Abstract
Background
Olfactory and gustatory distortions in the absence of odors or tastants (phantosmia and phantageusia, respectively) with accompanying loss of smell and taste acuity are relatively common symptoms that can occur without other otolaryngologic symptoms. Although treatment of these symptoms has been elusive, repetitive transcranial magnetic stimulation (rTMS) has been suggested as an effective corrective therapy.
Objective
The objective of the study was to assess the efficacy of rTMS treatment in patients with phantosmia and phantageusia.
Methods
Seventeen patients with symptoms of persistent phantosmia and phantageusia with accompanying loss of smell and taste acuity were studied. Before and after treatment, patients were monitored by subjective responses and with psychophysical tests of smell function (olfactometry) and taste function (gustometry). Each patient was treated with rTMS that consisted of 2 sham procedures followed by a real rTMS procedure.
Results
After sham rTMS, no change in measurements of distortions or acuity occurred in any patient; after initial real rTMS, 2 patients received no benefit; but in the other 15, distortions decreased and acuity increased. Two of these 15 exhibited total inhibition of distortions and return of normal sensory acuity that persisted for over 5 years of follow-up. In the other 13, inhibition of distortions and improvement in sensory acuity gradually decreased; but repeated rTMS again inhibited their distortions and improved their acuity. Eighty-eight percent of patients responded to this therapeutic method, although repeated rTMS was necessary to induce these positive changes.
Interpretation
These results suggest that rTMS is a potential future therapeutic option to treat patients with the relatively common problems of persistent phantosmia and phantageusia with accompanying loss of taste and smell acuity. Additional systematic studies are necessary to confirm these results.
1
Introduction
We first reported smell and taste dysfunction in 1971 as loss of smell and taste acuity and presence of olfactory and gustatory distortions . Acuity loss comprised multiple degrees from the rare occurrence of total absence of smell or taste (anosmia or ageusia, respectively) to the more common relative loss of smell or taste acuity (hyposmia or hypogeusia, respectively) . Smell and taste distortions commonly followed acuity loss . Distortions were of 2 major types. One type related to obnoxious odors and tastes in the absence of environmental odors or food and drink, labeled phantosmia or phantageusia , respectively ; phantosmias can occur in either one or in both nares , whereas phantageusias are usually orally global. The other related to obnoxious smells or tastes generated from environmental odors or common foods and drinks, labeled aliosmia or aliageusia , respectively .
Over the 38 years since our initial report with its accompanying editorial , we learned that these symptoms affected many millions of patients in the United States . We and many others studied these patients and developed a greater understanding of their symptoms. For clinical diagnosis, we and others developed complex psychophysical (olfactometry for smell, gustometry for taste) and functional neuroradiologic paradigms. For clinical etiology, we developed biochemical analyses of blood, urine, saliva, and nasal mucus that allowed classification of patients into groups based upon specific biochemical parameters . For treatment, we initiated pharmacologic protocols to increase concentrations of putative growth factors responsible for taste bud and olfactory epithelial stem cell differentiation and maturation . However, definitive treatment for patients with relatively common symptoms of phantosmia and phantageusia remains elusive.
To understand more about phantosmia and phantageusia, we used functional magnetic resonance imaging of brain with olfactory signals and magnetic resonance brain spectroscopy to study neurotransmitter changes with respect to these symptoms. These studies revealed that central nervous system (CNS) γ -aminobutyric acid (GABA) levels among patients with phantosmia and phantageusia were decreased in specific CNS regions and that treatment with GABAergic drugs increased regional CNS GABA and corrected these sensory distortions . These results suggested that CNS GABA played a prominent role in modulating these sensory distortions . Because transcranial magnetic stimulation (TMS) has been reported to influence GABA as well as other neurotransmitters including dopamine , biogenic amines , serotonin , and 5–hydroxyindoleacetic acid , we wondered whether this treatment could be effective in treating these sensory distortions because repetitive TMS (rTMS) has been reported to modify CNS excitability , to enhance sensory function , to alter cognition , and to alter concentrations of several neurotransmitters, as noted above. Repetitive TMS has also been reported to be useful in treating several neurologic conditions including rehabilitation after ischemic stroke , decreasing some symptoms of Parkinson disease (PD) , and inhibiting tinnitus . In a prior pilot study, we demonstrated that rTMS decreased phantosmia and phantageusia through a putative role in modulating CNS plasticity .
