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ANOSMIA
Audio-Digest Otolaryngology
Volume 46, Issue 12
June 21, 2013

Cleaning the Air: Can We Treat Anosmia? – Donald A. Leopold, MD
Chronic Rhinosinusitis and Anosmia – R. Peter Manes, MD
The Story of Zicam – Boris Paskhover, MD

   
From Taste And Smell: Dysgeusia? Anosmia? What Next? Sponsored By The New England Otolaryngological Society
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The following is an abstracted summary, not a verbatim transcript, of the lectures/discussions on this audio program.

Otolaryngology Program Info  Accreditation InfoCultural & Linguistic Competency Resources

Anosmia

From Taste and Smell: Dysgeusia? Anosmia? What Next? sponsored by the New England Otolaryngological Society

Educational Objectives

The goals of this program are to improve diagnosis, management, and prevention of anosmia. After hearing and assimilating this program, the clinician will be better able to:

1. Evaluate patients with chronic rhinosinusitis for olfactory dysfunction.

2. Diagnose syndromes associated with olfactory disturbances.

3. Use medical and surgical approaches in addition to olfactory training to treat or improve severity of anosmia.

4. Select which patients are more likely to benefit from endoscopic sinus surgery to improve olfactory symptoms.

5. Caution patients against use of homeopathic and other medications and exposures that may induce anosmia.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Leopold is a consultant for NeilMed Pharmaceuticals. Drs. Manes and Paskhover and the planning committee reported nothing to disclose. In their lectures, Drs. Leopold and Paskhover present information that is related to the off-label or investigational use of a therapy, product, or device.

Cleaning the Air: Can We Treat Anosmia?

Donald A. Leopold, MD, Professor, Division of Otolaryngology, Department of Surgery, University of Vermont College of Medicine, Burlington

Measures of olfactory function: University of Pennsylvania Smell Identification Test (UPSIT) — 40 odorants; anosmia if 20 identified correctly; hyposmia if 20 to 32 identified correctly; significant change in sense of smell indicated by difference of 3 correctly identified odorants on UPSIT or 6-point change in threshold discrimination identification (TDI) score on Sniffin’ Sticks test

Physiology: olfactory system programmed to recover (3-mo cycle); poor recovery after head trauma; 25% improvement after upper respiratory infection (URI) within 6 mo; pathway — from inside nose to top of nasal cavity, through cribriform plate, to olfactory bulb (OB), through olfactory tract into centers at base of brain; latency from presentation to perception of odor 400 to 500 msec

Etiology: mechanical obstructioneg, due to polyps; surgical correction of superior turbinate hypertrophy or septal deviation not effective at restoring sense of smell; missing or nonfunctioning olfactory tissue — possibly occurs during viral URI or chronic rhinosinusitis (CRS); recent data may refute this and indicate problem originating within brain; failure to transmit to OB — possibly due to obstruction in cribriform plate or damage to olfactory tract (caused by, eg, head trauma, frontal craniotomy); failure in brain — primitive areas of brain innervated by olfactory sense, with extensive connections; damage to any of these areas could affect ability to smell; anosmia associated with Alzheimer dementia and Parkinson disease; suggestion that if patient diagnosed with PD does not have anosmia, diagnosis incorrect

Treatment

Approach: multifactorial; no established standard; currently no approved treatments and no double-blind controlled trials demonstrating success at improving olfactory ability

Oral steroids: studied by Hummel in Germany; typically 30-50 mg of prednisone tapering over 2 to 3 wk; study demonstrated 37% of patients with CRS improved (not those with posttraumatic anosmia); unclear if improvement due to unclogging nose or modifying function of olfactory neurons

Intranasal steroids: side effects limited compared to oral steroids, but many studies found them ineffective for improving olfactory function; some studies demonstrated limited benefit from squirting liquid preparation, using pressure-pulsed machine or nebulizer, or administering steroid drops with head down and forward (mainly patients with CRS who responded to oral steroids)

Olfactory training: may be only effective treatment in patients who do not have CRS; no toxicity and simple to perform; German study — measured sense of smell with Sniffin’ Sticks; patients had mixed etiologies, including after head trauma and post-URI, and all unresponsive to steroids; patients smelled 4 scents twice daily for 2 mo; training plus nasal steroids led to 6.8-point increase on TDI score; training alone resulted in 2.5-point increase in score

