Olfactory Sarcoidosis Report of

Five Cases and Review of the Literature

Peyton Delaney, MD; Robert

I.

Henkin, MD; Herbert Manz, MD;

\s=b\ Changes in the olfactory system in five patients with sarcoidosis were studied by clinical and histopathological examination. Every patient studied had hypogeusia and/or hyposmia as measured by psychophysical testing. In two patients who died with this disease, the olfactory bulbs and tracts were involved by granulomatous infiltration. Two other patients showed granulomas and chronic inflammation in nasal biopsy specimens. The fifth patient was studied only clinically. Changes in olfactory and gustatory acuity are rarely searched for in patients with sarcoidosis, but they may be important indicators of major and later irreversible damage to the CNS. If diminished olfaction is established in suspect patients, nasal biopsy and examination of the CNS should be performed to confirm the presence of active sarcoidosis. Appropriate therapy may prevent damage to the patient's sensory capabilities and CNS function.

(Arch Otolaryngol 103:717-724, 1977)

Accepted

publication May 5, 1977. Departments of Neurology (Dr Delaney), Pathology (Drs Manz and Bauer), and Otorhinolaryngology (Dr Satterly), and the Center for

From the

for Molecular Nutrition and

Sensory Disorders (Dr Henkin), Georgetown University Medical

Center, Washington, DC. Reprint requests to Center for Molecular Nutrition and Sensory Disorders 3800 Reservoir Rd NW, Washington, DC 20007 (Dr Henkin).

R. Alan

Satterly, MD;

dysfunction Olfactory plaint hypothyroidism,

is a com¬ observed in many disease states.1" In more than half of the patients in one study were aware of altered olfactory func¬ tion,2 and in untreated adrenal corti¬ cal insufficiency, patients show de¬ creases in olfactory detection thresh¬ olds." Olfactory dysfunction in patients with sarcoidosis is rare since only nine cases have been reported.7~" Morphological descriptions of the ol¬ factory tracts are even rarer since only two cases have been reported.1213 However, on the basis of recent reports in the literature, intranasal lesions are not uncommon in patients with sarcoidosis.14 Although no refer¬ ence to changes in olfactory function was made by these latter authors, the nasal lesions of sarcoidosis may bear some relationship to the concomitant olfactory abnormalities. In our studies in patients with sarcoidosis, olfactory dysfunction is a common complaint and is often an early symptom of the disease. The purpose of this report is to present five cases of sarcoidosis with olfactory involvement. Three patients had hyposmia as the initial complaint of their disease. In one of the five patients, the typical granulomatous lesions of sarcoidosis were seen in the nasal mucosa. In two other cases, autopsy showed sarcoid granulomas in the olfactory bulbs and tracts and

Heinz Bauer, MD

other parts of the CNS. The fourth patient had nonspecific nasal inflam¬ mation and in the fifth, biopsy spec¬ imens of the nasal mucosa were not obtained. An attempt will be made to correlate the pathological aspects and CNS lesions with symptoms and other clinical data. MATERIALS AND METHODS Measurements of taste" and smell"1 have been previously described in detail. Briefly, subjective changes in taste and smell were evaluated in each patient by a standard set of questions. Changes in taste acuity were determined quantita¬ tively by measurement of detection and recognition thresholds for representatives of four taste qualities (sodium chloride for salt, sucrose for sweet, hydrochloric acid for sour, and urea for bitter) by a threestimulus, forced-choice drop technique.15 Forced scaling measurements were also obtained for each taste quality, and the responses were used to represent patterns of each quality tested.15 By these techniques, the entire range of taste responses for each taste quality was tested. To obtain one number to represent the entire scaling process, all appropriate taste responses at and greater than the upper limit of the normal recognition threshold for each tastant were summed and the mean value obtained. Olfactory acuity was determined quantitatively by measure¬ ments of detection and recognition thresh¬ olds for several vapors including pyridine, nitrobenzene, thiophene, amyl acetate, and camphor, by a three-stimulus forced-choice

acuity

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sniff

technique." Forced scaling

measure¬

obtained for all vapors at and greater than the upper level of normal recognition for each vapor tested in a manner similar to that previously carried out for tastante. As for taste, to represent the entire scaling process with one number, all appropriate smell responses at and greater than the upper limit of the normal recognition for each odorant were summed and the mean value obtained. Biopsy of the nasal mucous membrane was carried out by a technique previously described1 in an area that normally contains both squamous and respiratory epithelium. Biopsy specimens, taken from the same anatomical site in each patient, were obtained with a 3-mm punch followed by careful excision with fine iris scissors. Specimens were placed in buffered 10% formaldehyde solution for examination by light microscopy. Tissues were fixed, embedded, and sectioned in a uniform ments

were

manner.

