Evaluation of the efficacy of caffeine cessation, nortriptyline, and topiramate therapy in vestibular migraine and complex dizziness of unknown etiology☆

Evaluation of the efficacy of caffeine cessation, nortriptyline, and topiramate therapy in vestibular migraine and complex dizziness of unknown etiology☆

Anthony A. Mikulec MDa, b, Corresponding Author Contact Information, E-mail The Corresponding Author, Farhoud Faraji BAa, Laurence J. Kinsella MDa, c
a Saint Louis University School of Medicine, St. Louis, MO, USA
b Department of Otolaryngology, Saint Louis University School of Medicine, St. Louis, MO, USA
c Department of Neurology, Saint Louis University School of Medicine, St. Louis, MO, USA

Received 31 January 2011; Available online 24 June 2011.
Abstract
Objective

The aim of this study was to evaluate the efficacy of a therapeutic pathway for vestibular migraine (VM) and complex dizziness of undetermined etiology (CDUE) with caffeine cessation and pharmacotherapy.
Study Design

This study is a retrospective chart review.
Intervention(s)

Patients were recommended to stop intake of caffeine and other putative migraine-triggering agents. Pharmacotherapy was initiated with nortriptyline or topiramate if symptoms persisted despite diet modification.
Main Outcome Measure

Self-reported dizziness is the main outcome measure.
Results

Vestibular migraine and CDUE were considered contributing factors to dizziness in 34 and 10, respectively, of 156 patients. Fourteen percent of patients reported improvement in symptoms upon caffeine cessation, whereas 46% of patients reported a reduction in dizziness after nortriptyline therapy (P = .007). Topiramate reduced symptoms in 25% of patients. In total, 75% of VM patients and 56% of patients with CDUE received sufficient benefit from this therapeutic pathway to not progress to other treatments.
Conclusions

Vestibular migraine and CDUE can be treated effectively with a therapeutic pathway consisting of caffeine cessation followed by pharmacotherapy.
Article Outline

1. Introduction
2. Materials and methods
3. Results and analysis
4. Discussion
5. Conclusion
References

1. Introduction

A portion of patients presenting to dizziness clinics have symptoms that may be attributed to vestibular migraine (VM). Vestibular migraine, also known as migrainous vertigo and migraine-associated dizziness, is a migraine variant for which specific diagnostic criteria have been proposed [1]. However, VM has not been officially recognized by the International Headache Society as a migraine variant [2]. As a result, this lack of recognition may act as a contributing factor to a subset of patients with dizziness escaping categorization despite a thorough evaluation. In our practice, we describe another subset of patients as having “complex dizziness of unknown etiology” (CDUE)—those patients who do not have an underlying cause for their dizziness identified despite evaluation by both a neuro-otologist and neurologist specializing in dizziness. We have chosen to initially treat patients with CDUE equivalently to those with VM under the rationale that, because migraine is relatively common and VM is ill defined, it is possible that patients with CDUE may have a migraine variant as a cause of their dizziness.

Various treatments, including diet therapy, have been reported for VM [3]. Some patients with migraine, be it VM or other variants, appear to have dietary or environmental triggers, and avoiding such triggers can result in relief of symptoms. Both the use of caffeine and caffeine withdrawal have been suggested to be triggers of migraine for some patients, yet caffeine is a component of over-the-counter migraine medications and has also been used in clinical trials as a therapy against migraines [4], [5], [6], [7], [8] and [9]. In an effort to resolve the ambiguity currently in the literature regarding the role of caffeine in migraine and to identify an effective method to treat patients with VM and CDUE, the authors retrospectively reviewed the records of patients presenting to the clinic with the primary complaint of dizziness to evaluate the efficacy of a therapeutic pathway to VM and CDUE with long-term caffeine cessation as a first step and pharmacotherapy with nortriptyline or topiramate as the second step.
2. Materials and methods

In this retrospective study, the records of 156 consecutive patients seen at a tertiary combined dizziness clinic by a neurologist and a neurotologist from 2005 to 2009 were reviewed. The records of patients who had reported caffeine intake and caffeine cessation, had undergone treatment with topiramate or nortriptyline, or had been diagnosed with VM or CDUE were selected and examined in detail. All patients diagnosed with CDUE had undergone thorough evaluation, including assessment for vestibular, neurologic, autonomic, and cardiac dysfunction as an underlying cause of dizziness.

