Voice rest and sick leave after phonosurgical procedures: surveys among European laryngologists and phoniatricians.

PURPOSE: After surgery of vocal folds, almost every patient will need some voice rest. It is common to recommend total silence for some days, followed by less restricted voice use for variable periods. By now, we do not know how voice rest affects the healing process or the current practise in Europe. METHODS: Members of the European Laryngological Society (2012) and the Union of European Phoniatrics (2018) were sent a web-based questionnaire which included two patient cases with a short history and a still picture. The respondents were asked about the postoperative recommendation of absolute voice rest and sick leave. RESULTS: Over 90% of the respondents would recommend absolute voice rest after removing a polyp or after mucosal repair of Reinke's oedema. For both cases, the mean length of recommended absolute voice rest among UEP members was 4 days (range 0-10 days) and among ELS members was 5 days (range 0-14 days). The recommended sick leave ranged from 0 to 35 days. The mean figures suggested by ELS members for the receptionist with Reinke's oedema were 12 days and for the teacher with a polyp 13 days. On average, UEP members recommended 14 days of sick leave for both cases. CONCLUSION: The present scientific evidence is scant, but does not support for prolonged (over 3 days) absolute voice rest after simple phonosurgery. So far, there are no studies that could show absolute voice rest to be superior over relative voice rest. According to the present survey, there is considerable variation in recommending voice rest and sick leave after the removal of benign mucosal lesions. Many European laryngologists suggest voice rest that is longer and stricter than the present scientific literature supports.

Work-up of globus: assessing the benefits of neck ultrasound and videofluorography.

Globus patients with normal ear, nose, and throat (ENT) status are a diagnostic challenge. The symptom may be long lasting and cause concern about malignancy, leading to possibly unnecessary further investigation. The aim of the study was to assess whether radiological examinations are useful in globus diagnostics, how often patients suffer from persistent globus, and whether globus patients with normal ENT status develop a malignancy during a follow-up. We reviewed medical records of all 76 globus patients referred to Helsinki University Hospital, Department of Otorhinolaryngology-Head and Neck Surgery in 2009. Patient history and findings in physical and radiological examinations were registered. A questionnaire concerning patients' present pharyngeal symptoms was sent 3 and 6 years after their initial visit. Data from the Finnish Cancer Registry revealed whether patients developed malignancies within a 3-year follow-up. Based on medical records, neck ultrasound was performed for 37 (49 %) and videofluorography for 22 patients (29 %), with nonsignificant findings. After a 3- and 6-year follow-up, half patients indicated that they were asymptomatic or had fewer symptoms, whereas the rest had persistent symptoms. The Finnish Cancer Registry data confirmed that globus patients developed no head and neck malignancies during a 3-year follow-up. In the present study, neck ultrasound and videofluorography showed no additional benefit to evaluate the globus etiology in patients whose ENT status was normal. Half the globus patients suffered from persistent symptoms after a 3- and 6-year follow-up, indicating that globus may cause discomfort chronically. However, no patients developed malignancies during a 3-year follow-up.

Long-term outcome of endoscopic shortening and stiffening of the vocal folds to raise the pitch.

In this study, we aimed to assess the long-term effects of the mucosal layer plastic surgery of the vocal folds performed on the voices of male-to-female transgenders. This retrospective cohort study enrolled 22 patients who were operated during 2004-2010 by a combined technique of transmucosal anterior suturing and stiffening of the vocal folds through a longitudinal cordotomy incision using CO2 laser. Long-term effects were assessed based on completed questionnaires on four different categories including subjective evaluation of patient's own voice perception and a standardized voice inventory (VHI), as well as an acoustic assessment and videolaryngoscopic examination. Out of the 22 patients contacted, 16 returned the questionnaires, and 13 of them participated in the subsequent acoustic analysis and videolaryngoscopic assessment. Results of the study were as follows: The total VHI score, after the procedure, was 32. F0 increased significantly for both the vowel/a/ and text from 157 to 207 Hz and 139 to 162 Hz, respectively. Perturbation measures did not show a significant change. F0 did not correlate with the VHI score. One patient had symptomatic anterior perforation that needed re-operation. The combination of transmucosal anterior suturing and stiffening of the vocal folds by laser cordectomy results in significant elevation of the F0 in the long term and in acceptable levels of VHI score compared to other reports. In conclusion, the results of the procedures show that it is enough to get the mucosal edges sutured together without the need to suture either the ligaments or the muscle of the vocal folds. The need for revision is minimal with this procedure.