REPORT OF CASES Four patients with biopsy-proved sarcoi¬ dosis were studied at Georgetown (Wash¬

ington, DC) University Hospital (GUH) during 1969-1976 (cases 1 to 3, and 5) and one at Kingston General Hospital during 1968-1969 (case 4). Case 1.—A 28-year-old asymptomatic black woman had a routine roentgenogram of the chest in April 1974 that showed bilateral hilar adenopathy. A left axillary lymph node biopsy done at that time was consistent with sarcoidosis and no treat¬ ment was instituted. In June 1975, cuta¬ neous nodules of the lips developed from which biopsy specimens showed sarcoid granulomas. Bilateral cervical adenopathy was also noted at that time. Simulta¬ neously, she also complained of dyspnea and nasal stuffiness that persisted until March 1976 when an otolaryngological examination revealed probable sinus, nasal mucosal, and laryngeal involvement by sarcoidosis. She was referred to GUH in May 1976 for further evaluation. Results of physical examination at that time showed several 1- to 2-mm papular lesions of the lips as well as cervical, axillary, and inguinal adenopathy. The neurological ex¬ amination was normal except olfactory testing revealed a quantitative decrease in the ability to detect or recognize vapors at the primary olfactory area (type II hypos¬ mia).1" " Serum calcium level was normal, and lactic dehydrogenase, SGPT, and alka¬ line phosphatase levels were mildly ele¬ vated. A liver scan showed hepatomegaly. Anergy was demonstrated by skin testing, and a Kveim test was positive. Results of ophthalmological examination revealed no

abnormalities. Pulmonary function tests showed a restrictive pattern. Otolaryngological examination showed a pale nasal mucosa with a cobblestone pattern that on biopsy revealed granulomas and giant cells that had partially replaced the mucosal glands (Fig 1). By direct laryngoscopy, the polypoid lesion on the left arytenoid carti¬ lage also underwent biopsy and similar histological findings were observed. The patient was started on therapy with steroids, but follow-up is not yet avail¬ able. Case 2.-In July 1970, an 18-year-old black woman noted the gradual onset of a painless swelling below her right ear that was accompanied by decreased acuity of both taste and smell. These symptoms progressed for two weeks and were asso¬ ciated with right facial numbness. On admission to GUH, physical examination showed a swollen right parotid gland, type II hyposmia,'"1T hypesthesia of the right trigeminal nerve (division II), no facial paresis, and normal motor, sensory, and cerebellar function. A roentgenogram of the chest showed bilateral hilar adenop¬ athy and an EEG showed diffuse slowing. Findings for the following were normal: brain scan, skull roentgenograms, and CSF. Detailed otolaryngological examina¬ tion was unremarkable except for the swollen right parotid gland. A nasal biopsy specimen showed only chronic inflamma¬ tion and squamous metaplasia of the mucosal lining. While hospitalized, bilat¬ eral granulomatous uveitis developed that responded well to steroids as did the facial numbness, but the hyposmia persisted. After discontinuing steroid therapy for two weeks in October 1970, a right facial paresis developed that resolved with resumption of the medication. In Novem¬ ber 1971, the patient still had hyposmia and has since been lost to follow-up. Case 3.—A 42-year-old black woman first noted in July 1973 a decreased ability to smell, complained that all food tasted like sawdust, and stated that the addition of vinegar did not give food its expected sour taste. In 1974, the patient noted a gradual return in her ability to taste, but the hyposmia persisted. She experienced two household episodes of stove gas escaping without being able to smell it; on one of these occasions, a minor explosion resulted. The patient's family related that she unknowingly served spoiled food to them on several occasions. In January 1974, she began to experience difficulty with walk¬ ing that progressed to ataxia in October 1974. On admission to GUH, neurological examination revealed an inability to detect or recognize vapors at the primary olfac¬ tory area (type I hyposmia),1617 hypes-