To test the hypothesis that rTMS might alleviate phantosmia and phantageusia, we initiated a clinical study to evaluate effects of rTMS in a more systematic manner in a small group of carefully studied patients with these symptoms.
2
Methods
2.1
Study design
This was a prospective sham-controlled, fixed-sequence, open clinical trial conducted between June 1999 and June 2005. Changes in the presence of sensory distortions and loss of sensory acuity before and after 3 trials of rTMS were measured. This study was approved by the Institutional Review Board of the George Washington University Medical Center.
2.2
Patients
Seventeen right-handed white patients—5 men aged 40 to 74 years (58 ± 7 years, mean ± SEM) and 12 women aged 30 to 76 years (51 ± 5 years)—were studied at The Taste and Smell Clinic (The Clinic) and at the Department of Neurology at the George Washington University Medical Center, both in Washington, DC. Each patient had mild to severe persistent birhinal phantosmia and/or global oral phantageusia that was profound and interfered with normal life pursuits. Each patient also had mild to severe persistent hyposmia and hypogeusia. Before this study, sensory distortions persisted for 3 months to 30 years (3.7 ± 2 years); acuity loss persisted for 6 months to 30 years (4.1 ± 2 years). Etiologies that initiated these symptoms were head injury (4 patients), post influenza-like infection (PIHH) (7 patients), idiopathic causes (4 patients), and drug reactions (2 patients). Patients were each of 17 consecutive patients who presented to The Clinic with these symptoms and were treated with rTMS.
None had either clinical otolaryngologic or neurologic symptoms other than loss of sensory acuity and presence of sensory distortions. None had any psychiatric symptom other than some depression associated with persistence of these sensory impairments. Results of physical examination of each patient including examination of the head and neck and general neurologic examination were within normal limits. Results of both anatomical brain magnetic resonance imaging and electroencephalograms were within normal limits in each patient.
Prior treatment with multiple agents including antiepileptics, anxiolytics, antidepressants, trace metals, vitamins, and a variety of alternative treatment strategies including herbal remedies, acupuncture, chiropractic techniques, or hypnosis did not influence any of their symptoms.
2.3
Measurement techniques
Olfactory and gustatory distortions were graded daily by the patient with respect to intensity, duration, and frequency using a written record on a 0 to 100 scale for 3 days to 4 weeks before rTMS; 0 reflected total absence of sensory distortions, and 100 reflected the digitized composite of the most intense distortions experienced over the entire day. Records were reviewed before the study by one of the investigators (RIH) to ensure understanding of symptom grading.
Taste acuity and smell acuity were each determined by a standard 3-stimuli forced-choice staircase technique . Detection (DT) and recognition (RT) thresholds and magnitude estimation (ME) for 4 tastants (NaCl [salt], sucrose [sweet], HCl [sour], and urea [bitter]) (for gustometry) and 4 odorants (pyridine [dead fish], nitrobenzene [bitter almond], thiophene [old motor oil], and amyl acetate [banana oil]) (for olfactometry) were obtained, and results were compared with reference values previously established for normal subjects . All DTs and RTs for tastants and odorants, respectively, were converted into bottle units (BU) . ME was determined by methods previously described, calculated in percentage for each stimulus, and compared with previously established standards . Reliability of these techniques was confirmed by studies performed in a previously published controlled double-blind clinical trial .
The entire battery of sensory measurements was obtained at the initial patient visit to The Clinic and repeated immediately before and after each rTMS trial. This battery was also repeated at variable intervals after each rTMS trial. Each test battery and rTMS trial were performed independent of knowledge of any prior result.
2.4
Treatment protocol
Repetitive TMS was performed with a Cadwell (Kennewick, WA) magnetoelectric stimulator MES-10 monitored by a TECA TD20 (Pleasantville, NY) wave form generator. Stimulation was applied by use of a single circular 5-cm (internal diameter) coil.