Endoscopic sinus surgery (ESS): one of the more successful approaches; ESS can also worsen sense of smell by traumatizing nerves; patients should not be promised improvement in smell; obtain consent about risk for loss of smell from ESS; Russian study (2012) — 20 patients had ESS and 20 patients had intramuscular (IM) injection of dexamethasone; all patients used mometasone nasal spray; patients who had ESS had better improvement in smell at 4 mo; literature review — studies using ESS to improve olfaction; most patients remained hyposmic, but authors concluded ESS best chance of improvement for patients with nasal polyposis (NP); maximal benefit attained by 6 mo postoperatively; surgical repair of ethmoid may lead to decreased edema in olfactory cleft

Other treatments: acupuncture — study (2010) demonstrated possible benefit, but comment on study suggested that conclusions could not be made due to design; laryngectomy — volume of OB decreases after surgery, along with sense of smell; improved by restoring airflow through nose; transcranial magnetic stimulation — proposed for olfactory distortions; used for other types of neurologic processes; one study discredited by peers who suggested technique and choices of patients illogical; treatment of psychiatric disorders — sense of smell showed some nonsignificant improvement; in patients with major depression when successfully treated; inferior turbinate reduction — study of 40 consecutive patients who had this procedure; data demonstrated improved sense of smell; likely due to restoration of airflow; stellate ganglion block: in study by Moon, block done 7 times on 13 patients; 7 patients improved; mechanism not well described, possibly influencing sympathetic nerves of nasal cavity

Areas in Need of Further Study

Transplantation of olfactory tissue: performed in animals

Statins: study in mice — sense of smell destroyed; 9 of 12 mice receiving statins and 2 of 12 not receiving statins regained ability to find food; atorvastatin possibly associated with restoring olfactory function; Wisconsin Longitudinal Study — showed people who took lipid-lowering agents, exercised once weekly, and took oral steroids had reduced likelihood of decreased sense of smell over time

Congenital olfactory loss: studies in patients with single-gene disorders (eg, Kallmann syndrome) investigating effects of gonadotropin-releasing hormone on development and maturation of olfactory neurons from placode; may be possible to regenerate OB or other regional tissues

Inflammation vs obstruction: study at Johns Hopkins — transgenic mice with ability to turn off and on production of tumor necrosis factor-alpha (TNF-α); groups with TNF-α turned on had oppressive loss (preventable with prednisolone)

Dopaminergic pathways: study in rat model of Parkinson disease; administration of lithium and valproate prevented some olfactory impairments

Ineffective or Harmful Therapies

Zinc: worsens sense of smell, whether intranasal or oral

Nasal oxygen: study comparing 3 groups of patients (those with chronic obstructive pulmonary disease [COPD] with oxygen, COPD without oxygen, and healthy controls); sense of smell equivalent in all groups

Minocycline: implicated due to antiapoptotic properties; mouse study demonstrated olfactory volume restoration with antiapoptotic agents; double-blind placebo-controlled study of minocycline in 55 patients resulted in no effect

Vitamin A: mid-20th century study in New Zealand suggested restored sense of smell after parenteral vitamin A administration; study in Germany — patients with olfactory disturbance following URI and head trauma took vitamin A in highest allowable dose for 3 mo; no benefit shown

Herbals: Sinupret — widely available herbal remedy for common cold in Europe; study suggested effectiveness in CRS; double-blind study did not demonstrate improvement in sense of smell

Cigarette smoking: shown to cause decrease in OB volume before onset of anosmia; 557 people tested after cessation of smoking; hyposmia not improved in most patients; thought related to type of odorant used for testing (phenyl ethyl alcohol, ingredient in cigarettes); olfactory sensitivity to products in cigarettes diminished but no other odorants

Potentially relevant data: attention-deficit hyperactivity disorder (ADHD) — associated with olfactory dysfunction; 60 patients tested, 20 with ADHD on medication, 20 with ADHD off medication, and 20 normal controls; olfactory sensitivity highest in ADHD patients not taking medicines; threshold increased after taking ADHD medication (possibly linked to dopaminergic effects); mental illness psychiatric patients who do poorly on test of sense of smell less likely to improve psychiatrically; chemotherapy platinum agents known to cause dysosmia and dysgeusia; improves 3 mo after treatment; nasal polyps in olfactory cleft concern for scarring and removal of olfactory tissue if excised; study of 25 patients demonstrated no olfactory marker protein in polyps removed from this area confirming polyps removed did not contain olfactory tissue

Chronic Rhinosinusitis and Anosmia

R. Peter Manes, MD, Assistant Professor, Section of Otolaryngology, Department of Surgery, Yale University, School of Medicine, New Haven, CT