thesia of the left trigeminal nerve (divi¬ sions I and II), and a mild right hemipare¬ sis. Mental status and cerebellar function were normal. A chest roentgenogram showed hilar adenopathy; serum calcium level was 11.5 mg/100 ml (normal, 8.5 to 10.5 mg/100 ml) and anergy was demon¬ strated by skin testing. Findings for the following were normal: skull roentgeno¬ grams, brain scan, EEG, and CSF. A computerized tomographic scan showed mild hydrocephalus without atrophy or mass lesion. Pulmonary function tests showed a restrictive pattern, and mediastinoscopy with lymph node biopsy showed noncaseating granulomas. A diagnosis of sarcoidosis with arachnoiditis was made and the patient was treated with steroids. Follow-up showed improvement in pulmo¬ nary function but no change in CNS involvement. In July 1975, the patient's neurological examination revealed moder¬ ate dementia with frontal lobe signs. Find¬ ings for the following were normal: serum calcium level, brain scan, and EEG. The CSF protein level was 86 mg/100 ml. A cerebral arteriogram showed occlusion of the distal branches of the left middle cere¬ bral artery that was in keeping with the right hemiparesis. Cisternography demon¬ strated communicating hydrocephalus; however, the patient refused a shunt proce¬ dure. The patient was continued on steroid therapy but has responded poorly. Case 4.—A 22-year-old white man had been in good health except for "viral" meningitis in 1964. In October 1967, he noted progressive weight gain accompa¬ nied by diplopia and episodic vomiting. Skull roentgenograms and brain scan were normal while an EEG was abnormal. In March 1968, he complained of vertigo and an unsteady gait. Neurological examina¬ tion showed normal mentation and normal cranial nerves (no mention was made of olfactory testing). He had papilledema, generalized hyporeflexia, and a left Babinski sign. A chest roentgenogram as well as findings for sedimentation rate and serum calcium levels were normal. Skull roentgenograms showed erosion of the sella turcica. Brain scan showed a right

temporal

mass.

Electroencephalogram

re¬

vealed evidence of a deep midline lesion. Cerebrospinal fluid was xanthochromic with a protein level of 233 mg/100 ml, 30 lymphocytes, and negative cultures. Pneumoencephalogram showed communicating hydrocephalus. Findings from the follow¬ ing showed no abnormalities: cerebral arteriogram, myeloscintigram, and endocrinological studies. The patient began to demonstrate fluctuations in mentation, yet notable neurological improvement was observed with steroid therapy.

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Fig 1.—Case 1: Nasal biopsy specimen showing granuloma with typical centrally located multinucleated giant cell (arrow), residual glands, and mild chronic inflammation beneath meta¬ plastic squamous surface epithelium (hematoxylin-eosin, original magnification 225).

Fig 2.—Case 4: Basal view of brain depicting opaque, granular leptomeninges surrounding and covering olfactory tracts and bulbs (arrows), optic nerves and chiasm (arrowhead), and base of pons. Infundibular stalk is considerably enlarged (double arrow) due to granulomatous infiltration ( 1.2).

Fig 3.—Case 4: Active granuloma with

abundant epitheloid cells, lymphocytes, and giant anterior surface of inferior olive of medulla oblongata. There is also notable astroglial fiber formation and astrocytosis (left lower corner), and demyelination of axons

cells

on

(luxol-fast blue, hematoxylin-eosin, original magnification

100).

Fig 4—Case 5: Olfactory tract (bottom), subarachnoid space, and adjacent gyrus rectus (left upper corner). Degree of myelination in olfactory tract is reduced and there are numerous reactive astrocytes as well as considerably thickened layer of glial fibers bounding tract (arrows). Gyrus rectus shows chronic inflammatory focus composed predominantly of lymphocytes, and adjacent leptomeninges are fibrotic (luxol-fast blue, hematoxylin-eosin, original magnification 100).

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In July 1968, polydipsia and polyuria developed. Neurological findings at that

time were similar to those in March except for the presence of Horner's syndrome on the left side. Cerebrospinal fluid showed an elevated opening pressure, a protein level of 338 mg/100 ml, 21 lymphocytes, and a glucose level of 15 mg/100 ml; cultures were negative again. A brain scan revealed uptake in the region of the thalami. A brain biopsy specimen showed thickened meninges with a mononuclear cell infil¬ trate. A cervical lymph node biopsy spec¬ imen showed noncaseating granulomas and the Kveim test was reactive. In addi¬ tion to steroids, vasopressin injection (Pitressin) was administered that alle¬ viated the diabetes insipidus. However, the patient deteriorated over the next six months with development of diminished vision, dementia, ataxia, and quadriparesis with bilateral Babinski signs. A ventriculoatrial shunt was performed to control hydrocephalus. Subsequently, intermittent fever, fluctuations in sensorium, and seizures characterized the patient's wors¬ ening course and he died in March 1969 of aspiration pneumonia. Autopsy showed disseminated sarcoidosis. The basal me¬

ninges were thickened, notably granular, and adhering to all exiting cranial nerves (Fig 2). Granulomatous infiltration was prominent in the hypothalamus, the brain stem (Fig 3), and the pituitary gland and was also present in the ependyma, choroid

