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Long-term Follow-up of Surgically Treated Phantosmia
Donald A. Leopold, MD;
Todd A. Loehrl, MD;
James E. Schwob, MD, PhD
Arch Otolaryngol Head Neck Surg. 2002;128:642-647.
ABSTRACT
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Objectives To determine whether transnasal excision of olfactory epithelium is
a safe, effective therapy and to learn more of the pathogenesis of phantosmia
by studying the histological features of the excised mucosa.
Design A retrospective study consisting of a medical record review and telephone
survey. Follow-up ranged from 1 to 11 years (average, 5.4 years). Excised
tissues were histologically processed and descriptively compared with normal
and other abnormal olfactory tissues.
Setting Tertiary university medical referral centers.
Patients All patients who presented to the primary author (D.A.L.) from 1988
to 1999 with unremitting phantosmia lasting longer than 4 years.
Intervention Olfactory testing and transnasal endoscopic excision of olfactory mucosa.
Main Outcome Measures Tested olfactory function, patients' perception of phantom odor resolution,
and histological findings.
Results Of 8 patients, 7 have complete and permanent resolution of their phantosmia.
Postoperatively, the single nostril olfactory ability in the operated-on nostril
is decreased in 2 nostrils, remains unchanged in 7, and is improved in 1.
The excised olfactory mucosa generally shows a decreased number of neurons,
a greater ratio of immature to mature neurons, and disordered growth of axons
with some intraepithelial neuromas.
Conclusions Surgical excision of olfactory epithelium is an effective and safe method
to relieve phantosmia while potentially preserving olfactory ability. The
abnormal histological features of the excised olfactory tissue suggest at
least some pathological condition in the peripheral olfactory system. This
nasal surgery requires intensive olfactory evaluation and follow-up. It is
also extremely difficult with significant risks, and therefore should be limited
to specialized centers.
INTRODUCTION
PHANTOSMIA IS the intermittent or continuous perception of an odor when
no odorant stimulus is present. Some individuals with this symptom perceive
the odor independent of nasal airflow, and there is no change in the odor
perception when nasal airflow is blocked unilaterally or bilaterally. There
are other individuals, however, in whom blockage of uninasal airflow eliminates
the phantom odor, and they are the subject of the present article. Most commonly,
the perceived odor is unpleasant, and is typically described as "burned,"
"foul," "rotten," "sewage," or "chemically." A variety of extrinsic or intrinsic
stimuli such as changes in nasal airflow, strong odorants, or loud sounds
can trigger the odor or it may appear spontaneously. Some patients may have
an aura associated with the onset of the phantosmia. When the phantom perception
is present, everything the patient eats has this flavor, and foods do not
mask the perception. All of these patients with phantosmia have a self-admitted
poor quality of life, with each meal having the aroma of foul meat, burned
garbage, or feces. It is usual for the patients to have thought about suicide
because they had been offered no hope for resolution from other physicians.
The perceived odor usually lasts only a few minutes the first time it
is experienced, and it almost always has a spontaneous onset. It then will
recur at monthly, then weekly, then daily intervals over a period of 6 months
to a year. The duration that the perceived odor is present also increases
over the same time, often lasting most of the day after 1 year. For the first
year or two, the phantom smell spontaneously resolves with more than an hour
of sleep. Patients often describe stereotypical methods to relieve the unpleasant
odor perception, including bending over and holding the ankles while holding
the breath, forced crying, intranasal instrumentation, and gagging. All of
these manipulations, including sleep, eventually fail to resolve the phantosmia.
Many of the patients stated that their olfactory ability fluctuated,
with it being worse when the phantom odor perception was present. Olfactory
testing usually reveals a decreased olfactory ability in the involved nostril.
Because phantosmia is a rare and poorly understood disorder, there has
been no well-defined treatment. Often, patients are given ineffective therapy,
and numerous providers will instruct them to "just live with it." Because
of analogies with psychiatric conditions, some patients are told that they
have a mental illness.
A variety of treatments have been proposed both medically and surgically.