[Care of voice among transgender people]. / Transsukupuolisten äänen hoito.

In some cases transgender people spontaneously find vocal expression that is acceptable. The testosterone medication usually lowers the female voice (F to M) enough. Feminization of the male voice (M to F) needs more often care. Speech and voice therapy is usually the primary treatment. In some cases pitch-elevating surgery is needed. This will raise the pitch or at least eliminate spontaneous male voicing (cough, laughter). If cosmetically unacceptable, a prominent Adam's apple will be removed.

Long-term results of autologous fascia in unilateral vocal fold paralysis.

The objective of this retrospective clinical review was to evaluate the long-term results of injection laryngoplasty with autologous fascia as a single, primary procedure in unilateral vocal fold paralysis. Forty-three patients who had undergone injection laryngoplasty between 1996 and 2003 entered the study. Clinical examination and videostroboscopy were performed and the voice handicap index was analyzed postoperatively. Pre- and post-operative evaluation included computerized acoustic analysis and perceptual evaluation. The results remained stable 3-10 years and were not affected by the length of follow-up, the delay from paralysis to surgery, or the age of the patient. Although most mean values of voice parameters were significantly improved, results in individual patients were difficult to predict. Poor results were especially related to cases caused by intrathoracic lesions. Wide glottal gaps should not be treated with fascia injection. Fascia is a stable graft and most suitable for cases with less severe glottal insufficiency.

Respiratory viruses in laryngeal croup of young children.

OBJECTIVES: To determine the viral cause of laryngeal croup by use of highly sensitive methods, and including recently recognized viruses in the analysis. STUDY DESIGN: One hundred forty-four consecutive children with hoarse voice and inspiratory stridor attending the emergency department were enrolled. Age- and season-matched children presenting with a wheezing illness served as control subjects (n = 76). Nasopharyngeal swabs were analyzed by polymerase chain reaction for rhinovirus and enterovirus, coronavirus, respiratory syncytial virus (RSV), parainfluenza virus (PIV), influenza A and B virus, human bocavirus, human metapneumovirus, adenovirus, and Mycoplasma pneumoniae. RESULTS: Virus infection was documented in 80% of patients with croup and 71% of control subjects. Children with croup had significantly more positive test results for PIV 1 and 2 (31% vs 4% and 6% vs 0%, respectively) and significantly fewer positive test results for RSV (15% vs 28%) than wheezing children. Rhinoviruses and enteroviruses were present equally in both groups (21% vs 25%). There was no significant difference in the frequency of influenza A virus or human bocavirus. Few subjects with adenovirus or M. pneumoniae were detected. CONCLUSION: Acute laryngeal croup is most often associated with PIV, RSV, rhinovirus, and enterovirus. Rhinovirus and enterovirus appeared equally often in croup and in wheezing illness. During late fall, they were found in 39% and 40%, respectively, of the tested samples.

Regional differences in endoscopic sinus surgery in Finland: a nationwide register-based study.

OBJECTIVES: Endoscopic sinus surgery (ESS) is a common operation typically performed due to chronic rhinosinusitis (CRS). There are limited data on the nationwide ESS rate and factors contributing to its regional variation. The aim was to evaluate factors causing variation of ESS rate. DESIGN: Cross-sectional nationwide observational study. SETTING: A ll patients undergoing ESS in Finland 2013-2015. POPULATION: Nationwide Finnish population aged 15 years or over. MAIN OUTCOME MEASURES: ESS rate per 1000 inhabitants between 2013 and 2015 in all 21 hospital districts and independent factors for multilevel model analyses. METHODS: We used the Finnish register data of all patients with CRS who underwent ESS in 2013-2015. Patients aged under 15 years and those with ESS due to neoplasia were excluded. The age and gender standardised ESS rates were calculated, and multilevel Poisson regression models were used to evaluate variation in ESS in the 21 hospital districts. The likelihood ratio test was applied to assess the statistical significance of random components in the models. RESULTS: The nationwide annual rate of ESS is 0.71 per 1000 people in Finland. Hospital district rates varied from 0.25/1000 (95% CI 0.18 to 0.32) to 1.15/1000 (95% CI 1.09 1.21). Compared with males, females undergo ESS significantly more frequently (57% of the procedures), more often due to CRS without nasal polyps, and at a younger age (mean age 44.2 and 46.2 years, correspondingly). Multilevel analyses showed that lower age (between 24 years and 45 years) and availability/ease of medical services were independently associated with higher ESS rates. CONCLUSIONS: This study confirms marked regional variation in the ESS rate in Finland, explained only in part by patients' age and differing availability of medical services. To analyse ESS across different CRS phenotypes or to compare quality registers on ESS properly, more research on regional variation is needed.