Patient 1

¡trobenzene

1/00 p/00 Normal

IO-71O-3:

^/ -1

(65) (1) (0) (0) (69±5)

Examination showed with a temperature of 33.8 C. Except for previously noted blind¬ ness, the cranial nerves were normal. Olfactory function could not be tested because of the patient's stupor. She had a left Babinski sign. Values for the following were normal: admission red and white blood cell count, glucose, BUN, electrolytes, calcium, and magnesium. Serum anticonvulsant levels were not elevated. Arterial blood gases showed mild carbon dioxide retention. Cerebrospinal fluid was xanthochromic with an opening pressure of 240 mm H20, a protein level of 635 mg/100 ml, a glucose level of 20 mg/100 ml (blood glucose of 70 mg/100 ml), and no cells; cultures were negative. Roentgenogram of the chest, ECG, brain scan, and computer¬ ized tomographic scan of the head were normal. Hypothyroidism was documented by mildly depressed T3 and T4 levels, but it was thought that myxedema was not the cause of the patient's stupor. Increasing the dosage of steroids and using hyperthermic blankets restored the patient's normal sensorium and activities. At this point, the clinical picture was believed to be due to hypothalamic involvement by sarcoidosis. The steroid treatments were tapered and follow-up showed the patient to be stable. a

-1/-1 00/00 00/00

lu-VIO"2

(55) (1) (0) (0) (55 ±6)

P/P 00/00 00/00

IO-71O-3

woman

Camphor

Amyl Acetate

Thiophene 10"3/10-2

stuporous

Olfactory Sarcoidosis Moles/Liter

Moles/Liter

Moles/Liter

Moles/Liter

10-7101 P/P

increasing lethargy.

ulomatous uveitis was found. A roentgeno¬ gram of the chest showed hilar adenopa¬ thy, and a scalene lymph node biopsy spec¬ imen showed noncaseating granulomas. She was treated with both topical steroids and steroids for systemic effect, yet she nevertheless gradually became blind. In 1972, grand mal seizures developed and the patient was admitted to GUH. Neurolog¬ ical examination at that time showed only transient postictal left hemiparesis. An EEG showed nonfocal sharp and spike activity. Cerebrospinal fluid revealed a protein level of 280 mg/100 ml, 30 lympho¬ cytes, and a glucose level of 30 mg/100 ml; cultures for bacteria, fungi, and acid-fast bacilli were negative. The patient was treated with another course of steroids and anticonvulsants with good control of seizures. Because of polydipsia and poly-

Table 1 .—Olfactory Acuity in Four Patients With Pyridine

uria, she was extensively evaluated with no evidence of diabetes insipidus being found. She remained stable until February 1975 when she again came to GUH with

plexi, optic chiasm, oculomotor nerves, Gasserian ganglia, auditory nerves, and olfactory bulbs and tracts. The spinal cord as well as the dorsal root ganglia and the cauda equina were diffusely entrapped by granulomas and leptomeningeal fibrosis. Peripheral nerves and skeletal muscle were not involved, but the lungs, lymph nodes from multiple sites, and the lacrimal glands showed active granulomas. Special stains for mycobacteria and fungi failed to demonstrate any microorganisms. Case 5.-In 1969, a 30-year-old black noted the gradual onset of woman decreased vision, and on examination gran¬

(69) (1) (0) (0) (71 ±6)

10V10-2 P/°°§

(49) (0) (0) (0) (58 ±6)

00/00 00/00

lO-VlO"3

Moles/Liter (51) P/P P/°o (0) oc/00 (0) 00/00 (0) P/P# (52 ±6)

Numerator of fraction, detection threshold, in moles per liter; denominator, recognition threshold, in moles per liter. t The values in parentheses indicate mean forced scaling response, in percent; the number following the mean forced scaling determined in 31 normal subjects. indicates ability to detect or recognize only absolute, neat, undiluted solution. § 00 indicates inability to detect or recognize an absolute, neat, undiluted solution. I Median detection/ recognition threshold. # Only an undiluted sample was used. "

response is 1 SEM

Table 2.—Taste Acuity in Four Patients With Olfactory Sarcoidosis Sodium Chloride

