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

 Dextromethorphan Plus Quinidine For Headache Prophylaxis:  The First Case Report

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

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.