Medical treatments have included sedatives and antiepileptic drugs.1 Patients receiving these treatments may not experience
relief, or the adverse effects may limit their use. Surgical treatment has
included olfactory bulb ablation through a bifrontal craniotomy approach.2-3 This procedure results in bilateral
permanent anosmia and includes the risks associated with a craniotomy.
Although the pathophysiological mechanisms of phantosmia are poorly
understood, there is some evidence to suggest that it is either a peripheral
problem in the olfactory mucosa or axons or a central phenomenon with a peripheral
stimulus.4 Thus, resection of the olfactory
mucosa could possibly eliminate the phantom odor by eliminating the peripheral
disease or input. Previous experience with a single patient has suggested
that transnasal endoscopic excision of olfactory epithelium can successfully
eliminate phantosmia with preservation or regeneration of olfaction.4 To determine the safety and efficacy of this procedure
and to further explore the possible histological correlates, we have studied
a consecutive series of 8 patients on whom transnasal endoscopic excision
was performed.
PATIENTS AND METHODS
PATIENTS
Eight patients (7 women and 1 man) presenting to the primary author
(D.A.L.) from August 1988 to May 1999 with phantosmia lasting longer than
4 years were reviewed. The length of symptoms ranged from 4 to 19 years (average,
8.2 years). Preoperative evaluation included a thorough history, a complete
head and neck examination, nasal endoscopy, uninasal smell testing (eg, a
40-odorant scratch-and-sniff Smell Identification Test (SIT) [Sensonics Inc,
Haddonfield, NJ]), and computed tomography of the sinuses as well as magnetic
resonance imaging or computed tomography scan of the head to rule out intracranial
pathological conditions. All these patients were judged to be psychiatrically
stable in that they were all employed, displayed no unusual behavior, did
not have histories of alcohol or drug abuse, displayed a lively affect, and
had logical thought patterns. None of the patients thought the odors were
coming from them, or referred to the odor as being human in origin. Most importantly,
blocking the involved nostril could always stop the perceived odor.
All patients underwent a sequential uninasal anesthetization of each
olfactory cleft, which temporarily eliminated the phantom odor when the involved
nostril was selected. This was performed by dripping 1 cm3 of 4%
cocaine into the patient's nostril while their neck was fully extended and
they were supine. The level of anesthesia could be judged by the lack of response
to olfactory stimuli. Electroencephalograms had been obtained on 3 patients
to determine if there was any abnormal brain electrical activity. Positron
emission tomography of the brain using fluorodeoxyglucose is an imaging technique
that was performed in 3 patients to help understand the disease and to possibly
aid in their care.
Follow-up data were obtained through medical record review and telephone
interviews. Also, a SIT was mailed to each patient with instructions to perform
uninasal smell testing. The telephone interview included questions regarding
nasal and sinus status since surgery, perceived olfactory function, and whether
they would have the surgery if they had it to do over again. The length of
follow-up ranged from 1 to 11 years (average, 5.4 years). A meaningful change
in olfactory function was defined as a change of greater than 5 odorants on
the SIT.
SURGICAL TECHNIQUE
The surgery was performed under general anesthesia using transnasal
and transethmoidal endoscopic techniques on only 1 side and was generally
the same in each patient. The olfactory mucosa was removed along the length
of the cribriform plate, taking care to sharply cut the fila olfactoria as
they were identified. The area was then inspected for cerebrospinal fluid
leak. A mucoperiosteal graft was placed against the cribriform plate to prevent
cerebrospinal fluid rhinorrhea and treat it when it occurred. The patients
remained in the hospital overnight on bed rest with the head of the bed elevated.
All excised olfactory mucosa was sent for special immunostaining. The surgery
that was done in those patients who failed to improve the first time was performed
in a similar manner. This operation is difficult because the olfactory nerve
tissue is tough in character and difficult to cut sharply because of the angles
involved. Care is also needed to operate "gently" to avoid disturbing the
neural tissue of the olfactory bulb, and the orbital tissues that are close.
Finally, the operation must be done with attention to preserving ventilation,
stability, and mucosal coverage of all nasal and ethmoid tissues.