Sinusitis: CRS — olfactory dysfunction common complaint; querying patients with CRS about sense of smell recommended; allergic fungal rhinosinusitis — partly conductive due to polyps; removing polyps does not always improve olfaction

Endoscopic sinus surgery: studies by Kern — examined 30 patients who underwent ESS; obtained olfactory tissue for biopsy in 19 patients; 9 patients had normal olfactory epithelium and normal UPSITs; 10 patients had multiple pathologic changes within olfactory epithelium (increased lymphocytes, macrophages, and eosinophils); suggests olfactory deficit related to inflammatory changes in olfactory mucosa (eg, metaplasia, intraepithelial neuromas)

Histologic and predictive factors: identified in studies and include mucosal and serum eosinophilia; in patients with CRS, predictive factors include nasal polyps, asthma, age, smoking history; history of ESS and allergic rhinitis not found to predict olfactory impairment in one study

Quality of life: affected by impaired interpersonal relationships, diminished enjoyment of food, fear of associated risks; some studies show that QOL changes may have limited correlation with CRS-specific QOL status; patients seek validation and explanation of olfactory dysfunction and need counseling; ESS has beneficial effects on histologic markers, patient symptoms and health-related QOL

Conflicting data: first study — 111 patients undergoing ESS for medically refractory CRS with olfactory impairment; trend toward improvement in anosmia but not hyposmia; possibly anosmia more conductive and hyposmia more related to chronic inflammation; nasal polyps only predictor of improvement following ESS; second study — 206 patients, same criteria; 23% noted improvement in olfaction after ESS, 68% noted no change, 9% reported worsening of olfaction; nasal polyps and eosinophilia predicted improvement; third study — smaller subset of patients, same criteria; 74% reported olfactory impairment before surgery, and 68.6% reported olfactory impairment after surgery (not significant); analyzing other factors, no correlation found with nasal polyps, allergy status, or severity of CRS; fourth study — 101 patients undergoing ESS; eosinophil count higher in patients with olfactory disorders; patients with anosmia had greater severity of basement membrane thickening; no difference in lymphocytic cellular markers; no specific histologic inflammatory findings associated with improvement after ESS

Conclusions: pathophysiology of olfactory dysfunction in CRS multifactorial with conductive and inflammatory components; perform olfactory evaluation during work-up for CRS; improvement of CRS-related olfactory dysfunction following ESS variable and difficult to predict; patients with anosmia and nasal polyps may have greater likelihood of improvement after ESS, compared to those with hyposmia without polyps

The Story of Zicam

Boris Paskhover, MD, Section of Otolaryngology, Yale-New Haven Medical Center, New Haven, CT

Zinc gluconate (Zicam intranasal spray)-induced anosmia syndrome: includes characteristic sequence of events; sensation of burning following nasal inhalation of product, ultimately leading to anosmia

Creation of zinc gluconate intranasal cold remedy: homeopathic medication, previously marketed by Matrixx Initiatives, with supposed effects against common cold; developed in mid-1990s and sold as nasal gel and swab; did not require formal approval from Food and Drug Administration (FDA); United States Federal Food, Drug, and Cosmetic Act of 1938 — homeopathic preparations regulated and protected if they fall within US Homeopathic Pharmacopeia; zinc gluconate and acetate fall on this list; creators of product able to bypass formal new drug approval process and marketed product under title of homeopathic preparation)

Clinical evidence: study from Cleveland Clinic (2002) — initiating zinc gluconate within first 24 to 48 hr of common cold decreases symptom duration by 1.7 days; review at Stanford (2007) — 3 of 4 reports analyzed showed no benefit of zinc gluconate-containing products; study in 2006 — showed no benefit for zinc gluconate spray; overall — evidence for efficacy of zinc gluconate against common cold weak; no studies gave detailed mechanism of action for proposed benefit

FDA notice (2009): informed consumers that zinc gluconate product linked to olfactory disturbances; FDA then issued warning letter to Matrixx Initiatives that product does not formally fall under category of homeopathic medication and not shown to be safe for general use, and thus required formal FDA drug approval for marketing; company stopped marketing and distributing product following this; FDA decision prompted by 800 complaints directed to Matrixx Initiatives and 130 cases reported directly to FDA; before FDA notice, 2 studies detailed anosmia syndrome in patients after zinc gluconate nasal spray use; both studies cited evidence dating back to before World War II involving zinc sulfate nasal spray used in Canada that caused persistent anosmia in large cohort

