Estimates of numbers of people with taste and/or smell dysfunction in the United States vary widely from as few as 2 million to as many as 21 million . These patients have 2 major sets of symptoms associated with this unseen epidemic. The first is sensory acuity loss commonly followed by sensory distortions. These latter symptoms occur in 50%–60% of patients who experience sensory loss . There are many etiologies which initiate these symptom sets, and although several therapies have been attempted to correct them , none has achieved universal clinical acceptance. However, multiple biochemical abnormalities initiated these symptoms and those involving cyclic nucleotides , trace metals , and hormones have been well characterized, and their treatment has been defined.

Sensory acuity loss is due mainly to sensory receptor abnormalities related to failure of growth factor secretion in saliva and nasal mucus to stimulate gustatory and olfactory epithelial stem cells , respectively. This failure leads to subsequent development lack of the elegant repertoire of cells necessary to receive and initially process gustatory and olfactory information.

Sensory distortions usually occur days, weeks, or months after sensory acuity loss. Sensory distortions are caused by decreased brain neurotransmitter secretion which normally inhibits unwanted incoming sensory signals . These distortions have been ascribed to changes in brain neuroplasticity caused by loss of significant sensory inputs such as occurs after limb amputation with pain initiation in the imagined amputated limb or what is termed phantom limb syndrome .

In our clinical program, patients presented with both sensory acuity loss and specific sensory distortions , phantageusia (distorted taste in the mouth without any oral stimulus), and/or phantosmia (distorted smell in the nose without any external odor). Some patients only complained of sensory distortions and neglected to mention their initial sensory loss. Others complained only of sensory loss, and physicians may be misled by these patients because, without mentioning their sensory distortions, physicians may be required to probe clinical history to obtain this information.

After quantitation of smell or taste loss by use of specific, comprehensive psychophysical techniques , we quantitated degree of sensory distortions subjectively and by use of functional magnetic resonance brain imaging (fMRI) . Using fMRI patients with these sensory distortions exhibited extremely robust brain activation when focused on their distortions . By use of magnetic resonance brain spectroscopy (MRS), despite this intense activation, patients exhibited significant diminution of brain gamma-aminobutyric acid (GABA) , a major brain inhibitory neurotransmitter. This decrease is consistent with inability to inhibit unwanted sensory signals that otherwise would not be appreciated. Treatment with GABAergic drugs both inhibited the intense brain activation (by use of fMRI) and increased brain GABA (by use of MRS) .

Repetitive transcranial magnetic stimulation (rTMS) is a safe, painless, noninvasive method to deliver a brief pulse of current through the skull to the brain, thereby altering the biochemistry and firing patterns of neurons in the brain cortex 1.5–2.0 cm beneath the scalp. It has been in use since 1985 , can enhance neuroplasticity , can induce and modulate gene activity , can increase levels of several neurotransmitters including GABA , and can affect formation of proteins important for cellular signaling . It is applied externally and does not require anesthesia or electrode implantation. It has been used successfully to inhibit various types of somatic pain , reduce auditory hallucinations , inhibit tinnitus , and inhibit many symptoms associated with several neurological disorders . It was approved by the Food and Drug Administration in October 2008 for treatment of depression.

The critique by Doty et al. about our work seems displaced because this group has limited experience with use of rTMS in clinical practice. Although their criticism of “blinding” or placebo effects in our study may have some merit we have been concerned about this issue and have been extremely careful to deal with it. Indeed, if changes in phantageusia and/or phantosmia were the only responses elicited in our study , then the issue of “blinding” could be a major problem due to their subjective nature. To obviate this problem, we employed two sham series of stimuli prior to use of “actual” stimuli. Limited familiarity with rTMS may cause underestimation of the robust character of our sham stimulation. Each of the sham stimuli elicited a loud click and the flashing of a bright green light. Application of 0.8-T stimuli in the first set of 20 sham stimuli elicited significant movement of left and right arms, respectively, and significant flexion of the neck. No patient responded with any change in phantageusia and/or phantosmia to either sham series. However, there was a characteristic response of patients to “actual stimuli” with decreases in phantageusia and/or phantosmia only after stimulation at 1 of 4 skull locations. In patients who “escaped” from initial rTMS repetition of the 2 sham procedures was again unsuccessful in initiating any change in phantageusia and/or phantosmia but use of the actual stimuli was again successful in inhibiting these distortions but only after stimulation at the initially successful rTMS site. However, not only did inhibition of phantageusia and/or phantosmia occur after actual rTMS but there was also significant improvement in each of 3 major parameters of smell function as measured by specific, comprehensive psychophysical techniques . Furthermore, there were significant biochemical changes, performed in a blinded manner, with each rTMS procedure in these patients in which serum carbonic anhydrase I and II and serum zinc and copper increased as did salivary carbonic anhydrase VI and saliva zinc and copper. Increases in these neurotransmitters were previously published and published in detail in March 2010 with results available online since December 2009. Others have previously demonstrated that brain GABA increased in animals after rTMS . We have also demonstrated both decreased phantom induced brain activation with associated increased brain GABA by use of MRS in patients reported in this study . These previously reported brain, biochemical, and sensory changes associated mainly with use of rTMS make the “major problem with this study” as raised by the reviewers moot.

We chose to use rTMS to treat patients with phantageusia and phantosmia based upon these prior observations . Some patients responded to this treatment with total inhibition of sensory distortions within minutes after rTMS . Some required days to weeks to respond, and some, who responded quickly, slowly escaped this inhibition, and distortions resumed albeit at less intense levels than before rTMS. Repeat rTMS again inhibited distortions in many patients for extended time periods. Sensory acuity improved in concert with distortion inhibition.

Whereas patients with a variety of etiologies for phantosmia and phantageusia responded to this treatment, others did not. Patients with sensory acuity loss without phantageusia or phantosmia did not respond to rTMS with sensory acuity improvement. Patients without phantageusia or phantosmia but with distortions initiated by food in their mouth (aliageusia) or environmental odors in their nose (aliosmia) usually did not respond to rTMS with sensory distortion inhibition. Thus, phantageusia and phantosmia appear related to specific changes in brain plasticity which responds to rTMS.

How does the present study affect otolaryngologists? First, these patients are commonly seen by otolaryngologists due to failure of primary care physicians to understand and deal with these symptoms. Second, examination of their nasal passages by use of anterior rhinoscopy or nasal endoscopy usually reveals normal anatomy. Third, consistent with historical treatment practices, use of nasal sprays, antihistamines, antibiotics, or local or systemic adrenocortical steroids usually fail to produce symptomatic relief; this leaves otolaryngologists with few, if any, treatment options.

Repetitive transcranial magnetic stimulation opens a new avenue for otolaryngologists to deal with a large group of patients who need their understanding and help. However, to apply this technique effectively, it may be necessary to determine several parameters of taste and smell acuity loss by use of comprehensive psychophysical techniques , to define multiple possible etiologies of these symptoms to rule out other treatment modalities , and to use radiological techniques to insure normal brain anatomy with quantitation of olfactory bulb size and rectus gyrus anatomy . Results of these clinical studies are necessary to identify patients who may be candidates for this procedure.

Although programs such as ours at The Taste and Smell Clinic in Washington, DC, can help and advise physicians about these procedures, the main burden of evaluating and treating these patients falls upon the shoulders of otolaryngologists. Knowledge of whom to treat and how to do so will add great value to clinical acumen and practice and will be of great benefit to the many patients who require and who will benefit from these services.