Role of albumin coating of tympanostomy tubes: long-term clinical evaluation.

OBJECTIVE: Our previous work has shown that albumin coating of tympanostomy tubes prevented adhesion of proteins or bacteria on the tube surface in vitro and in a 9-month prospective follow-up study. This study was continued until all tubes were extruded. STUDY DESIGN: A prospective, clinical trial. METHODS: The randomized, double-blind clinical trial had 149 patients. The randomization was revealed after the follow-up period of 9 months. The number of tube sequelae in ears with human serum albumin (HSA)-coated titanium tympanostomy tubes was compared with the contralateral ears with uncoated, otherwise identical titanium tubes. The follow-up continued until all tubes were extruded, followed by evaluation of each tympanostomized patient. RESULTS: No significant difference between the two tube types emerged after the 9-month follow-up. Among the patients younger than 2 years, one of the three typical bacteria causing acute otitis media (AOM), Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis, was found in 45% of all bacterial cultures taken during AOM. However, among patients older than 2, one of these bacteria appeared in 17% of all the bacterial cultures and in 8% of cultures taken during the summer. CONCLUSIONS: After the first 9 follow-up months, no difference was found in the sequelae related to uncoated and HSA-coated tubes. The typical bacteria causing AOM were found less frequently among patients older than 2 years. A profile of tympanostomy patients in Finland will be given.

Medialization of paralyzed vocal fold does not increase respiratory resistance measured by impulse oscillometry.

Injection laryngoplasty restores voice in subjects with unilateral vocal fold paralysis, but knowledge of its effects on airflow dynamics is limited. Impulse oscillometry (IOS) is a non-invasive technique to investigate airway resistance. It is easily performed during normal breathing. A prospective study was conducted in order to investigate the effects of autologous fascia injection on airflow dynamics. IOS, flow-volume spirometry, acoustic analysis of voice, voice handicap index (VHI) questionnaire and subjective dyspnoea score were recorded before and 5-11 months after the operation. There was no significant change in respiratory resistance (Rres) or other variables of IOS. FEV1/FVC decreased from 0.80 to 0.77 (P = 0.02), but other variables of spirometry did not change significantly. Acoustic properties of voice (noise-to-harmonics ratio, shimmer, jitter, maximal phonation time) and VHI improved significantly. No change in dyspnoea occurred. In conclusion, medializing of a paralysed vocal fold improves voice, but does not have a clinically significant adverse effect on breathing. Flow-volume spirometry is more sensitive than IOS to changes in airflow dynamics after medialization.

Validation of the Distress Thermometer and Problem List in Patients with Recurrent Respiratory Papillomatosis.

Objective There is no specific clinical tool for physicians to detect psychosocial and physical distress or health care need in patients with recurrent respiratory papillomatosis (RRP). The main aim of this study is to validate the RRP-adapted Distress Thermometer and Problem List (DT&PL). Study Design Prospective cross-sectional questionnaire research. Setting Academic tertiary care medical centers in Groningen, Netherlands, and Helsinki, Finland. Subjects and Methods Ninety-one juvenile- and adult-onset RRP patients participated from the departments of otorhinolaryngology-head and neck surgery of the University Medical Center Groningen, Netherlands, and Helsinki University Hospital, Finland. The Hospital Anxiety and Depression Scale was used as the gold standard. Results A DT cutoff score ≥4 gave the best sensitivity and specificity. Thirty-one percent of patients had significant distress according to the DT cutoff. Significantly more patients with a score above than under the cutoff had a referral wish. The PL appeared to be reliable. Patients' opinions on the DT&PL were largely favorable. Conclusion The Dutch and Finnish versions of the DT&PL are valid, reliable screening tools for distress in RRP patients.