Patient

Normal

Moles/Liter 60/60* 12/30 60/60 300/500

12/30

(72)t (68) (62) (24) (68 ±4)

Sucrose

Moles/Liter 12/30 60/60 30/30 60/60 12/30

Hydrochloric Acid (87) (55) (63) (72)

(62±4)

Moles/Liter 6/6 3/3 6/500 3/3 3/3

%

(77) (65) (12) (54) (66 ±4)

Urea

Moles/Liter 120/120 90/90 300/300 120/500 120/150

(79) (75) (34) (40) (68 ±4)

Numerator of fraction, detection threshold, in mmoles per liter; denominator, recognition threshold, in mmoles per liter, t Values in parentheses indicate mean forced scaling response, in percent; the number following the mean forced scaling response is 1 SEM determined in 28 normal patients, Median detection/recognition threshold. "

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Because of persistent cellulitis of the feet, she was readmitted to GUH in October 1975 for parenteral antibiotic therapy. The patient failed to respond satisfactorily and a sacral decubitus ulcer developed from which atypical mycobacteria were isolated. At this time, her complaints of decreased olfactory acuity were first noted by the attending physicians. A detailed evalua¬ tion was performed that revealed hypos¬ mia, which by history had begun in 1969 at the time she first noted changes in visual acuity; she also had noted the onset of dysgeusia and stated that food tasted stale or peculiar. This symptom had persisted through the present time. She had no dysosmia, but in 1973 the patient experi¬ enced one episode of phantosmia of a "burning rag" type that persisted for months and spontaneously disappeared never to return again. A nasal biopsy spec¬ imen showed mild chronic inflammation, considerable fibrosis, squamous metapla¬ sia, and loss of submucosal glands. The patient continued to do poorly and died suddenly without obvious cause. Autopsy revealed a granulomatous basal meningitis with obsolescent granulomas infiltrating the olfactory bulbs and tracts; the astrocytic reaction was brisk and corpora amylacea were abundant (Fig 4). Old, inac¬ tive granulomas were present in the lungs and lymph nodes. Special stains for myco¬ bacteria and fungi failed to demonstrate them, but acid-fast bacilli were readily seen in the decubitus ulcer.

STUDIES OF SMELL AND TASTE

Olfactory acuity in each patient with sarcoidosis studied was impaired for the detection of nitrobenzene and thiophene and for the recognition of pyridine and nitrobenzene as given in Table 1. Two of the patients (cases 3 and 5) had type I hyposmia (inability to detect or recognize vapors at the primary olfactory area).1617 The other two patients (cases 1 and 2) had type II hyposmia (quantitative decrease in ability to detect or recognize vapors at the primary olfactory area)."117 Scal¬ ing values for the patients with type II hyposmia were within normal limits in case 1 but were significantly below normal (P < .001) in case 2; these values in the patients with type I hyposmia were, by definition, zero. Taste acuity in two of the patients with sarcoidosis (cases 3 and 5) was impaired although it was within normal limits in the other patients

(cases 1 and 2), as given in Table 2. In each of the

detection and thresholds and scaling recognition values for sucrose were within normal limits as were detection thresholds for hydrochloric acid. In case 5, detection and recognition thresholds and scaling values for sodium chloride were elevated above normal as was urea recognition and scaling; in case 3, hydrochloric acid recognition thresh¬ old and scaling values, and urea detec¬ tion and recognition threshold and scaling values were elevated above normal.

patients,

COMMENT

The frequency of olfactory abnor¬ malities in sarcoidosis is not estab¬ lished and its relationship to patholog¬ ical changes is unclear. The frequency of reported decreased olfactory acuity (nine of 635 cases) is 1.4%.10111318 In each of our patients in whom olfactory function was tested, olfactory abnor¬ malities were found. The rarity of this finding in cases reported by others probably reflects their failure to obtain a history and perform exami¬ nations of olfactory function. The frequency in our series is 100% if one considers only the patients tested. However, since only four of 78 patients with sarcoidosis seen at GUH during 1969-1976 had detailed olfac¬ tory evaluations, our data do not allow definitive conclusions to be drawn

concerning frequency. Table 3 gives a summary of the 11 reported cases of olfactory involve¬ ment in sarcoidosis. Ten (91%) were female. Nine of the patients (82%)

between the ages of 20 and 40 years, the average age being 33 years (range, 17 to 58 years). Nine (82%) had were

the

recognized stigmata of sarcoido¬ sis, including hilar adenopathy, hyper¬ calcemia, anergy, uveitis, or reactive Kveim tests. "Anosmia" was reported in nine (82%) of the 11 patients described in the literature, and de¬ creased olfactory acuity (hyposmia) was a complaint in three of four patients we studied. No olfactory

manifestations were mentioned in the patients in the two cases from the literature who had granulomas in the olfactory tract. In only one previously reported patient was decreased olfac-

tory acuity the presenting complaint.

