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Home , Hyperosmia, Phantosmia

ISSN 0017-8748 Headache doi: 10.1111/head.12890 VC 2016 American Headache Society Published by Wiley Periodicals, Inc. Expert Opinions

Phantosmia and With and Without Headache

Yasmin I. Jion, MD; Brian M. Grosberg, MD; Randolph W. Evans, MD

Phantosmia is a rare migraine . We present two cases of phantosmias occurring before migraine headaches and also without headaches. To our knowledge, these are the third and fourth cases of phantosmias ever reported due to migraine aura without headache.

Key words: phantosmia, olfactory , migraine, headache

(Headache 2016;00:00-00)

CASE HISTORIES take acetaminophen with relief in 1–2 hours. Stress Case 1.—This is a 53-year-old female with a 9- was a trigger. month history of smelling a dirty dog smell as often as She saw a cardiologist about 1 month after 2–3 times a day or up to 4 days without the smell with onset and had a CT of the brain without contrast an average duration of 5 minutes (range 30 seconds to on 1/19/15 that was normal. She saw two ENT phy- 1 hour) followed by a headache about every 2 weeks sicians who found normal exams. but most of the time without an associated headache. Past medical history of hyperlipidemia on prav- She described a bifrontal throbbing headache with an astatin. Family history: sister has migraine. Neuro- intensity of 6/10 associated with nausea, light and noise logical examination was normal. sensitivity but no vomiting. She always takes ibuprofen MRI of the brain with and without contrast was with relief in 1 hour. During the episodes, there is no normal. EEG was normal. A complete blood count, alteration of consciousness. She has no triggers. She chemistry profile, thyroid functions, erythrocyte sedi- denied , , or increased stress. mentation rate, antinuclear antibody, rheumatoid Prior to 9 months ago, she had occasional head- arthritis factor, and Sjogren’s antibodies were negative. aches since her 20s described as bitemporal aching She declined a trial of migraine preventive with an intensity of 7/10 associated with light and medication. noise sensitivity but no nausea or aura. She would Case 2.—This is a 69-year-old female with a his- tory of headaches since age 35 that have been occurring about 6 days per month the prior 12 weeks since starting onabotulinum toxin A 2 years From the National Neuroscience Institute, Singapore (Y.I. Jion); Hartford Healthcare Headache Center, Wethersfield, previously and before about 4–6 days per week CT, USA (B.M. Grosberg); Department of Neurology, Bay- since age 45–50 years. She described a top of the lor College of Medicine, Houston, TX, USA (R.W. Evans). head and/or then left or right sided throbbing with Address all correspondence to Y.I. Jion, National Neurosci- an intensity of 7–10/10 associated with nausea, light ence Institute, 11 Jalan Tan Tock Seng, 308433 Singapore, and noise sensitivity but no vomiting or visual, email [email protected]

Accepted for publication June 21, 2016. Conflict of Interest: None.