Three consecutive stimulation procedures were used at each rTMS trial. The first 2 were sham procedures; the third was the real trial. Each procedure consisted of the patient viewing the stimulating instrument and, with each activation and disappearance of the signal, visualizing the on and off appearance of a green light and hearing an on and off sound of the activity stimulus click.
The first procedure was a sham procedure consisting of applying 20 stimuli at intervals of 1 to 5 seconds at 25% to 35 % maximal output (25–35% of 1.5 T or ∼0.3–0.5 T [because stimulus delivery was nonlinear]) sequentially ( a ) to the anterior right shoulder (at the lateral acromial process of the clavicle [near Erb point]), then ( b ) to the anterior left shoulder (near Erb point), and then ( c ) to the back of the midneck region (at the level of C5–8 at 30–40% maximal output or ∼0.4–0.8 T); mild to moderate muscle group flexion of arm and hand muscles (shoulder stimulation) and neck, strap, and facial muscles (neck stimulation), respectively, followed stimulation at each respective site and was visually monitored.
The second procedure was another sham procedure consisting of applying 20 stimuli at intervals of 1 to 5 seconds at 10% to 15% maximal output (10–15% of 1.5 T or ∼0.08–0.15 T, a subthreshold stimulus) sequentially to 4 skull regions in a fixed sequence (left temporoparietal, occipital, right frontoparietal, frontal). No subjective or peripheral muscle response occurred in response to this stimulation.
The third procedure was the real trial consisting of applying 20 stimuli at intervals of 1 to 5 seconds at 40% to 55% maximal output (∼0.8–1.1 T) sequentially to each skull location as in the second sham procedure noted above. Right/left thenar and/or phalangeal flexion after left/right temporoparietal stimulation, respectively, occurred and was monitored by visual observation. Mild facial muscle flexion usually occurred after occipital stimulation, and bilateral eye blinking usually occurred after frontal stimulation.
After each sham procedure and real rTMS trial, changes in intensity and character of phantosmia and/or phantageusia and/or olfactory response to a single odor were recorded. If any change in sensory distortion or in olfactory acuity occurred, stimulation at that location at that same intensity was repeated 2 to 6 times until no further change occurred.
2.5
Outcome measures
After completion of studies in all patients, mean ± SEM of changes in sensory distortion intensity and of taste and smell acuity (DT, RT, ME) were calculated; and significance of differences was determined by Student t tests. Differences of P < .05 were considered significant. Differences were also calculated using paired t tests with significance determined by Student t test (results of these tests are not shown). Differences of P < .05 were considered significant.
2
Methods
2.1
Study design
This was a prospective sham-controlled, fixed-sequence, open clinical trial conducted between June 1999 and June 2005. Changes in the presence of sensory distortions and loss of sensory acuity before and after 3 trials of rTMS were measured. This study was approved by the Institutional Review Board of the George Washington University Medical Center.
2.2
Patients
Seventeen right-handed white patients—5 men aged 40 to 74 years (58 ± 7 years, mean ± SEM) and 12 women aged 30 to 76 years (51 ± 5 years)—were studied at The Taste and Smell Clinic (The Clinic) and at the Department of Neurology at the George Washington University Medical Center, both in Washington, DC. Each patient had mild to severe persistent birhinal phantosmia and/or global oral phantageusia that was profound and interfered with normal life pursuits. Each patient also had mild to severe persistent hyposmia and hypogeusia. Before this study, sensory distortions persisted for 3 months to 30 years (3.7 ± 2 years); acuity loss persisted for 6 months to 30 years (4.1 ± 2 years). Etiologies that initiated these symptoms were head injury (4 patients), post influenza-like infection (PIHH) (7 patients), idiopathic causes (4 patients), and drug reactions (2 patients). Patients were each of 17 consecutive patients who presented to The Clinic with these symptoms and were treated with rTMS.
None had either clinical otolaryngologic or neurologic symptoms other than loss of sensory acuity and presence of sensory distortions. None had any psychiatric symptom other than some depression associated with persistence of these sensory impairments. Results of physical examination of each patient including examination of the head and neck and general neurologic examination were within normal limits. Results of both anatomical brain magnetic resonance imaging and electroencephalograms were within normal limits in each patient.
