International Medical Journal Vol. 24, No. 5, pp.

1 - 2 , October 2017 1
CASE REPORT

Oral Theophylline for the Treatment of Hyposmia after Severe

Traumatic Brain Injury

Muhammad Hafiz H1), Mazlina M2)

ABSTRACT
Objective: This is a case illustration of improvement of smell sensation in a mild traumatic brain injury patient. We describe
in detail the events of this case management and outcome.
Method: We report a case of a female, a college student, who had mild traumatic brain injury in June 2013, which during
her recuperating period noticed that her smelling ability has been reduced compared to her pre accident state. During her follow
up 2 months post injury, we prescribed her with oral theophylline 20 mg OD for 2 months. Unfortunately, the drug was stopped
by other medical team who thought the drug was to treat asthma. We restarted the theophylline and this time she completed her
theophylline course, and noted improvement of her smelling ability comparable to her previous pre traumatic state.
Conclusion: This article illustrates another probable benefit of oral Theophylline in treating hyposmia in mild traumatic
brain injury.

KEY WORDS
traumatic brain injury, anosmia, theophylline

INTRODUCTION Upon initial rehabilitation assessment, her neurological deficits

Anosmia is one of the known complications of traumatic brain inju-
ry. It can lead to profound psychological effects which can result in the
feeling of physical and social vulnerability in the affected person1). This
impairment of olfactory function was described as a continuum , with
sufferers having inability to detect odour ranging from blunting to the
sense of total loss of olfactory ability1).
In this case report, we present a case of recovery from post-traumat-
ic hyposmia after treatment with 200 mg oral theophylline for 2 months.
Recovery of olfactory function was shown using quantitative olfactory
measurement.
CASE PRESENTATION
A 23 year old female college student with no significant prior medi-
cal history was brought to the Emergency Department (ED), Universiti
Malaya Medical Centre after being involved in a motor vehicle acci-
dent. She was the front passenger of her friend's car which collided with
a bus. On arrival to the ED, her Glasgow Coma Scale (GCS) score was
7/15 and she was immediately intubated.
Her head computed tomography (CT) scan revealed acute subarach-
noid hemorrhage in both front parietal regions with associated efface-
ment on cerebral sulci, and subdural hemorrhage in left frontal, tempo-
ral and occipital area. There was no midline shift or hydrocephalus
noted. There were also multiple facial bone fractures involving frontal
bone and frontal sinus, and bilateral orbits. The cribriform plate was
intact. She was reviewed by the neurosurgical and or maxillofacial sur-
gical teams and was treated conservatively. She was referred for rehabil-
itation after one week of injury.
included cognitive impairment, right hemiparesis and balance impair-
ment. Two weeks after rehabilitation, she was discharged with improved
cognition, Mini Mental State Examination score of 27/30 and Westmead
Post Traumatic Amnesia scale of 11/12), improved function and bal-
ance, Modified Barthel Index score of 90/100 and Berg Balance Scale
score of 54/56 respectively.
Two months later, the patient was seen in clinic and complained she
had difficulty to smell food since discharged. This was more prominent
when she ate spicy food with pungent ingredients. She became frustrat-
ed and felt unsatisfied, as she was unable to enjoy her favourite food.
On examination, there was no sign of infection or inflammation of her
olfactory system.
We proceeded with an assessment of her olfactory function using a
coffee sniff test in the clinic. The patient's eyes were closed and a coffee
sachet was opened and placed at about 2 cm from the tested nostril
while the untested nostril was closed using her own hand. The patient
was instructed to identify the smell. The intensity of smell was later
assessed using Numerical Rating Scale (NRS). She was asked to give a
numerical value from zero, indicating complete absence of smell to ten,
indicating normal smell intensity as before the accident. Similar method
was repeated to another nostril.
She could identify the coffee smell and recorded an NRS score of 6
for her right nostril and only NRS score of 2 for her left nostril. She was
counselled on her condition and educated on the complications follow-
ing smell disorders, such as inability to smell gas leak or smoke. She
was prescribed oral theophylline 20 mg OD for the treatment of hypos-
mia. After two months we repeated the coffee sniff test to each nostril.
She was able to identify the coffee smell and the hyposmia had com-
pletely recovered with NRS score of 10 for both nostrils.

Received on August 10, 2016 and accepted on April 4, 2017

1) Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia
Kubang Kerian, 16150 Kelantan, Malaysia
2) Department of Rehabilitation Medicine, Faculty of Medicine, University of Malaya
50603 Kuala Lumpur, Malaysia
Correspondence to: Muhammad Hafiz Hanafi
(e-mail: drmdhafiz@usm.my)