HISTOLOGICAL METHODS
Excised tissue was fixed by immersion in Bouin fluid for 2 to 4 hours
and embedded in paraffin. Serial sections were collected throughout the entirety
of the tissue, and selected ones were immunostained with antibodies against
olfactory marker protein (anti-OMP) (the gift of Frank Margolis, PhD, University
of Maryland, Baltimore), neurotubulin (antineurotubulin [anti-NT] monoclonal
antibody), and growth-associated protein GAP-43 (monoclonal antibody 7B10)
(the gift of Karina Meiri, PhD, Upstate Medical University, Syracuse, NY)
using standard techniques.5-6
RESULTS
As given in Table 1, 8 patients
underwent 14 procedures. In 4 patients, the excision needed to be repeated
because the phantom smell was not eliminated after the first operation; 2
patients underwent bilateral procedures; 1 patient had bilateral disease at
presentation, while another subsequently developed disease on the opposite
side. Ages ranged from 21 to 35 years in the women, and the only man was aged
54 years. All 8 patients were contacted by telephone, and in response to the
question, "If you had it to do over again, would you have the surgery?" all
responded affirmatively. Phantom smell persisted in 1 patient. Two patients
occasionally believed that the phantom was about to come on (aura), but it
never did. Complete resolution of the phantosmia occurred in 7 of the 8 patients.
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Smell Test Scores for 8 Patients Before and After Surgery for Phantomsia*
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The intent of the operation is to destroy the olfactory ability, and
all patients had no olfactory ability using olfactory testing in the first
few weeks after the surgery. Starting about 2 months after the operation,
the patient's olfactory ability usually returned and stabilized. Testing 1
to 11 years postoperatively showed the olfactory ability in the operated-on
nostril to be unchanged in 5 of 10, improved in 2 of 10, and decreased in
3 of 10 nostrils compared with preoperative levels. In the nonoperated-on
nostril, 3 of 6 remained unchanged, 1 of 6 decreased, and 2 of 6 improved.
Two cerebrospinal fluid leaks were noted intraoperatively, and these were
successfully treated with the surgical technique. There were no difficulties
with visual changes, epiphora, meningitis, or scarring resulting in chronic
rhinosinusitis.
Positron emission tomography scanning was done in 3 patients and revealed
increased activity in the opposite frontal, insular, and temporal regions,
which decreased after excision of the olfactory epithelium from the involved
nasal cavity.8 These changes add evidence to
the theory that phantosmia may be a "central" process. This information, however,
did not help in the clinical treatment of the patients, thus positron emission
tomography scanning was not performed on all patients.
The electroencephalograms did not show seizure activity, thus they were
not obtained in most of the patients. Most described olfactory "auras" associated
with seizures lasting seconds to minutes, and all of our patients had odor
symptoms lasting hours to days. Thus, seizure is unlikely to be the cause
of this symptom.
Olfactory epithelium and/or fascicles of the olfactory nerve were identified
in the excision specimens from all phantosmic patients. The comparison of
staining with anti-OMP and anti-NT on adjacent sections permits the discrimination
of mature (anti-OMP–stained) and immature (anti-NT–stained but
not stained with anti-OMP) neurons and the classification of axons in the
olfactory fascicles by the same criteria.5
Of the tissue from the patients complaining of phantosmia, 3 features were
different compared with biopsy specimens from normosmic volunteers without
nasal inflammation undergoing nasal procedures such as septoplasty and transnasal
pituitary surgery. First, in each of the phantosmic cases, the epithelium
contained a higher proportion of immature than mature neurons in contrast
with the predominance of mature neurons in the normosmic biopsy specimens
(Figure 1). Second, the epithelium
in many of the cases contained intraepithelial neuromas, which are tangles
of disordered axons situated superficial to the basal lamina. Invariably,
most of the neuromatous axons were elaborated by immature olfactory neurons
and were labeled by anti-NT but not anti-OMP (Figure 1). These first 2 features were also noted in our previous
report on phantosmia.4
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Figure 1. In the epithelium harvested from
phantosmic patients, immature neurons predominate and neuromas have formed.