This study was initiated with the purpose of assessing the prevalence of VM and the average quantity of caffeine consumption in our combined dizziness clinic, as well as to evaluate the efficacy of caffeine cessation, treatment with nortriptyline, and treatment with topiramate in patients with VM and CDUE. The caffeine concentrations used in this study were acquired either from company Web sites or by direct inquiry from the company and rounded to the nearest multiple of 5. The values for these calculations are listed in Table 1.
Table 1. Caffeine standards
Beverage Volume (oz) Caffeine (mg)
Generic brewed coffee 12 200
Decaffeinated generic coffee 12 15
Diet Coca Cola 12 50
Coca Cola Classic 12 35
Pepsi and Diet Pepsi 12 40
Dr Pepper and Diet Dr Pepper 12 40
Mountain Dew 12 55
Tea, brewed 12 75
Decaffeinated tea Negligible
Summary of the standard concentrations used to calculate patient daily caffeine intake.

Pharmacotherapy was initiated if patients continued to complain of dizziness symptoms after 4 to 6 weeks of caffeine cessation and diet modification. Nortriptyline was prescribed in an escalating fashion, starting with a dose of 25 mg nightly for 2 weeks, then escalating to 50 mg nightly for 2 weeks, and then finally escalating to 75 mg nightly. Patients were recommended to maintain the lower dose of 25 or 50 mg if they received sufficient benefit at that dose. Topiramate therapy was initiated at 25 mg twice daily and occasionally increased to 50 mg twice daily based on patient tolerance and preference. Drug selection was based on cost, side-effect profile, interactions with other patient medications, and familiarity of the prescribing physician with the medication. The Saint Louis University Institutional Review Board approved this study.

Statistical analysis was conducted using a 2-tailed Fisher exact test with the GraphPad QuickCalc online statistical tool: http://www.graphpad.com/quickcalcs/contingency1.cfm (accessed November 2010).
3. Results and analysis

Of the 156 charts reviewed, a total of 57 patients were suspected of VM, had reported caffeine intake and cessation results, or had been treated with topiramate or nortriptyline. This group ranged in age from 22 to 85 years, with a median age of 45 years, and was composed of 23% men and 77% women. For further analysis, the group was divided into patients with definite or probable VM and those with complex dizziness of unclear etiology (CDUE).

Based on vestibular testing and patient history, VM was considered a contributing factor to dizziness in 41 patients. The median age of the VM group was 44 years, ranged from 22 to 68 years, and was composed of 22% men and 78% women. These patients met the Neuhauser criteria for probable VM as described in Table 2[1]. Thus, probable VM had a prevalence of 26% at our tertiary dizziness clinic. The retrospective nature of this study precluded the authors to diagnose definite VM with certainty.
Table 2. Diagnostic criteria for definite and probable VM
Definite VM
• Episodic vestibular symptoms of at least moderate severity
• Current or previous history of migraine according to the 2004 criteria of the International Headache Society (IHS)
• One of the following migrainous symptoms during 2 or more attacks of vertigo: migrainous headache, photophobia, phonophobia, visual aura, or other aura
• Other causes ruled out by appropriate investigations
Probable VM
• Episodic vestibular symptoms of at least moderate severity
• One of the following:
(1) current or previous history of migraine according to the 2004 criteria of the HIS;
(2) migrainous symptoms during vestibular symptoms;
(3) migraine precipitants of vertigo in more than 50% of attacks: food triggers, sleep irregularities, or hormonal change; or
(4) response to migraine medications in more than 50% of attacks
• Other causes ruled out by appropriate investigations
Comment: Vestibular symptoms are rotational vertigo or another illusory self- or object motion. They may be spontaneous or positional. Vestibular symptoms are “moderate” if they interfere with but do not prohibit daily activities and “severe” if patients cannot continue daily activities.Adapted from Neuhauser and Lempert [1].

Sixteen patients were diagnosed with CDUE. Patients included in the CDUE group presented with an amalgamation of poorly defined symptoms defying easy categorization. Some patients reported symptoms consistent with episodic vertigo, some reported symptoms of disequilibrium without vertigo, others reported more vague sensations such fogginess or instability, and yet others reported a combination of the aforementioned symptoms. The age range in this group was 25 to 85 years, with median age of 58 years. The CDUE group was composed of 31% men and 69% women. Fig. 1 and Fig. 2 outline the therapeutic pathway used to treat patients with VM and CDUE, respectively.

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Fig. 1.