1 2 Month 2016 sensory, or language aura. She took naratriptan chronic migraine with onabotulinum toxin A with relief in about 3–4 hours. Change of weather injections. was a trigger. Alterations in the of smell can be broadly For the past 20 years, once every 1–2 weeks, classified into quantitative dysfunction (, she would smell something burning like a campfire , and ) and qualitative dysfunction 90% of the time and like burning rubber 10% of ( and phantosmia).1,2 A distortion of the the time lasting 15 minutes to 2 hours. Three times, perceived is termed parosmia or troposmia, first about 18 years ago and last about 1 month while the of an odor when there is no ago, she had a menthol smell lasting about 1 hour odorant stimulus present in the environment is to 2 days. The smell would precede a typical head- termed phantosmia, cacosmia, or olfactory halluci- ache 1 hour to a few hours later. She also reported nation.3,4 Phantosmia typically lasts longer than a occasional episodes of the abnormal smell occurring few seconds, while olfactory hallucination usually without a headache. Since starting onabotulinum lasts only a few seconds.4,5 toxin A injections, the frequency of olfactory hallu- The occurrence of abnormal perception of odor cinations decreased to every few months. When she has long been described in ancient times as early as went 10 months between injections, the hallucina- 131 A.D. by Aretaeus, a Cappodocian: “a heavy smell tions increased after 5 months to about twice a sometimes preceded the accession of a paroxysm.”6 month. In migraine, the majority of patients have normal Propranolol, , divalproex, and verap- olfactory function.7 During a migraine episode, olfac- amil were not effective for prevention. MRI of the tory acuity may be impaired with a minority exhibit- brain in 2015 showed non-specific white matter ing microsmia or hyposmia during acute attacks and abnormalities. decreased olfactory sensitivity.7,8 However, a height- Past medical history of hyperlidemia and fibro- ened /olfactory hypersensitivity has also myalgia. Recent nuclear cardiac stress test negative. been described during both a migraine attack and Neurological examination was normal. between attacks in up to 46 and 35%, respectively.9–11 Questions. What is the diagnosis? How com- These patients tend to have greater frequency of mon is this disorder in adults and children? What , odor-induced migraines and visual hyper- might be the mechanism? How do you distinguish sensitivity. About 50% of migraineurs report that phantosmias due to migraine from other disorders? can also trigger their migraine attacks and olfac- What is the treatment? tory sometimes develop during What Is the Diagnosis?.—Case 1 presents with a migraine.9,12–15 There is suggestion of the role of the phantosmia of a dirty dog lasting 30 seconds to 1 and antero-superior temporal gyrus in hour with an average of 5 minutes sometimes fol- olfactory hypersensitivity in migraine, as well as dys- lowed by a migraine headache and often occurring function in central olfactory processing.8,16,17 without a headache. MRI of the brain and EEG The description of phantosmia in both cases were normal. meets the criteria of aura, 5–60 minutes, followed Case 2 presents with a 34 year history of by headache and is consistent with similar case migraine without aura and a 20 year history of a series and not consistent with as discussed burning smell lasting 15–120 minutes and rarely a below.18 Case 2 did have some episodes of phantos- menthol smell before a migraine headache. She mia lasting more than 1 hour which is not uncom- also reported occasional episodes of the burning mon for various migraine auras and phantosmia smell occurring without a headache. MRI of the (discussed below).19 Interestingly, the International brain showed only non-specific white matter abnor- Classification of Headache Disorders (ICHD) does malities. The frequency of the episodes of phantos- not yet recognize the presence of olfactory aura as mias significantly decreased after treatment of a migrainous aura.20 Headache 3