A, Anti-NT–stained section of epithelium from a 35-year-old woman (original
magnification x100). Boxed area is shown in higher power (original magnification
x280) in B. Curved arrows (A, B, and D) indicate intraepithelial neuromas.
C, Adjacent section stained with anti-OMP (original magnification x100).
Boxed area is shown in higher power (original magnification x280) in
D. Note that the staining of the neuromas is weaker with anti-OMP. Note also
that the fascicles are weakly stained with anti-OMP or not at all (open arrows
in A and C) and that the number of OMP-positive neurons is commensurately
less than the number of NT-positive/OMP-negative neurons (compare B vs D).
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The last feature has not been described previously. Much of the cross-sectional
area of large fascicles of the olfactory nerve lacked axons as evidenced by
an absence of immunostaining with anti-NT and anti-OMP. Those axons that were
retained in the nerve were predominantly immature in their phenotype, ie,
they stained with anti-NT and not anti-OMP (Figure 2). The reduction in axonal
staining was true of all phantosmic patients. Examination of fascicles lacking
immunopositive fibers in other patients without phantosmia demonstrates replacement
of axons by collagen fibers (J.E.S., unpublished observation, 1992). By extension,
we interpret the lack of anti-NT immunostaining in phantosmic patients as
an indication that the large fascicles have lost a significant number of axons.
In contrast with the loss of staining (and axons) in large fascicles, the
staining of smaller subepithelial fascicles was uniform and without interruption
(Figure 2). The loss of axons from
large fascicles of phantosmic patients contrasts with the greater complement
of stained axons, albeit also immature in phenotype, in the fascicles of patients
who complain of hyposmia of anosmia after head trauma (Figure 2).
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Figure 2. Large fascicles of the olfactory
nerve are sparsely populated with axons in patients complaining of phantosmia,
while smaller fascicles look as though they contain a more normal complement
of axons. A, Large and small olfactory fascicles from a 36-year-old woman
with a 15-year history of phantosmia. The large fascicles show limited staining
with anti-NT (one marked by single arrowheads and a second marked by the double
arrowhead). In contrast, the smaller fascicles are densely stained (examples
indicated by the straight arrows) (original magnification x50). B and
C, A large olfactory nerve fascicle from a 26-year-old woman complaining of
phantosmia (original magnification x250). B, Hematoxylin-eosin–stained
section: the nerve fascicle (delineated by arrowheads) is clearly distinct
from the surrounding tissue. C, Anti-NT–stained section: many portions
of the nerve fascicle are unstained (open arrows). D and E, A large olfactory
nerve fascicle from a 36-year-old female patient rendered anosmic subsequent
to head trauma from a motor vehicle crash (original magnification x250).
D, Anti-NT–stained section: in contrast with the fascicle from the phantosmic
patient, in this case of head trauma the fascicle is densely and completely
filled with NT-positive fibers. E, Anti-OMP–stained section: the reduced
level of OMP-staining compared with NT staining is indicative of the predominance
of immature neurons in the epithelium. Some smaller fascicles are largely
if not completely devoid of OMP staining (open arrow).
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COMMENT
The pathophysiological mechanisms of this disorder are yet to be determined.
The site of the disorder may be anywhere along the olfactory pathway. The
histological findings suggest that the growth of olfactory axons is disordered
in these patients. The presence of intraepithelial neuromas is not unique
to this population and has been observed in patients with idiopathic olfactory
loss, congential anosmia (including Kallmann syndrome), and head trauma among
others9-10 (J.E.S., unpublished
observation, 1992). In experimental animals, in which the timing, primary
locus, and nature of the insult is better controlled, the generation of neuromas
is indicative of either prior damage to the epithelium that is severe enough
to prevent axons from exiting the vicinity of their parent neurons or damage
to the olfactory bulb or nerve that causes the axons to grow back into the
epithelium at some distal point along their course to the bulb.11
Thus, neuroma formation by itself does not permit us to distinguish whether
the primary lesion underlying the phantosmic symptoms is central or peripheral.