This decision tree illustrates the therapeutic pathway for patients in the vestibular migraine group.


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Fig. 2.

This decision tree illustrates the therapeutic pathway for patients in the complex dizziness of unclear etiology group.

Of the 57 patients, 34 in the VM group and 10 in the CDUE group had caffeine intake records specific enough to quantify by estimation. The mean caffeine intake for all patients was 320 ± 270 mg/day and ranged from 40 to 1200 mg/day. Caffeine intake in the VM group ranged from 50 to 850 mg/day, with a mean intake of 275 ± 215 mg/day. The CDUE group had caffeine intake in the range of 40 to 1200 mg/day, with a mean intake of 440 ± 360 mg/day. Vestibular migraine and CDUE groups did not differ significantly in caffeine intake. Data on patient age, sex, and caffeine intake are stratified into VM and CDUE groups and summarized in Table 3.
Table 3. Summary of patient age, sex, and caffeine intake
Age (y), median (range) Sex (M:F) Caffeine intake (mg/d), mean (range)
Overall 45 (22–85) 23:77 320 (40–1200)
VM 44 (22–68) 22:78 275 (50–850)
CDUE 58 (25–85) 31:69 440 (40–1200)

Cessation effective 40 (33–68) 17:83 200 (50–300)
The row entitled “Cessation effective” specifies the characteristics of patients who reported at least a partial reduction in dizziness symptoms after caffeine cessation and diet modification.

All patients who reported caffeine intake and consumption of other putative migraine precipitants—including aged cheeses and monosodium glutamate—were recommended to completely discontinue all intake of migraine precipitants, especially caffeine. Overall, 14% of patients reported any reduction in symptoms of dizziness or headache upon caffeine cessation. In the VM group, 5 (15%) of the 34 patients who had caffeine intake on record reported any benefit from caffeine cessation. In the CDUE group, 1 patient (10%) reported a reduction in symptoms upon caffeine cessation (Table 4). No significant difference was noted between the efficacy of caffeine cessation between VM and CDUE groups. The caffeine intake in the 6 patients who improved upon caffeine cessation ranged from 50 to 300 mg/day, with an average of 200 ± 85 mg/day. It should be noted that most patients who reported a benefit from caffeine cessation did not find caffeine cessation alone as sufficient relief from dizziness symptoms. In fact, only 1 patient received sufficient relief from caffeine cessation and diet modification to decline pharmacologic intervention. Because this patient was part of the CDUE group, the progression-free benefit rate of caffeine cessation is 10% in the CDUE group and 2.3% overall in this study. Most patients who attempted caffeine cessation and dietary modification went on to be prescribed either nortriptyline or topiramate. Dosage regimens for both drugs are detailed in “Materials and methods.”
Table 4. Efficacy of caffeine cessation, nortriptyline therapy, and topiramate therapy
Caffeine cessation Total (n = 44) VM (n = 32) CDUE (n = 10)
Effective 6 (14%) 5 (15%) 1 (10%)
Not effective 38 (86%) 29 (85%) 9 (90%)

Nortriptyline Total (n = 24) VM (n = 17) CDUE (n = 7)
Effective 11 (46%) 8 (47%) 3 (43%)
Not effective 13 (54%) 9 (53%) 4 (57%)

Nortriptyline in caffeine cessation nonresponders Total (n = 21) VM (n = 14) CDUE (n = 7)
Effective 11 (52%) 8 (57%) 3 (43%)
Not effective 10 (48%) 6 (43%) 4 (57%)

Topiramate VM (n = 16)
Effective 4 (25%)
Not effective 12 (75%)

Topiramate in caffeine cessation nonresponders VM (n = 6)
Effective 1 (17%)
Not effective 5 (83%)
Summary of patients who reported results of caffeine cessation, nortriptyline, and/or topiramate therapy. Results have been reported for all patients (total), the VM group (VM), and the complex dizziness of unclear etiology group (CDUE). For patients who underwent pharmacotherapy with either agent, results of the efficacy of pharmacotherapy are reported for all patients and for those who reported no benefit from caffeine cessation. Only patients in the VM group were treated with topiramate.