How Common Is This Disorder in Adults and interestingly found to predict the development of Children?.—Phantosmia has been found to occur in clinical at a 10-year reevaluation.33 Olfac- 6% of community dwelling adults and up to 12% in tory hallucination has also been described in a tertiary otolaryngology clinic.21,22 The majority depression (19–33%) and in up to 10% of non- had concomitant anosmia/hyposmia, and most demented Parkinson’s disease patients, though phantosmias presented with no history of upper prevalence is less (5%) in those without accompa- respiratory tract infection, head trauma or aging nying visual and .35,36 In tem- (idiopathic).1,4,22 A typical history begins in a wom- poral lobe epilepsy, estimated prevalence ranges an between the ages of 15–30 years old, who no- from 0.6 to 30%.35,37–40 A higher prevalence has tices odor perception that is not appreciated by been reported in those with and those others. Odors last 5–20 minutes each time and with decreased smell and acuity in up to resolve spontaneously. Recurrent episodes may 40–60% of patients.35 occur more frequently and may last longer subse- What Might Be the Mechanism?.—The mecha- quently. They may be perceived arising from one nism behind phantosmia has not been clearly eluci- or both nostrils, and resolve with sleep, Valsalva dated. Theories of abnormal peripheral as well as maneuver, or occlusion or instrumentation of the central mechanisms have been postulated.2,4,5 nostril.4 Proponents of the peripheral theory highlight The first case of olfactory hallucination in phantosmia being worse in the nostril with the migraine was described in 1982.12 The late Oliver poorer olfactory ability, the fact that phantosmia can Sacks also reported seeing several migraine patients be eliminated by occluding air flow and anesthetiz- with hallucinations of smell associated with forced ing the olfactory mucosa in the affected nostril. His- reminiscence and feelings of deja  vu.23 Since then, topathological studies also demonstrated decreased multiple case reports have highlighted this phenome- number of , greater ratio of immature to non with migraines.13,20,24–27 Estimated prevalence mature neurons and disordered growth of olfactory ranged from 0.1% in consecutive migraine patients to axons.41,42 A combination of peripheral hypersensi- 1% in a sample of 200 patients with vascular head- tivity, endogenous loss of inhibitory GABAergic ache attending a neurologic institute and up to 10.9% neurons, and possibly estrogen may play a role in in a headache clinic among consecutive female the pathogenesis of phantosmia.2,35 Ultimately, migraineurs, though high prevalence may be con- abnormal signals arise from primary olfactory neu- founded by depression.14,28,29 More recently, case rons, which then trigger a central process.4,41 series from a single headache center found a preva- Arguments for a central cause include a hyper- lence of 0.66% (14/2110 patients) in primary head- functioning central area which could generate odor ache disorders, including migraine (84.6%), cluster perception.4,41 Olfactoryaurathatsometimesaccom- headache (7.7%), new daily persistent headache pany in suggests a central origin as (2.6%), hemicrania continua (2.6%), and chronic well. These seizures typically arise from the mesial daily headache (2.6%).30 In pediatric primary head- temporal lobe, particularly the uncal region with the aches, 2.5% (21/839 patients) reported experiencing entorhinal cortex, and possibly the and phantosmias, all of whom had migraine.31 Among if unpleasant, and from the insular cor- migraineurs in children, 3.9% had phantosmia. tex if pleasant.40,43 The persistence of symptoms Olfactory hallucinations have also been despite excision of – similar to a described in patients with , schizoaf- “phantom limb” phenomenon – as well as functional fective disorder, and type 1, with imaging studies which demonstrated increased activity an estimated prevalence of 17.3–20, 22.8, and 8.1%, in the contralateral frontal, insular, and temporal respectively.32,33 This varies across countries from 3 region, which subsequently decreased after excision to 27%.34 Deviant olfactory experiences in an ini- of the olfactory epithelium, suggests involvement of tially nonpsychotic group of college students was central processes in phantosmia.4 Phantosmia is also 4 Month 2016

Table 1.—Comparison of Features of Phantosmias in Different Syndromes (Adapted From Ref. 30)

Duration Identifiability Source Insight Quality of Phantosmia

Migraine 5–60 min Usually precise Extrinsic 1 Unpleasant > pleasant Epilepsy Seconds to Usually vague Extrinsic 1 Unpleasant > pleasant minutes Depression Continuous Variable Intrinsic 2 Unpleasant Schizophrenia Variable Variable Extrinsic 2 Unpleasant