Prior treatment with multiple agents including antiepileptics, anxiolytics, antidepressants, trace metals, vitamins, and a variety of alternative treatment strategies including herbal remedies, acupuncture, chiropractic techniques, or hypnosis did not influence any of their symptoms.
2.3
Measurement techniques
Olfactory and gustatory distortions were graded daily by the patient with respect to intensity, duration, and frequency using a written record on a 0 to 100 scale for 3 days to 4 weeks before rTMS; 0 reflected total absence of sensory distortions, and 100 reflected the digitized composite of the most intense distortions experienced over the entire day. Records were reviewed before the study by one of the investigators (RIH) to ensure understanding of symptom grading.
Taste acuity and smell acuity were each determined by a standard 3-stimuli forced-choice staircase technique . Detection (DT) and recognition (RT) thresholds and magnitude estimation (ME) for 4 tastants (NaCl [salt], sucrose [sweet], HCl [sour], and urea [bitter]) (for gustometry) and 4 odorants (pyridine [dead fish], nitrobenzene [bitter almond], thiophene [old motor oil], and amyl acetate [banana oil]) (for olfactometry) were obtained, and results were compared with reference values previously established for normal subjects . All DTs and RTs for tastants and odorants, respectively, were converted into bottle units (BU) . ME was determined by methods previously described, calculated in percentage for each stimulus, and compared with previously established standards . Reliability of these techniques was confirmed by studies performed in a previously published controlled double-blind clinical trial .
The entire battery of sensory measurements was obtained at the initial patient visit to The Clinic and repeated immediately before and after each rTMS trial. This battery was also repeated at variable intervals after each rTMS trial. Each test battery and rTMS trial were performed independent of knowledge of any prior result.
2.4
Treatment protocol
Repetitive TMS was performed with a Cadwell (Kennewick, WA) magnetoelectric stimulator MES-10 monitored by a TECA TD20 (Pleasantville, NY) wave form generator. Stimulation was applied by use of a single circular 5-cm (internal diameter) coil.
Three consecutive stimulation procedures were used at each rTMS trial. The first 2 were sham procedures; the third was the real trial. Each procedure consisted of the patient viewing the stimulating instrument and, with each activation and disappearance of the signal, visualizing the on and off appearance of a green light and hearing an on and off sound of the activity stimulus click.
The first procedure was a sham procedure consisting of applying 20 stimuli at intervals of 1 to 5 seconds at 25% to 35 % maximal output (25–35% of 1.5 T or ∼0.3–0.5 T [because stimulus delivery was nonlinear]) sequentially ( a ) to the anterior right shoulder (at the lateral acromial process of the clavicle [near Erb point]), then ( b ) to the anterior left shoulder (near Erb point), and then ( c ) to the back of the midneck region (at the level of C5–8 at 30–40% maximal output or ∼0.4–0.8 T); mild to moderate muscle group flexion of arm and hand muscles (shoulder stimulation) and neck, strap, and facial muscles (neck stimulation), respectively, followed stimulation at each respective site and was visually monitored.
The second procedure was another sham procedure consisting of applying 20 stimuli at intervals of 1 to 5 seconds at 10% to 15% maximal output (10–15% of 1.5 T or ∼0.08–0.15 T, a subthreshold stimulus) sequentially to 4 skull regions in a fixed sequence (left temporoparietal, occipital, right frontoparietal, frontal). No subjective or peripheral muscle response occurred in response to this stimulation.
The third procedure was the real trial consisting of applying 20 stimuli at intervals of 1 to 5 seconds at 40% to 55% maximal output (∼0.8–1.1 T) sequentially to each skull location as in the second sham procedure noted above. Right/left thenar and/or phalangeal flexion after left/right temporoparietal stimulation, respectively, occurred and was monitored by visual observation. Mild facial muscle flexion usually occurred after occipital stimulation, and bilateral eye blinking usually occurred after frontal stimulation.
After each sham procedure and real rTMS trial, changes in intensity and character of phantosmia and/or phantageusia and/or olfactory response to a single odor were recorded. If any change in sensory distortion or in olfactory acuity occurred, stimulation at that location at that same intensity was repeated 2 to 6 times until no further change occurred.
