but the doses of Q used in the combination treatment for PBA is over 10-fold lower than the doses used for cardiac arrhythmias.

Rationale:
Despite the unlikelihood of any interaction between fingolimod and fixed dose DM/Q for PBA, fingolimod’s PI change, no longer allows concomitant treatment with these medications. Since no patients in the pivotal phase III trials for either medication were treated with the other, the current study is aimed at exploring the experience of a single MS Center with concomitant use of these medications, prior to the PI update in April 2012.

Methods:
Retrospective case series of six MS patients at a single MS Center treated with concomitant fingolimod and fixed dose DM/Q.

Results:
The mean length of time between starting fingolimod and starting DM/Q was 5 months (range: 1 – 8). There were no symptomatic bradycardias during either the first dose administration of fingolimod or subsequent to the initiation of DM/Q. Two weeks after initiation of DM/Q, the median decrease in heart rate and increase in QTc was 7 bpm and 14.5 msec (and QTc was never greater than 427 msec). Aside from improvement in their PBA, the following other improvements were reported with initiation of DM/Q: improved cognition, concentration, energy and initiation/completion of tasks, with reduction in spasticity, fatigue and feeling of being overwhelmed from pain.

Conclusion:
Initiating DM/Q in fingolimod-treated patients may be safe and effective. PBA is a potentially disabling MS symptom and there is a need to clarify whether the recent change to fingolimod’s PI should exclude concomitant treatment with DM/Q. Further controlled safety trials of concomitant fingolimod and DM/Q is needed.

- Dr. Daniel Kantor, MD
  Medical Director
  Neurologique

  info@neurologique.org
  www.neurologique.org