Concomitantly, other cranial nerves were involved, including the facial (73%) and optic (55%) nerves. Other neurological manifestations were less frequent. Diabetes insipidus was pres¬ ent in four

cases

(36%). Results of

therapy were variable, yet all patients treated with steroids improved. Only one individual with proved olfactory dysfunction died. Although the age, sex, olfactory abnormalities, stigmata of sarcoido¬ sis, and associated cranial nerve

involvement in our series were similar to the previously reported cases, they differed in two respects. First, de¬ creased olfactory acuity was the pre¬ senting symptom in three of four patients tested, and second, no im¬ provement in olfactory acuity has been seen with steroid therapy thus far. This latter aspect was limited by the brief time of observation, since one patient died soon after olfactory evaluation was made, two patients were lost to follow-up, and one has not had an adequate period of therapy to date. No clinical feature distinguished the steroid-responsive patients de¬ scribed by others from the nonrespon¬ sive cases in our series. The frequent occurrence of basal meningitis in sarcoidosis is well recog¬ nized.1" This predilection often results in compression and infiltration of various components of the CNS. Of special interest are the observations of Lenartowicz and Rothfeld12 and Longcope and Freiman" who each reported a case of basal sarcoid meningitis with olfactory bulb and tract infiltration by granulomas. Two of our cases (4 and 5) that came to autopsy, also had basal meningitis, with involvement of the olfactory bulbs and tracts that were atrophie and covered by thickened meninges

(Fig 2). Microscopically, granulomatous in¬ filtration and demyelination were seen (Fig 4). Apart from the granu¬ lomatous or nonspecific chronic in¬ flammatory reaction in these two cases, the demyelination, gliosis, and deposition of corpora amylacea were qualitatively similar to the senile changes described by Liss and Gom¬ ez.20 However, our patients ranged in

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Table 3.—Olfactory Sarcoidosis Decreased

Reference,

yr

Lenartowicz and

Rothfeld,121930

Age/Sex 17/F

Stigmata

Olfactory

Abnormalities None mentioned

of

Sarcoidosis*

Smell

as

Presenting Complaint

Neurological

Manifestations

Seizures, papilledema, R hemiparesis,

L,

No

bilateral Babinski signs, enlarged sella turcica L facial palsy, deafness, ataxia diabetes insipidus, oral

Levin,7 1935

28/M

Thompson,81937

28/F

Bilateral "anosmia"

No

Lesneetal,91938

23/F

Bilateral "anosmia"

No

Longcope and Freiman,131952

31/F

None mentioned

Pupillary abnormalities, facial diplegia, ageusia Seizures, optic atrophy bilateral, diabetes insipidus

Matthews,10 1965

35/F

"Anosmia"

No

All cranial

25/F

"Anosmia"

No

58/F

"Anosmia" on R

No

37/F

Bilateral "anosmia"

No

Personality changes R facial paresis, bulbar palsy, granulomas in muscle biopsy specimen Unilateral facial paresis

51/F

"Anosmia"

No

Bilateral

on

hyposmia on

Wiederholt and

Siekert,11

"Anosmia"

R

paresthesias Papilledema, L facial palsy, bulbar paresis, CSF pleocytosis

nerves

involved except III, IV, and VI, paresthesias Optic neuritis, facial diplegia, bulbar palsies, ataxia

1965 on

L

optic pallor and

Babinski signs, diabetes insipidus, anterior pituitary

insufficiency 28/F

Bilateral "anosmia"

Yes

Facial paresis, bilateral deafness, ataxia, diabetes insipidus, granulomata in muscle

28/F

Hyposmia type II

No

None

18/F

Hyposmia type II

Yes

42/F

Hyposmia type I

Yes

Dysgeusia, R facial paresis, R trigeminal hypesthesia, abnormal electroencephalogram Dementia, L trigeminal hypesthesia, R hemiparesis, hydrocephalus, elevated CSF protein