The abnormalities in the large fascicles of the olfactory nerve are
more consistent with the suggestion that the locus of damage is in the peripheral
olfactory system—either the epithelium per se or along the course from
the epithelium to the cribriform plate. The contrast in the status of the
fascicles of the olfactory nerve between patients with dysosmia secondary
to head trauma and the phantosmic population tends to rule out the notion
that damage at the cribriform plate and/or to the olfactory bulb is responsible
for the aberrant axonal growth in phantosmic patients.
Given the tentative localization of the lesion, at least 2 alternatives
may be offered as explanation for the phantosmia: (1) The phantosmia sensation
may arise because neurons located near intraepithelial neuromas have an altered
response to olfactory stimuli; in this case, activity may be modulated by
ionic shifts occasioned by a large mass of activated axons. (2) Alternatively,
ephaptic transmission between axons that are disconnected and others that
innervate the bulb might result in disordered signaling in response to a stimulus.
Ephaptic activation of neighboring axons is known to mediate altered patterns
on activity in other nerves. The histopathological observations suggest that
the cross-talk might take place at the transition from small olfactory nerve
bundles (which appear intact) to large fascicles (which lack their normal
complement of axons). A more definitive test of that hypothesis awaits 3-dimensional
reconstruction of the course of axons from the epithelium to the larger fascicles.
Despite the abnormalities of axon distribution in the periphery, we
cannot exclude the hypothesis that altered central processing of the stimulus
is primarily responsible for the phantosmic symptoms. The improvement in symptoms
after excision of the olfactory mucosa does not exclude that interpretation.
For example, decreased olfactory input to the bulb is known to down-regulate
dopaminergic periglomerular interneurons, which may affect both the transmission
of the signals from the olfactory nerve to bulb and the processing of those
signals by the bulb itself. Findings from the positron emission tomographic
scan studies are also consistent with this central hypothesis. In any event,
disrupting the olfactory input seems to somehow eliminate the phantosmia.
The improvement or maintenance of some of the patients' olfactory ability
was unexpected because the surgery was intended to destroy all olfactory ability.
One possible explanation is that some of the olfactory receptor cells were
spared during the resection. Another possibility is the regeneration and reconnection
of the receptor neurons to the olfactory bulb, something known to occur in
mammals,12 but only suggested in humans.4
With regard to the patient whose phantosmia did not resolve, several
points can be made. He is somewhat older (54 years) and is the only man in
the series. It seems from our clinical experience (and others1)
that phantosmias are more common in women; however, the reason for this is
unclear. Similarly, the significance of his age is also unknown, although
the regenerative potential of his olfactory neurons likely decreases with
increasing age.13 Finally, his case of phantosmia
had a burning component, which is suggestive of a trigeminal nerve involvement.
Consistent with this suggestion, his was the only phantom odor in our series
that was not masked by food. The fact that we were still able to eliminate
the perceived odor with nasal anesthesia even after bilateral surgical olfactory
ablation further supports the possibility that this is a trigeminal phantom
perception.
In conclusion, our experience in this series indicates that transnasal
endoscopic excision of olfactory epithelium is a safe and effective treatment
for patients with unremitting phantosmia. In addition, olfactory function
is potentially spared. Although the histopathological features are suggestive
of an abnormal process occurring in the peripheral olfactory mucosa, the exact
mechanism has yet to be determined. The surgery, however, is technically challenging,
is associated with major risks, and should be relegated to specialized centers.
AUTHOR INFORMATION
Accepted for publication November 15, 2001.
This study was presented at the Association for Chemoreception Sciences
Meeting, Sarasota, Fla, April 14-18, 1999.
Corresponding author: Donald A. Leopold, MD, Department of Otolaryngology–Head
and Neck Surgery, University of Nebraska Medical Center, 981225 Nebraska Medical
Center, Omaha, NE 68198-1225 (e-mail: dleopold{at}unmc.edu).
From the Departments of Otolaryngology–Head and Neck Surgery,
University of Nebraska Medical Center, Nebraska Medical Center, Omaha (Dr
Leopold), Otolaryngology–Head and Neck Surgery, Medical College of Wisconsin,
Milwaukee (Dr Loehrl), and Anatomy & Cellular Biology, Tufts University
School of Medicine, Boston, Mass (Dr Schwob).
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