Quality of life of patients with recurrent respiratory papillomatosis.

OBJECTIVES/HYPOTHESIS: Recurrent respiratory papillomatosis (RRP) is a disease with a high disease burden. Few studies have assessed quality of life (QoL) of RRP patients. This study compares QoL of these patients with controls. Associations between QoL and sociodemographic and illness-related factors are examined, as is uptake of psychosocial care and speech therapy. STUDY DESIGN: Prospective cross-sectional questionnaire research. METHODS: Ninety-one RRP patients (response = 67%) from two university hospitals in the Netherlands and Finland completed the following patient reported outcome measures: (HADS), 15-dimensional health-related quality-of-life scale (15D), Voice Handicap Index (VHI) and the RAND 36-item health-related quality-of-life survey instrument (RAND-36) assessing health-related QoL and voice handicap, and they provided sociodemographic, illness-related, and allied healthcare use. Descriptive analyses, χ2 tests, t tests, analysis of variance tests, and Pearson correlations were computed to describe the study population and to examine differences between groups. RESULTS: RRP patients had significantly higher mean scores on depression, health-related QoL (15D) and on voice problems (VHI), and significantly lower mean scores on anxiety than controls. Dutch patients had more pain and a decreased general health perception (RAND-36) than controls. Dutch patients and older patients were more depressed, women were more anxious, older patients had lower health-related QoL, and smoking was significantly associated with voice handicap. Patients who had received psychosocial care had significantly higher HADS-depression mean scores than patients who did not receive psychosocial care. CONCLUSIONS: Having RRP has significant effect on voice-related QoL and depression, but has no negative effect on anxiety and health-related QoL. Risk factors for decreased functioning are different than previously hypothesized by many authors. Prevention should be aimed at these risk factors. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:1826-1831, 2017.

Dysphagia and malignancy: A three-year follow-up and survey of National Cancer Registry data.

OBJECTIVES/HYPOTHESIS: Dysphagia may cause concern about malignancy. Symptoms are often unspecific; thus, it is essential to identify those requiring further investigations. STUDY DESIGN: Retrospective study combined with patient survey. METHODS: Case records of the 303 dysphagia patients referred in 2009 to Helsinki University Hospital, Department of Otorhinolaryngology-Head and Neck Surgery were surveyed. Based on clinical data, the main cause of symptoms divided patients into five groups. Alarming signs were food sticking in the throat or in the esophagus, weight loss, and progressive dysphagia symptoms. A questionnaire sent 3 years after the primary visit concerned the present symptoms. To investigate whether dysphagia could have been early symptom of malignancy, we surveyed the Finnish Cancer Registry database until the end of 2012. RESULTS: Most diagnoses remained descriptive: unspecific dysphagia (167, 55%). Five (0.02%) had malignant disease, for all of whom the suspicion of malignancy was evident. Finnish Cancer Registry data indicated that unspecific dysphagia did not develop into malignancy during a 3-year follow-up. Returned questionnaires numbered 154 (62%), of which 30 (19%) were asymptomatic patients; relieved symptoms in 36 (23%), fluctuating or unchanged symptoms in 43 (28%), and worse symptoms in 12 (8%). The remaining patients (33, 21%) had not answered that question or the answer was uninterpretable. CONCLUSION: Further investigations to reveal malignancy seemed unnecessary if alarming clinical signs or findings were lacking. After 3 years, almost half the patients were asymptomatic or had milder symptoms revealing the condition's potential for spontaneous recovery. LEVEL OF EVIDENCE: N/A. Laryngoscope, 126:2073-2078, 2016.

Human papillomavirus in larynx.