22/F

None mentioned

biopsy specimen Present series, 1976

level

Dementia, seizures, chronic meningitis with CSF

hypoglycorrhachia, quadriparesisand Babinski signs, papilledema, hydrocephalus, diabetes insipidus 30/F

Hyposmia, type dysosmia,

Seizures, chronic meningitis with CSF

I

hypoglycorrhachia,

cacosmia,

Babinski signs,

phantosmia *

Stigmata of sarcoidosis: hilar adenopathy, hypercalcemia, anergy,

tND indicates not done.

hypothermia, diabetes insipidus or

reactive Kveimtest,

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age from 18 to 42 years. Mechanical

Nasal

Biopsy NDt

Therapy None

Course

Died2yr

after onset

Autopsy Granulomata in R olfactory bulb and tract, and gyrus

rectus

ND

ND

Vasopressin injection

Diabetes insipidus

Antisyphilitic

All deficits

None

Gradual

improved

resolved except anosmia and

papilledema ND

improvement

over

ND

Unknown

1 yr

Died2yr

after onset

Granulomata in nasal cavities and olfactory tracts

ND

Steroids

AM deficits

resolved except VII

ND

ND

Steroids

Steroids

paresis Improved

ND

Surgery

Died

Granulomata in

hypothalamus, pituitary gland optic nerve, andchiasm

ND

Steroids

Improved

Granulomata, giant cells

Steroids

Undetermined as

Chronic inflammation

Steroids

All deficits

ND

Steroids

yet

improved except hyposmia Poor response,

disease

progressive

ND

Steroids, rasopressin injection,

anticonvulsants

Transient

improvement, but disease

progressed and

Granulomata in

olfactory

bulbs and

tracts

patient died

Chronic inflammation

Steroids,

anticonvulsants

Initially improved, but disease

progressed and patient died

only a residual inflammatory response was no longer granulomatous in nature. Biopsy specimens from the

that

nasal

recovery except for unilateral facial paresis All deficits resolved except unilateral facial

None

The nasal mucosa is another site at which sarcoidosis causes lesions.14 In one of our patients (case 1), the involvement was typically granuloma¬ tous. Nonspecific chronic inflamma¬ tion and fibrosis were noted in biopsy specimens from two other patients (cases 2 and 5) who had been treated with steroids. These patients may have had granulomas before treat¬ ment, with the biopsy specimens taken after steroid therapy showing

mucosa

demonstrated loss of

glands that may be casually related to

Complete

ND

compression by fibrotic leptome¬ ninges and infiltration by granulomas strongly implicate damage to the olfactory tract as the cause of olfac¬ tory dysfunction in sarcoidosis.

Granulomata in

olfactory

bulbs and

tracts

the observed symptoms of nasal stuf¬ finess, dryness, and hyposmia. Since nasal olfactory function is dependent on the presence of an effective mucous layer covering the olfactory epithelium, the finding of a decreased nasal mucous production may repre¬ sent an important pathogenic factor in the production of hyposmia in this disease. In addition, the changes in the nasal mucous membrane in sarcoidosis in¬ clude granulomatous infiltration of the mucous membrane and glands. These changes were observed in the lacrimal glands of case 4 and were associated with decreased tearing. These changes are similar to the gran¬ ulomatous replacement of mucous glands in Sjògren's syndrome in which both xerorhinia and xerophthalmia are commonly associated with hypos¬ mia and decreased tearing, respec¬

tively.4

The results of

our

studies suggest

that, in addition to olfactory tract involvement, olfactory dysfunction may be related, at least in part, to the

nasal mucosal sarcoidosis. As noted in previous studies,14 large lesions in the nasal airway can cause physical obstruction to the passage of vapors to the olfactory epithelium, thereby causing hyposmia. In addition experi¬ mental destruction of the nasal muco¬ sa in rats has resulted in secondary

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degenerative changes in the olfactory tract21 that would be consistent with

the production of hyposmia on the basis of CNS changes. Nasal biopsies were not performed in any of the reported cases from the literature (Table 3). Nasal mucous membrane biopsy is a safe and relatively simple method for studying a variety of diseases involving the nose. One of us (R.H.) has performed more than 500 biopsies without any major complica¬ tion. Biopsy may be useful not only for

detecting

the nasal lesions of sarcoi¬ dosis that may contribute to olfactory impairment, but also for following the results of therapy by serial sam¬

pling.

