Abstract
We performed a multicenter prospective study on the incidence and prognosis of Guillain-Barre syndrome (GBS) in the Emilia-Romagna region (3,909,512 inhabitants), Italy, over a 2-year period (1992-1993). The case finding method was based on a surveillance system including neurologic departments, all private and public general hospitals, and all practicing neurologists. We also reviewed all the ICD codes of hospital discharges. Ninety-four patients with GBS were identified, giving a mean incidence rate of 1.20 per 100,000 per year. Men/women ratio was 1.94. Incidence rate increased with age for both sexes. There were no significant incidence variations among seasons or months. Antecedent infections were reported in 59% of the patients. There was an overall good prognosis. After 6 months, 64% of patients had recovered and only 4% was still severely disabled. Acute mortality was 3%. Older age was the strongest predictor of poor outcome.
NEUROLOGY 1997;48: 214-221
Guillain-Barre syndrome (GBS) is a worldwide-recognized disease. Studies based on the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) [1] criteria for GBS provide incidence ranges from 0.4 [2] to 2 [3] per 100,000 population per year. All of these studies were based on reviews of clinical records [2-15] or performed on small populations. [2-5,7,11] To estimate the incidence of GBS in Italy, and to evaluate its prognosis, we performed the first incidence study based both on a prospective design and a large population. We also collected incident cases to perform a case-control study on both clinical risk factors and immunologic findings.
Material and method.
Area of investigation.
The Emilia-Romagna region is located in North-Eastern Italy (Figure 1), covers 22,125 km2, and is divided into eight provinces (Bologna, Ferrara, Forli-Cesena, Modena, Parma, Piacenza, Ravenna, Reggio Emilia). The resident population at 1991 Italian census was 3,909,512 inhabitants. For the single provinces the incidence rates were calculated on the available data at December 31, 1992. The nonresident population of the provinces of Ferrara, Ravenna, and Forli-Cesena markedly increases during the summer because of tourism. The study period was from January 1, 1992 to December 31, 1993.
Figure 1. Emilia-Romagna region and participating centers.
Case collection method.
All the neurologic units (Departments, Services, and University Clinics) of the Public Health System within the area of investigation participated in the survey. No private neurologic clinics are present within the region. In each unit one or more investigators were identified to apply the study protocol. All the departments of intensive care, rehabilitation, general medicine, geriatrics, and pediatrics within the region were informed about the study by means of personal contacts and a circular letter. They were also asked to refer patients with acute peripheral nerve disease to the investigators of the nearest neurologic unit. In order to keep attention high the letter was sent to these departments every 6 months throughout the study period. The same letter was also sent to all private clinics and to practicing neurologists. Moreover, family physicians were informed of the study by means of periodical announcements published on their Official Bulletin.
Discharges from Public and Private Hospitals are codified according to ICD IX, and these codes are available online with a maximum delay of 6 months. In order to check completeness of case ascertainment we reviewed all discharges codified 357.XX (any peripheral neuropathy) every 6 months during the study period.
Inclusion criteria and patient study protocol.
Patients were eligible if they were resident within the study area and if they fulfilled NINCDS criteria for the diagnosis of GBS. In order not to miss possible cases, some centers also recruited "atypical" patients, i.e., not completely fulfilling the NINCDS criteria. Therefore each recruited case was discussed during periodical meetings of the research group. Patients were then classified as GBS (those who met NINCDS criteria), Miller Fisher syndrome (MFS: patients presenting with the triad of ataxia, ophthalmoplegia, and areflexia in the absence of relevant limb weakness), [16] GBS variants (acute monophasic peripheral nervous system diseases with albumino-cytologic dissociation not fulfilling criteria for GBS or MFS), or non-GBS. For each recruited patient a standardized data sheet was filled in, including the following information: (1) date of onset; (2) information on infective antecedents during the month preceding onset and relevant associated diseases; (3) date of observation or admission; (4) standardized neurologic examination; (5) information on presence/absence of fever at onset and autonomic symptoms or signs; (6) results and date of CSF examination(s); (7) results of the electrophysiologic study. The latter was performed utilizing conventional recording techniques and included the following minimal requirements: motor (MCV) and sensory (SCV) conduction velocities of ulnar nerve, SCV of sural nerve, MCV and F wave study of peroneal nerve on both sides. Because of the lack of uniformity in reference values among the laboratories, each one classified the amplitude of compound muscle action potential (CMAP) as normal or reduced (a reduction below the lower limit of normality) and classified the findings of the electrophysiologic study as normal, axonal, demyelinating, or mixed (both features).