Pathophysiology: much literature (some predating marketing of zinc gluconate nasal spray) linking zinc to neuronal structures, neurotoxicity, and diseases with other neuronal death processes (eg, Alzheimer); zinc effects on nasal mucosa — study in Seattle examined human nasal tissue explants to determine effects of zinc gluconate spray; using lactate dehydrogenase (LDH) levels as marker for cellular death, exposed tissue to lidocaine, zinc gluconate nasal spray, epinephrine, triamcinolone (Nasacort; discontinued in United States), and oxymetazoline (Afrin); only tissue exposed to zinc gluconate had statistically significant elevation in LDH levels

Etiology for zinc gluconate-induced anosmia: potentially direct application of nasal spray to olfactory mucosa caused cellular death and inflammation, leading to perceived olfactory disturbance; some improvement over time but complete resolution rare

Acknowledgements

Drs. Leopold, Manes, and Paskhover were recorded at Taste and Smell: Dysgeusia? Anosmia? What Next? held April 5, 2013, in Boston, MA, and sponsored by the New England Otolaryngological Society. Information about upcoming events from the New England Otolaryngological Society can be found at neos-ent.org. The Audio-Digest Foundation thanks the speakers and sponsors for their cooperation in the production of this program.

Suggested Reading

Bhutta MF et al: Nasal polyps do not contain olfactory structures. Rhinology 2011 Jun;49(2):185-9; Costanzo RM, Yagi S: Olfactory epithelial transplantation: possible mechanism for restoration of smell. Curr Opin Otolaryngol Head Neck Surg 2011 Feb;19(1):54-7; Davidson TM, Smith WM: The Bradford Hill criteria and zinc-induced anosmia: a causality analysis. Arch Otolaryngol Head Neck Surg 2010 Jul;136(7):673-6; Henkin RI et al: Improvement in smell and taste dysfunction after repetitive transcranial magnetic stimulation. Am J Otolaryngol 2011 Jan-Feb;32(1):38-46; Hummel T et al: Effects of olfactory training in patients with olfactory loss. Laryngoscope 2009 Mar;119(3):496-9; Kern RC et al: Pathology of the olfactory mucosa: implications for the treatment of olfactory dysfunction. Laryngoscope 2004 Feb;114(2):279-85; Kim HY et al: Effects of statins on the recovery of olfactory function in a 3-methylindole-induced anosmia mouse model. Am J Rhinol Allergy 2012 Mar-Apr;26(2):e81-4; Lane AP et al: A genetic model of chronic rhinosinusitis-associated olfactory inflammation reveals reversible functional impairment and dramatic neuroepithelial reorganization. J Neurosci 2010 Feb 10;30(6):2324-9; Lim JH et al: Zicam-induced damage to mouse and human nasal tissue. PLoS One 2009 Oct 30;4(10):e7647; Moon HS: Long-term Results of Stellate Ganglion Block in Patients with Olfactory Dysfunction. Korean J Pain 2013 Jan;26(1):57-61; Mori E et al: Risk factors for olfactory dysfunction in chronic rhinosinusitis. Auris Nasus Larynx 2013 Feb 16; Reden J et al: Treatment of postinfectious olfactory disorders with minocycline: a double-blind, placebo-controlled study. Laryngoscope 2011 Mar;121(3):679-82; Reden J et al: Olfactory function in patients with postinfectious and posttraumatic smell disorders before and after treatment with vitamin A: a double-blind, placebo-controlled, randomized clinical trial. Laryngoscope 2012 Sep;122(9):1906-9; Reden J et al: The effect of a herbal combination of primrose, gentian root, vervain, elder flowers, and sorrel on olfactory function in patients with a sinonasal olfactory dysfunction. Rhinology 2011 Aug;49(3):342-6; Rudmik L, Smith TL: Olfactory improvement after endoscopic sinus surgery. Curr Opin Otolaryngol Head Neck Surg 2012 Feb;20(1):29-32; Schriever VA et al: Treatment of smell loss with systemic methylprednisolone. Rhinology 2012 Sep;50(3):284-9; Schriever VA et al: Olfactory bulb volume in smokers. Exp Brain Res 2013 Mar;225(2):153-7; Schubert CR et al: Olfactory impairment in older adults: five-year incidence and risk factors. Laryngoscope 2011 Apr;121(4):873-8; Steinbach S et al: Effect of platinum-containing chemotherapy on olfactory, gustatory, and hearing function in ovarian cancer patients. Arch Gynecol Obstet 2012 Aug;286(2):473-80; Vent J et al: Effects of traditional Chinese acupuncture in post-viral olfactory dysfunction. Otolaryngol Head Neck Surg 2010 Apr;142(4):505-9


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