An olfactory history should be taken in all patients with sarcoidosis. If any dysfunction is discovered, it should be regarded as a sign of possible nasal or brain involvement. Neurological and CSF studies as well as a nasal biopsy may help to identify disease at these sites in an early stage

before scarring from basal meningitis and granulomatous inflammation in the nose have caused irreversible damage to the mucosa, olfactory bulbs, or to intracranial structures. Disorders of smell and taste in patients with sarcoidosis may, there¬ fore, be another indication for steroid therapy, even in the otherwise rela¬

tively asymptomatic patient.

Drs Z. E. Deeb and A. G. DiBiasio provided assistance during the course of this study.

References 1. Henkin RI, Larson AL, Powell RD: Hypogeusia, dysgeusia, hyposmia and dysosmia following influenza-like infection. Ann Otol Rhinol Laryngol 84:672-682, 1975. 2. McConnell RJ, Menendez CE, Smith FR, et al: Defects of taste and smell in patients with hypothyroidism. Am J Med 59:354-364, 1975. 3. Powell RD, Larson AL, Henkin RI: Nasal mucous membrane biopsy in Sj\l=o"\gren'ssyndrome: A new diagnostic technique. Ann Intern Med 81:25-31, 1974. 4. Henkin RI, Talal N, Larson AL, et al: Abnormalities of taste and smell in Sj\l=o"\gren's syndrome. Ann Intern Med 76:375-383, 1972. 5. Henkin RI, Smith FR: Hyposmia in acute viral hepatitis. Lancet 1:823-826, 1971. 6. Henkin RI, Bartter FC: Studies on olfactory thresholds in normal man and in patients with adrenal cortical insufficiency: The role of adrenal cortical steroids and of serum sodium concentration. J Clin Invest 45:1631-1639, 1966. 7. Levin PM: The neurological aspects of uveoparotid fever. J Nerv Ment Dis 81:176-191, 1935. 8. Thompson WC: Uveoparotitis. Arch Intern

Med 59:646-659, 1937. 9. Lesn\l=e'\F, Coutela, Levesque J: Syndrome de Heerfordt, forme particuliere de la "maladie" de Besnier-Boeck-Schaumann. Bull Soc Med Hop Paris 54:9-15, 1938. 10. Matthews WB: Sarcoidosis of the nervous system. J Neurol Neurosurg Psychiatry 28:23-29, 1965. 11. Wiederholt WC, Siekert RG: Neurological manifestations of sarcoidosis. Neurology (Minneap) 15:1147-1154, 1965. 12. Lenartowicz J, Rothfeld J: Ein fall von hautsarkoiden (Darrier-Roussy) mit identischen veranderungen im gehirn und den inneren organen. Arch Dermatol Syphilis (Berl) 161:504\x=req-\ 519, 1930. 13. Longcope WT, Freiman DG: A study of sarcoidosis: Based on a combined investigation of 160 cases including 30 autopsies from the Johns Hopkins Hospital and Massachusettes General Hospital. Medicine 31:1-132, 1952. 14. Gordon WW, Cohn AM, Greenberg SD, et al: Nasal sarcoidosis. Arch Otolaryngol 102:11-14, 1976. 15. Henkin RI, Schecter PJ, Hoye RC, et al:

Idiopathic hypogeusia with dysgeusia, hyposmia dysosmia: A new syndrome. JAMA 217:434\x=req-\ 440, 1971. 16. Marshall JR, Henkin RI: Olfactory acuity, and

menstrual abnormalities and oocyte status. Ann Intern Med 75:207-211, 1971. 17. Henkin RI: The definition of primary and accessory areas of olfaction as the basis for a classification of decreased olfactory acuity, in Hayashi T (ed): Olfaction and Taste II. London, Pergamon Press, 1967, pp 235-252. 18. Colover J: Sarcoidosis with involvement of the nervous system. Brain 71:451-475, 1948. 19. Aszkanazy CL: Sarcoidosis of the central nervous system. J Neuropathol Exp Neurol 11:392-400, 1952. 20. Liss L, Gomez F: The nature of senile changes of the human olfactory bulb and tract. Arch Otolaryngol 67:167-171, 1958. 21. Meurman OH: Experimental studies of the effect of pathological changes in the nasal mucous membrane on the olfactory bulb. Acta Otolaryngol 38:477-483, 1950.

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Olfactory Sarcoidosis Report of Five Cases and Review of the Literature Peyton Delaney, MD; Robert I. Henkin, MD; Herbert Manz, MD; \s=b\ Changes...
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