Clinical follow-up.
Patients were clinically followed up at regular intervals (every day for the first 10 days, twice a week from days 11 to 30, once a week during the second month, and once a month for the next four months or until recovery) with Hughes' scale [17] (grade 0 = healthy; grade 1 = minor signs or symptoms of neuropathy but capable of manual work; grade 2 = able to walk without support of a stick but incapable of manual work; grade 3 = able to walk with a stick, appliance, or support; grade 4 = confined to bed or chairbound; grade 5 = requiring assisted ventilation; grade 6 = dead). The last follow-up examination was in June 1994.
Improvement was defined as an improvement by one or more grades on Hughes' scale, and recovery as a grade 0. A relapse was defined, according to Kleyweg and van der Meche, [18] as either stabilization of symptoms or improvement of at least one functional grade for more than 1 week, followed by a worsening of at least one functional grade lasting 1 week.
Each center was free to decide about patient's treatment.
Statistical analysis.
The Poisson distribution was utilized in calculating the 95% confidence intervals for incidence rates, according to Schoenberg. [19] Distribution of improvement and recovery times were described with Kaplan-Meier "survival"-type curves. Since improvement, and especially recovery, could not be expected to occur for all patients, the Kaplan-Meier curves were used to choose appropriate cut-off times for occurrence of these events, and logistic regression was performed to assess the prognostic role of the candidate factors. Deceased patients were analyzed according to the GBS status last observed before death (improved or recovered). After an exact univariate logistic regression for each of the candidate factors, a forward stepwise exact multivariate regression was performed, until all statistically significant factors (p < 0.05) entered the model. Factors that subsequently were found nonsignificant (p > 0.05) were removed from the model. In the case of missing data, when the whole sample was analyzed, variables with incomplete data could not be considered candidate prognostic factors and were necessarily excluded.
Results.
The participating centers recruited 117 patients among inpatients; two more patients, not hospitalized, were referred by a practicing neurologist. Out of these 119 cases, 85 were diagnosed as having GBS fulfilling NINCDS criteria (including the outpatients), seven as MFS, 11 as GBS variants, and 16 were excluded (13 because diagnosed as non-GBS, and three because of being nonresidents).
During the study period 857 patients were discharged in the study area with ICD 357.XX; among them we found five more cases of GBS (fulfilling NINCDS criteria) not reported by the participating centers. Three of them were excluded because they were not resident within Emilia-Romagna. The two other cases had been observed from participating centers and followed according to the study protocol but had not been referred to the research group. In both cases a transfer occurred between two centers during the early course of GBS, which determined a misunder-standing between the investigators concerning referral.
Overall we collected 87 cases of GBS according to NINCDS criteria, seven cases of MFS, and 11 cases of GBS variants.
Incidence rates.
The mean GBS incidence throughout the study period was 1.34 per 100,000/year (95% CI 1.10-1.62) including MFS cases and GBS variants. It was 1.20 (95% CI 0.97-1.46) for GBS and MFS only (men 1.64, CI 1.25-2.09; women 0.79, CI 0.54-1.11) (men/women ratio: 1.94).
In order to make our study comparable with other previously published reports, GBS variant cases were excluded from further analysis and cases of MFS included under the term of GBS.