OBJECTIVES: The core of the present clinical and basic research knowledge of laryngeal human papillomavirus (HPV) infection is described. STUDY DESIGN: Review. METHODS: A computer-aided search of MEDLINE database supplemented by hand searches of key journals was conducted. RESULTS: One of the tumor-promoting factors in the larynx is the HPV found both in normal laryngeal epithelium and in laryngeal tumors. The most important manifestation of laryngeal HPV infection is laryngeal papillomatosis, a rare disease caused by HPV types 6 and 11. In laryngeal carcinogenesis, the role of HPV remains uncertain. The means of transmission of HPV are partly unknown, and the course of laryngeal HPV infection is unpredictable and variable. Treatment of laryngeal papillomatosis is based on surgery, especially on CO2 laser and shaver. Alpha-interferon is the drug of choice in patients whose response to surgery is poor. However, neither interferon nor other antiviral drugs are able to eradicate the virus from laryngeal mucosa. Little is known about immunological mechanisms involved in laryngeal HPV infection, but in defense against HPV cellular immunity is considered a more important mechanism than humoral immunity. A good experimental model of HPV infection is lacking in which the entire viral life cycle can take place. Organotypic cell cultures (collagen rafts) are useful, but the rate-limiting step in this method is the difficulties in culturing HPV-positive epithelial cells. CONCLUSIONS: Although laryngeal papillomatosis is clinically well defined, the mechanisms and treatment modalities of laryngeal HPV infection need further investigations.

Albumin-coated tympanostomy tubes: prospective, double-blind clinical study.

OBJECTIVES: Coating an implant with albumin prevents adhesion of proteins, bacteria, and platelets and thus may lead to its improved and prolonged function. Previously, we have demonstrated the inhibition of binding of fibronectin, one of the most adhesive glycoproteins, on human serum albumin (HSA)-coated tympanostomy tubes and the durability of this binding inhibition in a 8-month trial. We have also demonstrated that the HSA coating inhibits the binding of Staphylococcus aureus and Pseudomonas aeruginosa to titanium plates. This prospective study evaluated the effect of albumin coating on tympanostomy tube sequelae and on the outcome of tympanostomized patients. STUDY DESIGN: Double-blind, prospective, randomized clinical trial. METHODS: Two otolaryngological centers in southern Finland enrolled 179 pediatric patients. Number of tube occlusions and otorrhea and tube ventilation time in the ears with HSA-coated titanium tympanostomy tubes were compared with the contralateral ear with its uncoated, otherwise identical titanium tube during a 9-month follow-up period. RESULTS: In HSA-coated tubes, average ventilation time was slightly longer and the number of early tube occlusions significantly less (P < .05). Moreover, in patients with perioperative bleeding, the coating prolonged average ventilation time of tympanostomy tubes significantly (P < .05). CONCLUSIONS: HSA coating reduces early tube occlusions by preventing adherence of blood and secretion.

Processing of fascia for vocal fold injection. A study in vitro and in paralyzed canine vocal folds.

To evaluate the simplest and safest method to mince fascia for autologous vocal fold injection, we performed an in vitro study applying porcine fascia and a prospective study using a canine model. Six different surfaces were tested in the laboratory for mincing fascia. The ease of handling of tissue on each surface was noted. Minced fascia was studied by microscope under polarized illumination, and the number and nature of foreign particles were recorded. After the safest method to mince fascia was established, 2 dogs were operated on. The recurrent nerve was sectioned, and a piece of fascia lata was harvested and cut with scissors on a steel surface. Fascia injection deep into the thyroarytenoid muscle was performed. The dogs were painlessly sacrificed 6 months later, and the larynges were removed for histomorphological study. On cutting, all polymer surfaces released small amounts of particles. These were not evident when we used glass or steel plates, but their hard surfaces were difficult to work on. Cutting a piece of fascia with scissors was found to be effective and safe in terms of microscopic foreign particles. The two dogs suffered no perioperative or late complications. Six months later, a well-preserved, vascularized, collagen-rich tissue was in its place without any evidence of acute or chronic inflammation. The histomorphological findings were identical to those of our previous study, with the exception that this time, no foreign particles from the mincing surface were present. An autologous fascia graft proves to be well preserved and well tolerated in the augmentation of a paralyzed vocal fold, and scissors are simple and effective in mincing it for injection.

Results of fascial augmentation in unilateral vocal fold paralysis.

The objective of this study was to evaluate the effects on voice quality of augmentation by injection of minced fascia in patients with unilateral vocal fold paralysis. Preoperative and postoperative voice samples from 14 patients (6 men and 8 women; mean age, 59 years) were analyzed by computerized acoustic analysis and blinded perceptual evaluation. Statistically significant improvements were seen in perturbation measurements (jitter and shimmer), noise-to-harmonics ratio, and maximum phonation time. A panel of evaluators rated 10 of the 14 postoperative voices as normal or near-normal. Injection laryngoplasty with minced fascia offers a new, effective, well-tolerated, and inexpensive method to medialize a paralyzed vocal fold. The graft seems to survive well, as indicated by good vocal results with a follow-up ranging from 5 to 32 months.

