2.1

Patients

Nineteen patients, aged 8–57 years (25 ± 3, SEM), five men and 14 women with Type II congenital hyposmia were studied. These were each of the patients with Type II congenital hyposmia evaluated at The Taste and Smell Clinic in Washington, DC between 1997 and 2014 treated with oral theophylline. All studies were approved by the institutional review board of the Georgetown University Medical School in Washington, DC and by the Chesapeake Institute Review Board in Columbia, MD.

No patient had any family history of smell loss. All reported they never could smell any external odor although some reported that some noxious odors irritated their nose or eyes. No patient had any history of nasal or systemic disease, head injury or any pathology which contributed to their smell loss. Each patient was the result of a normal pregnancy and delivery and normal developmental milestones. Loss of smell function was usually a gradual discovery, usually around age 9–12 years, after noting others being able to perceive and respond to the presence and character of external odors but they could not. Telling parents about this loss was successful in some patients being evaluated by their pediatricians but usually without significant understanding of either the cause of the loss or any treatment for the condition. With persistence of this symptom and with use of the internet and other means some patients were evaluated by otolaryngologists and referred to The Taste and Smell Clinic in Washington, DC.

Patients were evaluated at The Taste and Smell Clinic by use of an extensive history, physical examination of their head and neck, measurements of both subjective and systematic studies of smell (olfactometry) and taste [gustometry (results not shown)], studies of their blood, urine, saliva and nasal mucus and radiological studies of the brain.

2.2

Clinical studies of head and neck

All studies of head and neck including anterior rhinoscopy of the nasal airways with use of vasoconstrictive agents were within normal limits in each patient. Prior studies by otolaryngologists using nasal endoscopy were also within normal limits.

2.3

Radiological measurements

MRI of the brain of each patient was evaluated critically . Anatomical structures of the brain by use of either computed tomography (CT) or magnetic resonance imaging (MRI) of brain were within normal limits in each patient. Olfactory bulbs were present at least unilaterally in each patient although bulbs were generally smaller in diameter than in normal subjects . One patient had smaller than normal olfactory bulbs which were duplicated bilaterally . Olfactory grooves and clefts were present in each patient although less well defined than in normal subjects in several patients .

2.4

Sensory measurements

All patients reported never being able to smell any external odor although some reported that some noxious external vapors were detected causing them to perceive the sensation and to sneeze, cough or attempt to escape from the noxious vapor.

Subjective responses were graded on both historical information and after treatment on a scale of 0–100% with 0 representing no smell and 100 representing total ability to smell all odors with values less than 100 representing lesser ability to smell odors.

Olfactometry was performed in each patient before and after treatment using systematic tests . These tests measured detection thresholds (DT), recognition thresholds (RT), magnitude estimation (ME) and hedonics (H) for four odors [pyridine (pungent), nitrobenzene (bitter almond), thiophene (petroleum) and amyl acetate (banana)] using a standard three stimuli, forced choice staircase technique previously performed on thousands of patients including a large number of normal subjects . Results were compared between patients and normals with patients categorized into four groups of loss of smell: anosmia (DT = 0, RT = 0, ME = 0, H = 0), Type I hyposmia (DT ≥ 0, RT = 0, ME = 0, H = 0), Type II hyposmia (DT > 0 < normal, RT > 0 < normal, ME > 0 < normal, H = present < normal) and Type III hyposmia (DT = normal, RT = normal, ME > 0 < normal, H = present < normal).

There can be some confusion distinguishing patients with Type II congenital hyposmia – using a capital “T” – from patients with various types of smell loss – using a lower case “t”. The “type” of congenital hyposmia (e.g., Type I, Type II) is signified by a capital “T”. The “type” of smell loss is signified by a lower case “t” (e.g., type I hyposmia, type II hyposmia or type III hyposmia). These designations have been used for the past 32 years. Each designation has a physiological and pathological basis which has been carefully delineated previously .

One patient had anosmia, 15 patients had type I hyposmia and three patients had type II hyposmia . The anosmic patient was a woman. Of the 15 patients with type I hyposmia 11 were women and four were men. Of the three patients with type II hyposmia all were women.

Results of patient responses were calculated and results of each odorant evaluated in concentrations of moles per liter (M/L), translated into bottle units such that mean ± SEM of responses could be calculated with results for each test for each odorant determined .

2.5

Analytical methods

Mean ± SEM of each patient for each test for each odorant were calculated. Results were compared to those of normal volunteers and to each patient before and after treatment for their smell loss. Significant differences were considered if p < 0.05 using Student t-tests were determined.

2.6

Treatment

Patients were treated with oral theophylline, 200–800 mg daily in divided doses for periods of 2–36 months with patients reevaluated at The Clinic at the end of each treatment period as previously described in detail . Patients were initially treated with oral theophylline, 200 mg in divided doses for 2–6 months. Patients returned at the end of this period for reevaluation of any change in sensory function (subjective measurements and olfactometry) and measurements of serum theophylline. If patients expressed subjective improvement in sensory function and olfactometry improvement they were continued on this treatment. If patients did not express subjective improvement in sensory function and olfactometry did not improve the dose of theophylline was increased to 400 mg in divided doses for 2–6 months at which time the patients returned to The Clinic for reevaluation and serum theophylline measurements as they did previously. If patients expressed subjective improvement in sensory function and olfactometry improved they were continued on that therapy. If they did not express subjective improvement and olfactometry did not improve then the dose of theophylline was increased to 600 mg in divided doses and they returned after 2–6 months on that therapy as they did previously. Similarly, if no response occurred after 600 mg the dose was increased to 800 mg which was the highest theophylline dose administered. Serum theophylline was measured at each period using a standard fluorescent method .