The 1992 incidence was 1.27 (95% CI 0.95-1.69), whereas during 1993 it was 1.12 (95% CI 0.82-1.51). The incidence did not significantly differ within the different provinces during the study period (Table 1). The incidence rates adjusted by age and sex to the 1991 Italian population were 1.11 (95% CI 1.02-1.20) for both genders, 1.50 (1.36-1.65) for men and 0.74 (0.64-0.85) for women. Age-and sex-specific incidence rates are shown in Table 2. A progressive increase in incidence with age was observed for both sexes, although for women there was a peak at 20 to 29 years. Higher incidence rates were found in spring, but there were no statistically significant differences among seasons, with a maximum in spring (1.4; CI 0.92-2.03) and a minimum in fall (0.97; CI 0.58-1.51). The same occurred for the months, with a maximum in March (1.99, CI 1.06-3.40), and a minimum in May (0.46, CI 0.09-1.34).
Table 1. Incidence of Guillain-Barre syndrome from Emilia-Romagna provinces
Table 2. Distribution of Guillain-Barre syndrome sex-and age-specific mean annual incidence rates per 100,000 population (Emilia-Romagna population, 1991 census)
Clinical antecedent events and concomitant diseases.
Fifty-six patients reported at least one clinical infectious antecedent in the month preceding GBS onset, and nine patients had more than one antecedent. Single antecedents were distributed as follows: upper respiratory tract infections 46%, influenza 13%, and gastrointestinal tract infections 11%.
In six patients parenteral administration of gangliosides (mixture containing exogenous GM1, GD1a, GD1b, and GT1b or GM1 alone, marketed for peripheral and central nervous diseases) preceded the first symptoms of GBS. In three patients GBS occurred concomitant with HIV infection (in one of these, HIV infection was disclosed because of GBS); four patients had thyroid disease (hypothyroidism in three cases, hyperthyroidism in one); ulcerative colitis, Crohn's disease, and rheumatoid arthritis were present in one case each.
In four cases GBS onset occurred in hospitalized patients (three men; age 20-63 years) who had been admitted in 1992, for cerebral hemorrhage, surgery for cerebral metastasis, glioblastoma, and ulcerative colitis.
Early course and severity.
The mean time delay between first symptoms and nadir (maximal severity) was 10.8 days (SD, 10.3; median, 8 days). The mean delay between first symptoms and first neurologic examination was 8.7 days (SD, 10.5; median, 5).
(Table 3) shows the mean delay from onset to nadir and the distribution of severity at the nadir according to Hughes' scale. Grades 3 and 4 accounted for 60.6% of all cases, whereas 15% needed ventilatory assistance. However, 24.4% had a mild disease (grades 1 and 2).
Table 3. Days from onset to nadir and distribution of grades at nadir by gender
Laboratory findings.
At least one CSF examination was performed in 88 patients (94%); in 26 patients (29%) CSF was examined twice. Overall, albumino-cytologic dissociation was found in 72 (77%). The mean delay between admission and the first CSF examination was 5.4 days (SD, 11.9; median, 2); for the second CSF examination the mean delay was 20.4 days (SD, 12.7; median, 17). Among 23 patients whose first CSF was normal 14 received a second examination, and in seven patients an albuminocytologic dissociation was found. A neurophysiologic examination was performed in 85 patients (90%). Pathologic findings were found in 83 patients (98%): a demyelinating pattern was identified in 51 cases (62%), axonal in six (7%), and mixed in 26 (31%). In one patient, who died before receiving electrophysiologic examination, the diagnosis was supported by autopsy findings.
Treatment.
As first therapy, 30 patients (32%) received intravenous immune globulins (IVIg), 32 (34%) plasma-exchange (PE), and 11 (12%) steroids. Twenty-one (22%) patients received no therapy. No differences were found between PE and IVIg treatment groups as concerns patients' age, sex, grading at nadir, percentage of reduced peroneal CMAP, and infective antecedents.
Prognosis.