Nortriptyline was prescribed to a total of 30 VM and CDUE patients with the primary intention of alleviating dizziness symptoms. The patients whose response to treatment could not be found in their records are summarized as “Unknown Result” and are not included in the efficacy analysis. Six such patients were treated with nortriptyline; thus, only 24 patients were included in the analysis. Eleven (46%) patients reported a reduction in dizziness after therapy with nortriptyline, which was a statistically significant difference relative to caffeine cessation and diet modification (P = .007). Fig. 3 compares the efficacy of caffeine cessation, nortriptyline therapy, and pharmacotherapy with either nortriptyline or topiramate. Nortriptyline improved the symptoms of 8 (47%) patients in the VM group and 3 (43%) patients in the CDUE group (Table 4).

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Fig. 3.

The efficacy of caffeine cessation vs pharmacotherapy. The pharmacotherapy columns represent combined nortriptyline or topiramate efficacy results. Combined data from VM and CDUE groups are shown.

Included in the 13 (54%) patients who received no benefit from nortriptyline therapy are 2 patients who were unable to tolerate the adverse effects and thus discontinued nortriptyline (Table 5). One patient showed a temporary reduction of symptoms but subsequently developed refractoriness to the drug. Nortriptyline worsened the symptoms of 1 patient, was not tolerated by 2 patients, and became refractory in 1 patient. For the purposes of the analysis, nortriptyline was deemed not effective in all of these patients.
Table 5. Comparison of tolerability and the development of refractoriness of nortriptyline and topiramate
Unable to tolerate Developed refractoriness to effects
Nortriptyline 2/24 (8%) 1/24 (4%)
Topiramate 1/16 (6%) 3/16 (19%)

Nortriptyline was administered to 21 patients who did not respond to caffeine cessation. It reduced dizziness in 11 (52%) of these patients (Table 4).

Topiramate was administered to 16 patients, all of whom were diagnosed with probable VM. It proved effective in reducing dizziness and headache in 4 (25%) patients (Table 4). One (6%) patient discontinued topiramate due to the adverse effects, 3 (19%) patients developed refractoriness to the drug, and 1 patient whose symptoms were improved by discontinuing topiramate were all included in the not effective group. Table 5 depicts a comparison of the tolerability and development of refractoriness of nortriptyline and topiramate. Because patients only in the VM group were treated with topiramate, Fig. 4 compares the efficacy of topiramate, nortriptyline, and caffeine cessation therapy in VM patients. The difference between the efficacy of topiramate and that of caffeine cessation was not statistically significant.

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Fig. 4.

Caffeine cessation vs topiramate vs nortriptyline in patients with VM.

Six patients who did not respond to caffeine cessation were administered topiramate. Topiramate was effective in 1 (17%) patient. Topiramate was ineffective in 1 patient and was refractory in 2 patients, and 2 patients discontinued use because of their inability to tolerate the adverse effects, all of whom were counted in the not effective group (Table 4). As shown in Fig. 5, the difference between the efficacies of nortriptyline therapy vs topiramate therapy in caffeine cessation nonresponders was not statistically significant.

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Fig. 5.

Topiramate vs nortriptyline in caffeine cessation nonresponders.

Overall, 75% (12/16) of the patients with VM and 56% (5/9) of the patients with CDUE who completed the therapeutic pathway received sufficient benefit from it to not progress on to other treatments.
4. Discussion

Various treatments for VM have been described including physical therapy [10], diet therapy [3] and [11], and prophylactic pharmacologic therapies [12] and [13]. The drug of choice for VM has not been standardized, with selection of medication, as in this study, often determined by physician familiarity and preference. Generally, the pharmacologic treatment of VM involves trial and error of various medications. In this retrospective study, we evaluated the efficacy of a therapeutic pathway for the treatment of VM and CDUE wherein the first step for patients who reported caffeine intake, as assessed by questionnaire, was discontinuation of caffeine. Patients without a significant caffeine intake and those who failed caffeine cessation were then treated with prophylactic pharmacologic therapy with either nortriptyline or topiramate. The choice between the 2 drugs was not based on the patient's symptom complex, but rather on ancillary characteristics such as cost, side-effect profile, interactions with other patient medications, and familiarity of the prescribing physician with the medication (A.A.M. being more familiar with nortriptyline and L.J.K. being more familiar with topiramate). Overall, 75% (12/16) of the patients with VM and 56% (5/9) of the patients with CDUE who completed the pathway received sufficient benefit from it to not progress on to other treatments.

In this study, 14% of patients received at least some reduction in dizziness symptoms with caffeine cessation and diet modification alone. However, many of these patients did not find caffeine cessation and diet modification alone as sufficient relief from their dizziness symptoms. The approximate amount of caffeine present in various beverages is shown in Table 1. It should be noted that those who responded to caffeine cessation tended to have moderate, rather than extreme, caffeine intakes, suggesting that physicians could reasonably recommend caffeine cessation for these patients and not only for those who have very high caffeine intake.