C 2017 Japan Health Sciences University

& Japan International Cultural Exchange Foundation
2 Muhammad Hafiz H. et al.
DISCUSSION
Olfactory impairment which include anosmia (complete loss of
smell) and hyposmia (partial loss of smell), is a common sequelae of
traumatic brain injury (TBI)2). A study by Callahan et al.2) showed that
more than half of the TBI patients (56%) exhibited abnormality in olfac-
tory function and almost 40% of these persons were unaware of their
deficits. In one study conducted in Netherland, the prevalence of hypos-
mia was found to be higher than anosmia after mild TBI3). In this case
report, the patient sustained severe TBI and was unaware of her deficit
during the acute period. She was only diagnosed to have hyposmia at 4
months post injury when she was asked of the possible symptom in the
clinic.
There are many causes of injury that could affect olfactory func-
tion.4) In this case, the multiple facial bone fractures and intracranial
bleed from the TBI might disturb the olfactory pathway and lead to her
partial loss of smell. In most cases, post traumatic anosmia would have
recovered spontaneously within the first couple of months5). There is no
guideline on the treatment of hyposmia or anosmia after TBI.
Pharmacological treatment using phosphodiesterase inhibitor such as
theophylline has shown to improve the levels of cyclic adenosine mono-
phosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which
were found to be deficient in people with anosmia6-8).
From literature review, dosage used for oral theophylline range
from 200 mg to 800 mg daily for 2 to 8 months8). In one study, involving
312 patients who reported loss of smell sensation range from 2 months
to 40 years, they found that greater improvement in hyposmia recovery
were noted at dosage of 600 mg and 800 mg than 200 mg and 400 mg8).
The most common delivery method of theophylline is oral and intrana-
sal. There is no randomized control trial specifically evaluates effective-
ness of this two routes n treatment of anosmia, but in one pilot study,
intranasal administration was found to be safer and more effective than
oral route9). In this patient, we prescribed her with lowest therapeutic
dosage (200 mg) to reduce the unwanted side effect. The oral route was
chosen as it is more convenience for the patient who also had facial and
nasal bone fracture. Patients deny having any unwanted side effects
from theophylline administration such as nervousness, jitteriness and
difficulty sleeping or gastric discomfort.
In our patient, full recovery was reported after two months of start-
ing oral theophylline. We quantify the improvement using the coffee
sniff test and charted the improvement using NRS. Coffee has been fre-
quently used as one of the odors tested in discrimination tests after
anosmia10). There is no standardized test to evaluate olfactory function11).
The most commonly performed test in major studies is the University of
Pennsylvania Smell Identification Test (UPSIT) 12) which is costly,
requires time to perform and is not readily available in the rehabilitation
clinic. Thus we resorted to a more practical test using new coffee
sachets from same manufacturers and same batch of production to main-
tain consistency of odor strength in each nostril.
Recovery from anosmia due to traumatic brain injury is believed to
occur because of regeneration of olfactory nerve fibers and their recon-
nection with central neurons of the olfactory bulb 13). Theophylline
administration can increase the concentration of cAMP and cGMP in
nasal mucosa. These cyclic nucleotides act as growth factors for several
neural tissues which include olfactory tissues and thus can improve the
olfactory recovery12).
CONCLUSION
Two months session of oral theophylline 20 mg per day started 4
months after severe traumatic brain injury was useful in treating post
traumatic hyposmia. Further research is warranted to investigate the
fundamental and therapeutic usage to reduce the possible complication
that may affect the social integration in anosmic traumatic brain injury
patient.
REFERENCES
1) Van Toller S. Assessing the impact of anosmia: review of a questionnaire's findings.
Chem Senses 1999; 24: 705-712.
2) Callahan CD, Hinkebein JH. Assessment of anosmia after traumatic brain injury: per-
formance characteristics of the University of Pennsylvania smell identification test. J
Head Trauma Rehabil 2002; 17(3): 251-256.
3) De Kruijk JR, Leffers P, Menheeres P, et al. Olfactory function after mild traumatic
brain injury. Brain Injury 2003; 17(1): 73-78.
4) Zasler N, Katz D, Zafonte RD. Post-concussive disorder: brain injury medicine.
Principle practice 2007; 23: 383.
5) Mueller CA, Hummel T. Recovery of olfactory function after nine years of post-trau-
matic anosmia: a case report. Journal Medical Case Reports 2009; 3: 9283.
6) Henkin, RI, Velicu I, Papathanasiu AN. cAMP and cGMP in human parotid saliva:rela-
tionships to taste and smell dysfunction, gender and age. Am J Med Sci 2007; 334:
431-40.
7) Henkin RI, Velicu I. cAMP and cGMP in nasal mucus: relationships to taste and smell
dysfunction, gender and age. Clinical Invest Med 2008; 31: E71-E77.
8) Henkin RI, Velicu I, Schmidt L. An open-label controlled trial of theophylline for treat-
ment of patients with hyposmia. American Journal Medical Sciences 2007; 337(6):
396-406.
9) Henkin RI, Schultz M, Minnick-Poppe L. Intranasal theophylline treatment of hypos-
mia and hypogeusia. Arch Otolaryngol Head Neck Surg 2012; 138(1): 1064-1070.
10) Mehdizade J, Saedi B, Fotouhi R, et al. A novel test to differentiate anosmic malinger-
ers from actually anosmic patients. Am J Rhinol Allergy 2012; 26(6): 485-488.
11) Jafek BW, Murrow B, Linschoten M. Evaluation and treatment of anosmia. Curr Opin
Otolaryngo head Neck Surg 2000; 8: 63-67.
12) Stinton N, Atif MA, Barkat N, et al. Influence of smell on taste function. Behavioral
Neuroscience 2010; 124(2): 256-264.
13) Costanzo RM. Neural regeneration and functional reconnection following olfactory
nerve transection in hamster. □ Brain Res 1985; 361: 256-266.