Rhinovirus RNA in children with longstanding otitis media with effusion.

BACKGROUND: Earlier studies indicate that respiratory viruses may play a role in the pathogenesis of otitis media with effusion (OME). OBJECTIVES: To study the presence of rhinovirus RNA in middle ear mucosa in children with OME without signs of present acute infection. METHODS: Eighteen children scheduled for tympanostomy tube placement due to longstanding OME were recruited and a biopsy of the promontory mucosa was obtained. In addition, adenoidectomy was performed for eight of these children and a biopsy of adenoid tissue was taken as well. The samples were collected from December to May. Rhinovirus RNA was studied by in situ hybridization (ISH). RESULTS: Seven out of eight adenoid biopsies were positive for rhinovirus by ISH. However, rhinovirus RNA was not found in any of the 18 middle ear biopsies. CONCLUSIONS: These results show that children with longstanding OME do not have a rhinovirus infection in the middle ear mucosa, although the same children frequently harbor large amounts of rhinovirus RNA in their adenoid tissue.

Rhinovirus in adenoid tissue.

OBJECTIVE: Rhinovirus (RV) infection is the most common single cause of acute respiratory illness in children. The purpose of the study was to evaluate the prevalence of RV in adenoid tissue throughout the year. MATERIAL AND METHODS: Fifty-six samples of adenoid tissue removed either due to recurrent otitis media or adenoid hypertrophy were collected for in-situ hybridization (ISH) of RV. To confirm the specificity of the ISH probe, eight adenoid biopsies were investigated by reverse transcriptase-polymerase chain reaction (RT-PCR) as well. RESULTS: ISH was positive for RV RNA in 45% of the specimens. There was a statistically significant difference (P = 0.002) in the prevalence of RV positive adenoid biopsies from late fall to spring (65%) in comparison to late spring to early fall (20%). Children with middle ear effusion were more often ISH positive than those with dry ears, but the number of past ear infections, signs of chronic nasal obstruction or recent runny nose did not correlate to the finding in ISH. There was a good concordance between the results obtained by ISH and by RT-PCR. CONCLUSION: Both epithelial and/or germinal cells of adenoid tissue are frequently loaded with RV during the cold months of the year, also known to have a high incidence of RV infections among population. Children with otitis media with effusion are more likely to harbor RV in adenoid tissue than those with dry ears. Further studies are, however, needed to show whether the effusion is due to RV or whether this association exists by coincidence.

Voice quality after treatment of early vocal cord cancer: a randomized trial comparing laser surgery with radiation therapy.

OBJECTIVE: Early laryngeal cancer is usually treated with either transoral laser surgery or radiation therapy. The quality of voice achieved with these treatments has not been compared in a randomized trial. METHODS AND MATERIALS: Male patients with carcinoma limited to 1 mobile vocal cord (T1aN0M0) were randomly assigned to receive either laser surgery (n=32) or external beam radiation therapy (n=28). Surgery consisted of tumor excision with a CO2 laser with the patient under general anaesthesia. External beam radiation therapy to the larynx was delivered to a cumulative dose of 66 Gy in 2-Gy daily fractions over 6.5 weeks. Voice quality was assessed at baseline and 6 and 24 months after treatment. The main outcome measures were expert-rated voice quality on a grade, roughness, breathiness, asthenia, and strain (GRBAS) scale, videolaryngostroboscopic findings, and the patients' self-rated voice quality and its impact on activities of daily living. RESULTS: Overall voice quality between the groups was rated similar, but voice was more breathy and the glottal gap was wider in patients treated with laser surgery than in those who received radiation therapy. Patients treated with radiation therapy reported less hoarseness-related inconvenience in daily living 2 years after treatment. Three patients in each group had local cancer recurrence within 2 years from randomization. CONCLUSIONS: Radiation therapy may be the treatment of choice for patients whose requirements for voice quality are demanding. Overall voice quality was similar in both treatment groups, however, indicating a need for careful consideration of patient-related factors in the choice of a treatment option.