The success of diet therapy for VM has been previously reported [3]. Although we recommended avoidance of many known dietary triggers of migraine, our study focused, in particular, on caffeine cessation under the rationale that expecting Americans to transition abruptly to a completely migraine friendly diet free of MSG, preservatives, and all other migraine triggers was unrealistic. Not all patients were treated with caffeine cessation because they already exhibited little or no caffeine intake. Although only a low percentage of patients responded to caffeine cessation, we feel that caffeine cessation and diet modification should be the first step in treatment of patients with VM or CDUE. It remains unclear what level of caffeine intake, if any, is acceptable for patients with VM. The allowable amount may well be none.

Nortriptyline has been previously described in the treatment of VM [13]. Adverse effects of nortriptyline include somnolence, which is why the medication was prescribed to be taken at night. Care must also be taken when prescribing this medication to women of childbearing age because both nortriptyline and topiramate are listed category C agents in pregnancy [14]. Other common adverse effects included weight gain and sexual dysfunction [15]. In this study, the success rate of treating VM with nortriptyline as initial or secondary pharmacologic management was 46%, a statistically significant improvement in symptoms relative to caffeine cessation and diet modification.

Topiramate has also been used in the treatment of VM alone [11], in children [16] and in combination with amitriptyline, an analog of nortriptyline, in the treatment of migraine in general [17], [18] and [19]. Topiramate has shown to be efficacious for general migraine prophylaxis [19] and [20]. In this study, the success rate of treating patients with VM with topiramate, either as initial pharmacologic therapy or after nortriptyline failure, was 25%.

Few studies of CDUE exist because this is, by definition, a cryptic category. Some patients with CDUE may experience a yet undescribed underlying cause of dizziness. Given the known heterogeneity of migraine presentation and the high prevalence of migraine, it is reasonable to deduce that some patients who do not fit the criteria of probable or definite VM as defined by Lempert and Neuhauser [21] may, in fact, have migraine. The fact that patients with CDUE were less likely than patients with VM to respond to caffeine cessation or treatment with nortriptyline or topiramate suggests that patients with CDUE are either less likely to have migraine as an underlying pathology or have a variant of migraine that is less responsive to these 2 medications than VM. We have included the category of CDUE in this study to demonstrate that it can, in some cases, be successfully treated with antimigraine medications.

Limitations of this study include its retrospective nature, lack of randomization, and relatively small number of patients. Nonetheless, despite the relatively small sample size, statistical significance was achieved in some analyses, and other analyses may approach significance in larger patient populations, supporting the pursuit of larger scale, prospective, controlled, randomized clinical trials to validate this therapeutic pathway. Like all studies regarding VM, ours suffers from the lack of a firm and accepted definition of the entity in question. Because the choice of initial pharmacologic prophylactic therapy is, as in this study, often somewhat arbitrary, and clear data regarding efficacy are lacking, prospective randomized trials comparing various medications would be of great value to the field. We feel that nortriptyline and topiramate represent 2 medications worthy of further analysis in the treatment of VM.
5. Conclusion

Vestibular migraine and CDUE can be treated with a therapeutic pathway, with caffeine cessation being a reasonable first step. The ideal pharmacologic intervention for VM remains to be determined. Patients with dizziness of unknown cause may reasonably be treated with the same medications used for VM.
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☆Declarations: 1. Each of the authors has contributed to read and approved this manuscript. 2. None of the authors has any conflict of interest, financial or otherwise. 3. This manuscript, or any part of it, has not been previously published; nor is it under consideration for publication elsewhere. In consideration of the American Journal of Otalaryngology's reviewing and editing my submission, “Evaluation of the Efficacy of Caffeine Cessation, Nortriptyline, and Topiramate in the Treatment of Vestibular Migraine and Complex Dizziness of Unknown Etiology,” the authors undersigned transfers, assigns, and otherwise conveys all copyright ownership to Elsevier Inc. In the event that such work is published in the American Journal of Otolaryngology.


Corresponding Author Contact InformationCorresponding author. 3635 Vista Avenue, 6FDT, St. Louis, MO 63110, USA.

Fuente: American Journal of Otolaryngology
Volume 33, Issue 1, January-February 2012, Pages 121-127