We did not encounter any relapses. Five patients (four men) died, respectively at 8, 9, 31, 66, and 386 days from GBS onset. The following causes were reported: acute pulmonary edema, iatrogenic pneumothorax, pulmonary embolism, glioblastoma, bowel carcinoma with hepatic metastases. Improvement occurred in 71 of 92 patients (77%) at 1 month, and in 87 of 90 (97%) at 6 months. At 30 days, 18 cases (20%) had a grade >or=to4. At 6 months, 64% had recovered, 20% had a grade 1, only four (4%) had a grade 4, whereas no patient had grade 5.
The course of the disease is shown in Figure 2 for improvement and Figure 3 for recovery; no differences in the overall course of the disease were observed between sexes.
Figure 2. Kaplan-Meier curves for improvement of one or more grades on Hughes' scale [17] in patients with GBS according to gender (A = men, B = women).
Figure 3. Kaplan-Meier curves for recovery (grade 0 on Hughes' scale [17]) in patients with GBS according to gender (A = men, B = women).
Prognostic factors.
We considered the following prognostic factors: age >or=to40 years, infective antecedents (at least one) in the month preceding GBS onset, reduced peroneal CMAP amplitude, axonal type of EMG, grade at nadir >or=to4, time interval from onset to nadir <or=to7 days.
No prognostic factors had statistically significant odds ratios (OR) with respect to lack of improvement within 30 days. The two highest odds ratios corresponded to axonal type of EMG (OR = 7.07, 95% CI 0.93-7.07) and age >or=to40 years (OR = 2. 26, 95% CI 0.64-10.2). With respect to lack of recovery at 6 months, age >or=to40 years, reduced peroneal CMAP amplitude, and grading at nadir >or=to4 had statistically significant univariate odds ratios. We obtained two adequate multivariate models: age >or=to40 years and reduced peroneal CMAP amplitude obtained from the sample of 85 patients and age >or=to40 years and grading at nadir >or=to4 in the whole sample of 94 patients. Because of the missing values of CMAP amplitude for nine patients, it was not possible to choose between the models. A fit containing age >or=to40 years as well as both reduced peroneal CMAP amplitude and grading at nadir >or=to4 using 85 patients recognized only age as a significant prognostic factor. The univariate analysis and the two multivariate models are shown in Table 4. Rate of recovery over time according to the presence or absence of prognostic factors is shown in Figure 4.
Table 4. Univariate and multivariate analysis of factors associated with lack of recovery at 6 months*
Figure 4. Kaplan-Meier curves for recovery (grade 0 on Hughes' scale [17]) in groups of GBS patients according to prognostic factors (A = age <40 years, normal peroneal CMAP amplitude and grade at nadir <4; B = age >or=to40 years or reduced peroneal CMAP amplitude or grade at nadir >or=to4; C = combination of two or three of the above factors).
Prognosis according to therapy.
Since patients treated with IVIg or PE were comparable as for main prognostic indicators, we analyzed the prognosis in both groups. At 30 days, 73% had improvement in the IVIg group and 84% in the PE group. As concerns recovery at 180 days, 63% in the IVIg group and 59% in the PE group had recovered. No significant differences were observed either for improvement or recovery. Minor side effects were observed in seven patients treated with PE (six vagal reactions, one transient hypocalcemia) and three treated with IVIg (two vagal reactions, one transient skin rash).
Discussion.
Our study aimed to estimate the incidence of GBS, to evaluate its prognosis and prognostic factors, and to collect incident cases to perform a case-control study. The study design was prospective. We set up a key informant system involving the active cooperation of all neurologic clinics and departments in the Emilia-Romagna region. Furthermore, we alerted all physicians that might possibly see GBS cases. We also screened all the discharge codes for peripheral neuropathy and found only two cases that escaped our case collection method. In both cases, the lack of case signalling was due to a misunderstanding and the two patients were followed according to the study protocol. Among Italian regions, Emilia-Romagna has one of the highest standard health services and therefore it is unlikely that residents would have been treated outside the region either during the acute phase or during rehabilitation, thus escaping our surveillance. We therefore believe that our case ascertainment method was reliable. Reliability was also supported by the high percentage of patients with mild disease at nadir observed in our study. We discussed and verified all patients and included only patients satisfying NINCDS criteria. Moreover, we also observed a number of patients with GBS variants that will be the subject of a separate report.