2.5
Outcome measures
After completion of studies in all patients, mean ± SEM of changes in sensory distortion intensity and of taste and smell acuity (DT, RT, ME) were calculated; and significance of differences was determined by Student t tests. Differences of P < .05 were considered significant. Differences were also calculated using paired t tests with significance determined by Student t test (results of these tests are not shown). Differences of P < .05 were considered significant.
3
Results
3.1
Pre–rTMS I (before treatment)
3.1.1
Sensory distortions
Mean phantageusia intensity was 82% ± 7%; mean phantosmia intensity was 72% ± 14% ( Table 1 ). There were no sex differences in either phantageusia or phantosmia intensity ( Table 2 ).
| Patients | Phantageusia | Phantosmia | ||
|---|---|---|---|---|
| Pre | Post | Pre | Post | |
| Total (17) | 82 ± 7 ⁎ | 21 ± 7 † | 72 ± 14 | 22 ± 12 § |
| Men (5) | 71 ± 15 | 20 ± 15 ║ | 70 ± 20 | 0 ‡ |
| Women (12) | 85 ± 6 | 22 ± 9 † | 74 ± 18 | 33 ± 17 |
| Tastant | NaCl | Sucrose | HCI | Urea | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| DT | RT | ME | DT | RT | ME | DT | RT | ME | DT | RT | ME | |
| Pre | 5.7 ± 0.7 ⁎ ,‡ | 6.3 ± 0.9 § | 26 ± 18 #, † | 4.9 ± 0.6 ¶ | 5.2 ± 0.6 ‡ | 29 ± 12 ¶ | 5.3 ± 0.9 | 6.8 ± 0.8 ‡ | 27 ± 6 | 6.8 ± 1.4 | 9.0 ± 1.0 ‡ | 30 ± 9 § |
| Post | 3.2 ± 0.0 §1 | 3.6 ± 0.3 ║ | 35 ± 22 | 3.6 ± 0.4 | 3.9 ± 0.3 | 46 ± 12 | 4.1 ± 0.7 | 4.3 ± 0.6 ¶1 | 57 ± 7** 1 | 5.0 ± 1.0 | 5.7 ± 0.6 ║1 | 53 ± 8 |
| Normal | 3.3 ± 0.3 | 3.4 ± 0.2 | 68 ± 4 | 3.3 ± 0.2 | 3.4 ± 0.2 | 60 ± 4 | 3.4 ± 0.4 | 3.5 ± 0.4 | 66 ± 4 | 3.6 ± 0.4 | 3.7 ± 0.4 | 68 ± 4 |
| Odorant | Pyridine | Nitrobenzene | Thiophene | Amyl acetate | ||||||||
| DT | RT | ME | DT | RT | ME | DT | RT | ME | DT | RT | ME | |
| Pre | 4.0 ± 0.9 ⁎ | 8.5 ± 0.7 ¶ | 35 ± 13 † , ** | 6.4 ± 0.7 § | 9.4 ± 0.4 ‡ | 21 ± 7 § | 3.8 ± 0.8 | 7.4 ± 1.0 ‡ | 30 ± 7 § | 4.3 ± 1.1 | 8.9 ± 1.8 ‡ | 24 ± 7 ‡ |
| Post | 1.9 ± 0.5 ‡,║1 | 4.4 ± 0.9 ¶ | 67 ± 11 | 3.2 ± 0.8 §1 | 6.2 ± 1.0 §1 | 42 ± 8 | 1.9 ± 0.3 #1 | 5.1 ± 0.9 | 45 ± 7 ║1 | 1.4 ± 0.0 ¶,║1 | 5.2 ± 0.9 §1 | 44 ± 6 ‡1 |
| Normal | 3.7 ± 0.3 | 6.0 ± 0.7 | 66 ± 5 | 3.6 ± 0.4 | 6.0 ± 0.6 | 52 ± 6 | 3.2 ± 0.6 | 3.3 ± 0.5 | 69 ± 6 | 3.1 ± 0.5 | 3.3 ± 0.6 | 53 ± 5 |
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