associated with severe depression, with speculation of interaction between the olfactory and the trigeminal abnormal functionality in the systems.46 The overlap of the neural circuits of the affecting olfactory processing, reduced grey-matter and trigeminovascular system volume in anterior insular, anterior cingulate cortex, involved in the pathogenesis of migraine suggests hippocampus, and left orbitofrontal cortex.44 migraine and trigeminal activation as one of the Phantosmia may also be accompanied by pri- causes of olfactory hallucination.31,47 Those with aura mary headache disorders similar to the typical aura and migraine usually exhibited both normal EEGs described in migraine with aura. In a case series and CT brain scans;48 however, migraine patients can and literature review of olfactory hallucinations in also exhibit paroxysmal EEG and other neuronal primary headache disorders, the authors described abnormalities suggesting an underlying neuronal com- the majority (64%) having olfactory hallucinations ponent in the generation of these symptoms.49–55 lasting 5–60 minutes that occurred before, during There may also be genetic influences at play with aura and within an hour of headache onset.30 A third of susceptibility genes in migraine, predisposing some patients had another aura fulfilling criteria for patients to having aura and some without.56 Another migraine with typical aura. Olfactory aura may proposed mechanism includes increased dopaminer- occur simultaneously or follow the visual aura prior gic periglomerular cells in olfactory bulbs as dopa- to or during the headache phase. Similarly, in mine may have a role in premonitory symptoms in Mainardi’s case series of 11 patients with olfactory migraines.57,58 aura, the majority of auras lasted less than 10 How Do You Distinguish Olfactory Hallucina- minutes (range 3 minutes to 24 hours) and occurred tions Due to Migraine From Hallucinations Due to before or with the onset of headache.45 Hence the Other Disorders?.—Olfactory hallucinations have authors proposed that it be classified as a distinct been described in psychotic disorders, depression, form of migraine aura as it fulfills most criteria of olfactory reference syndrome, epilepsy (temporal an aura. If so, the underlying electrophysiological lobe, uncinate, or orbitofrontal seizures), dementia, substrate of the aura of migraine is the phenome- Parkinson’s disease, drugs and non of cortical spreading depression which propa- states (including alcohol), migraines, aneurysms, gates through the deep temporal structures and and arterial-venous malformations, tumors, and orbitofrontal cortex and generates the olfactory head injury.2,4,33,57,59–71 Olfactory hallucination has symptoms as it spreads. This was also proposed by also been reported without a known cause, or with Morrison, who described similar symptoms with a remote history of sino-nasal disease.35 Features transient mood symptoms during migraine that distinguish olfactory hallucinations due to attacks.29 As odors tend to be recognizable, the migraine from hallucinations due to other disorders authors suggest possible involvement of the piri- are summarized in Table 1. form cortex, an olfactory association area.30 At the In psychotic disorders like schizophrenia, olfac- same time, there have been reports showing sites of tory hallucinations are rarely the dominant Headache 5 symptoms of the illness, and usually pales in com- Hallucinations tend to be perceived as extrinsic, high- parison to other forms of visual, auditory, or somat- ly specific in nature with odors being identifiable. Typ- ic hallucination and front rank symptoms of ically an unpleasant burning smell is noted by the schizophrenia.3,34,72 Hallucinations are typically per- patient.26,30,45 Other smells that have been described ceived as extrinsic in nature, ie, arising externally by patients include certain food smells, decomposi- and being caused or forced upon them by another tion, and chemical smells. Some may have more than person or agency.3,65 The perceived odors are odd 1 smell type or smells that evolved over time. Phan- in content, such as smells of holiness or of space tosmias can have sudden or gradual onset, last aliens, and usually do not result in patients attempt- minutes to hours, and tend to respond to migraine ing to remove the odor, though they may complain prophylaxis medications including non- to the police.72 Patients often retain insight into in addition to anticonvulsants.27,30,31,45 their symptoms.3 This is in contrast to olfactory ref- Some patients had concomitant typical visual and sen- erence syndrome (ORS), a non-psychotic disorder sory auras occurring simultaneously.31 Imaging and characterized by perceived dominant foul odors EEG were negative in these patients.30,45 Phantosmia arising from himself (intrinsic) and resulting in also occurred about a decade later than the mean overwhelming contrite response and attempts to rid onset of headache, 32–34 years compared to 18–21 themselves of the odor with excessive washing of years of age.30,45 hands, change of clothes, and resultant avoidance In epilepsy, olfactory hallucinations tend to be of other people.72 There may be associated second- crude and unrecognizable, unpleasant, and lasting ary low mood, though milder than in those with seconds to minutes instead.40,43,74,75 Olfactory aura depression. ORS