2.1

Patients

Nineteen patients, aged 8–57 years (25 ± 3, SEM), five men and 14 women with Type II congenital hyposmia were studied. These were each of the patients with Type II congenital hyposmia evaluated at The Taste and Smell Clinic in Washington, DC between 1997 and 2014 treated with oral theophylline. All studies were approved by the institutional review board of the Georgetown University Medical School in Washington, DC and by the Chesapeake Institute Review Board in Columbia, MD.

No patient had any family history of smell loss. All reported they never could smell any external odor although some reported that some noxious odors irritated their nose or eyes. No patient had any history of nasal or systemic disease, head injury or any pathology which contributed to their smell loss. Each patient was the result of a normal pregnancy and delivery and normal developmental milestones. Loss of smell function was usually a gradual discovery, usually around age 9–12 years, after noting others being able to perceive and respond to the presence and character of external odors but they could not. Telling parents about this loss was successful in some patients being evaluated by their pediatricians but usually without significant understanding of either the cause of the loss or any treatment for the condition. With persistence of this symptom and with use of the internet and other means some patients were evaluated by otolaryngologists and referred to The Taste and Smell Clinic in Washington, DC.

Patients were evaluated at The Taste and Smell Clinic by use of an extensive history, physical examination of their head and neck, measurements of both subjective and systematic studies of smell (olfactometry) and taste [gustometry (results not shown)], studies of their blood, urine, saliva and nasal mucus and radiological studies of the brain.

2.2

Clinical studies of head and neck

All studies of head and neck including anterior rhinoscopy of the nasal airways with use of vasoconstrictive agents were within normal limits in each patient. Prior studies by otolaryngologists using nasal endoscopy were also within normal limits.

2.3

Radiological measurements

MRI of the brain of each patient was evaluated critically . Anatomical structures of the brain by use of either computed tomography (CT) or magnetic resonance imaging (MRI) of brain were within normal limits in each patient. Olfactory bulbs were present at least unilaterally in each patient although bulbs were generally smaller in diameter than in normal subjects . One patient had smaller than normal olfactory bulbs which were duplicated bilaterally . Olfactory grooves and clefts were present in each patient although less well defined than in normal subjects in several patients .

2.4

Sensory measurements

All patients reported never being able to smell any external odor although some reported that some noxious external vapors were detected causing them to perceive the sensation and to sneeze, cough or attempt to escape from the noxious vapor.

Subjective responses were graded on both historical information and after treatment on a scale of 0–100% with 0 representing no smell and 100 representing total ability to smell all odors with values less than 100 representing lesser ability to smell odors.

Olfactometry was performed in each patient before and after treatment using systematic tests . These tests measured detection thresholds (DT), recognition thresholds (RT), magnitude estimation (ME) and hedonics (H) for four odors [pyridine (pungent), nitrobenzene (bitter almond), thiophene (petroleum) and amyl acetate (banana)] using a standard three stimuli, forced choice staircase technique previously performed on thousands of patients including a large number of normal subjects . Results were compared between patients and normals with patients categorized into four groups of loss of smell: anosmia (DT = 0, RT = 0, ME = 0, H = 0), Type I hyposmia (DT ≥ 0, RT = 0, ME = 0, H = 0), Type II hyposmia (DT > 0 < normal, RT > 0 < normal, ME > 0 < normal, H = present < normal) and Type III hyposmia (DT = normal, RT = normal, ME > 0 < normal, H = present < normal).

There can be some confusion distinguishing patients with Type II congenital hyposmia – using a capital “T” – from patients with various types of smell loss – using a lower case “t”. The “type” of congenital hyposmia (e.g., Type I, Type II) is signified by a capital “T”. The “type” of smell loss is signified by a lower case “t” (e.g., type I hyposmia, type II hyposmia or type III hyposmia). These designations have been used for the past 32 years. Each designation has a physiological and pathological basis which has been carefully delineated previously .

One patient had anosmia, 15 patients had type I hyposmia and three patients had type II hyposmia . The anosmic patient was a woman. Of the 15 patients with type I hyposmia 11 were women and four were men. Of the three patients with type II hyposmia all were women.

Results of patient responses were calculated and results of each odorant evaluated in concentrations of moles per liter (M/L), translated into bottle units such that mean ± SEM of responses could be calculated with results for each test for each odorant determined .

2.5

Analytical methods

Mean ± SEM of each patient for each test for each odorant were calculated. Results were compared to those of normal volunteers and to each patient before and after treatment for their smell loss. Significant differences were considered if p < 0.05 using Student t-tests were determined.

2.6

Treatment

Patients were treated with oral theophylline, 200–800 mg daily in divided doses for periods of 2–36 months with patients reevaluated at The Clinic at the end of each treatment period as previously described in detail . Patients were initially treated with oral theophylline, 200 mg in divided doses for 2–6 months. Patients returned at the end of this period for reevaluation of any change in sensory function (subjective measurements and olfactometry) and measurements of serum theophylline. If patients expressed subjective improvement in sensory function and olfactometry improvement they were continued on this treatment. If patients did not express subjective improvement in sensory function and olfactometry did not improve the dose of theophylline was increased to 400 mg in divided doses for 2–6 months at which time the patients returned to The Clinic for reevaluation and serum theophylline measurements as they did previously. If patients expressed subjective improvement in sensory function and olfactometry improved they were continued on that therapy. If they did not express subjective improvement and olfactometry did not improve then the dose of theophylline was increased to 600 mg in divided doses and they returned after 2–6 months on that therapy as they did previously. Similarly, if no response occurred after 600 mg the dose was increased to 800 mg which was the highest theophylline dose administered. Serum theophylline was measured at each period using a standard fluorescent method .