may also be associated with may also be combined with other auras, in particu- depression, personality disorders, schizophrenia, lar sensation of epigastric rising, nausea and . hypochondriasis, alcohol and drug abuse, obsessive They are linked temporally with epileptic symp- compulsive disorder, body-dysmorphic disorder, toms, and are seldom in isolation.3,67 The majority brain damage, and dementia.3,73 Patients with ORS have a structural lesion in the mesial temporal tend to be young males, with referential ideas, and region.40 most do improve with neuroleptics, , In Parkinson’s disease patients, phantosmias and psychotherapy.73 In depression with olfactory were generally rare and infrequent (1–2 times/ hallucinations, there usually is associated retarda- month), lasting seconds to minutes and not fright- tion, depressed mood, and morbid thoughts.72 ening to the patient as they have good insight. There is a correlation between phantosmia and Most had associated hyposmia.36 degree of depression.44 Unlike those with depres- Lastly, there is a group of patients with olfacto- sion, ORS patients tend to be more self-critical.3 ry hallucination without clinical motor activity and Hence, origin of the hallucination, whether being no clear cause found.1,4,35 The phantosmia tends to extrinsic or intrinsic, its dominance with respect to be spontaneous, worse after coughing, laughing, other psychiatric symptoms, associated depression and shouting. They typically last 5 seconds to 20 or psychotic symptoms as well as the patient’s reac- minutes, are unpleasant (putrid/chemical) in nature tion to the hallucination may help to distinguish and episodes increase in intensity, duration, and between the different psychiatric disorders.3 frequency over time. Valsalva maneuvers, naps/ In primary headache disorders, the olfactory aura sleep as short as 20 minutes, nasal plugging, and is usually temporally related to the headache phase, topical tetrahydrocannabinol (THC) transiently with the headaches meeting criteria for migraine.30 relieves symptoms. However, a recent Italian case series of 11 patients What Is the Treatment?.—The presence of olfac- reported 2 patients who had olfactory aura without tory dysfunction is not without significant impact to the headache phase at times, presenting as an isolated the patient. A large study involving 750 Parkinson’s symptom akin to visual aura without migraine.45 disease patients with olfactory dysfunction showed 6 Month 2016 a high proportion reporting altered quality of life CONCLUSION (68%), changes in appetite or body weight (46%), Phantosmia is not an uncommon presentation and adverse influences on daily living or psychological of a neurological, psychiatry, or local ear, nose and well-being (56%).76 In the United Kingdom, British throat (ENT) cause. Though not commonly appre- sufferers of olfactory disorders suffer significant physi- ciated and highlighted, they cause considerable cal, social, psychological, and emotional impacts with impact on sufferers. These patient vignettes high- higher rates of weight gain, isolation, depression, light phantosmia as a rare aura in migraine and, to stress, and resignation to their disability.77 our knowledge, the third and fourth cases of phan- Treatment ranges from reassurance with no tosmia ever reported occurring without headache. active therapy and watchful waiting, to topical and It needs to be emphasized that while symptoms ful- systemic medications, anesthesia to parts of the nose fill criteria for migraine and that there are propo- and rarely surgical excision of olfactory neurons.4,5 nents of incorporating olfactory aura as a migraine Unfortunately, mixed outcomes in treatment have aura in the ICHD criteria, due diligence must be been reported, mostly in case reports and small taken to ensure that secondary causes are excluded, series of patients, highlighting lack of good evidence especially on initial presentation of onset in this on treatment options in this condition. age group. Patients who present with olfactory hal- Analgesics were not found to be helpful for lucinations need careful neurological and mental phantosmia in children, though sleep helped to state examination especially to exclude partial seiz- minimize or terminate it.31 Administration of topi- ures when the olfactory symptoms last seconds to cal nasal saline drops as needed in the head down minutes. Treatment options remain anecdotal, and forward (Mecca) position, oxymetazoline HCl, though prophylaxis for background migraine seems and topical HCl blocks air flow and anes- to be a good way to move forward if patients have thetizes the olfactory cleft with improvement in frequent or bothersome symptoms. symptoms.1,4 However, olfactory cocainization was shown to be an ineffective long-term solution for Acknowledgment: B.M.G. acknowledges the gener- phantosmia with resolution and improvement being ous support of Richard and Martha Byrne, who under- transient and unsustained and retreatment neces- wrote the preparation of this manuscript. sary in 2 weeks to 4 months.78 In primary headache disorders, greater than 75% responded with initiation of prophylaxis therapies for migraine.30,45 Medications used included topiramate, REFERENCES nortriptyline, amitriptyline, flunarizine, propranolol, 1. Zilstorff K. Parosmia. 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