Due to the size of population investigated, we think that our estimate of incidence of GBS is accurate. In fact, estimates of incidence on small populations, and for short periods, may be inaccurate and therefore incidence rates may vary considerably, as indicated in the recent paper of Jiang et al. [15] in South-West Stockholm and our findings disaggregated by provinces. Previous population-based studies performed in Italy employing NINCDS criteria showed incidence rates ranging from 0.4 per 100,000 in Sardinia [2] to 1.26 in the province of Ferrara. [11] However, case ascertainment in Sardinia was based on review of clinical records of neurologic clinics and may have not been complete. Therefore, comparison with our results is difficult. The incidence rates we found in Emilia-Romagna are in agreement with most previously reported findings in Europe using NINCDS criteria ranging from 0.93 [4] to 2.0. [3] Jiang et al. [15] reported a slightly higher incidence rate (1.49) in South-West Stockholm, but their study was based on registered hospital diagnosis, and 17% of patients were included despite the lack of clinical records; an overestimate is therefore possible. Halls et al. [3] reported a high incidence rate (2) in North Copenhagen, but they included five cases not fulfilling NINCDS criteria and the study was performed on a small population; this high incidence rate may be due both to overestimate and chance.
There are also reports of higher values in Olmsted County, Minnesota (1.8), [5] Libya (1.74), [7] Vermont (1.6), [12] and Quebec (1.78). [14] However these rates were not standardized to the same population and differences could be due to different age and sex composition of the populations studied. Moreover, all the above studies were retrospective and based on a search for clinical documentation or ICD codes. In some cases, small populations were investigated and the differences among the values of incidence rates found did not reach statistical significance, as shown by confidence intervals [5,12]; in other cases neither reference populations nor confidence intervals were given, thus precluding comparison with our results. [7] In some areas, a slightly higher incidence of GBS may be present, but most values are within the range from 1 to 1.6, supporting the view that GBS is uniformly distributed throughout the world.
In agreement with most previous studies. [5,6,8,11-14] we found a higher incidence rate among men. Many studies have found an increase in incidence with age for both sexes [5-7,9,12,14] while some have reported a bimodal pattern. [3,8,13,15] We found an increased incidence with age for both sexes; in women, we also observed a peak at 20 to 29 years. However, the number of women in our study was too small to establish a bimodal pattern.
In agreement with most of the previous studies, [5,6,9-15] we did not find a significant relationship between GBS and seasons.
An infectious disease in the month preceding onset was present in 59% of patients, although the frequency of gastrointestinal antecedents (11%) was lower than values previously reported ranging from 21 to 32%. [3,5,12] We also found that HIV infection was present in 3% of our cases, but comparison with other studies is not possible since this association has not been reported in an epidemiologic study. However, HIV infection should be ruled out in all patients with GBS. We also found two cases associated with inflammatory bowel disease (IBD), i.e., Crohn's disease and ulcerative colitis. Such an association, considering the rarity of these two diseases, seems higher than that expected by chance, thus confirming a recent report [20] based on clinical series of higher risk of GBS among patients with IBD. This point needs further study.
We observed six cases of GBS following gangliosides administration. In all these cases we ruled out the so-called "protopathic bias" (i.e., administration because of first symptoms of GBS). However, gangliosides therapy was common among the general population of Emilia-Romagna until March 1993, so that the possible association of GBS with gangliosides administration requires the case-control results analysis that is now under way.
We found an overall good prognosis for GBS. At 6 months 97% of patients had improvement of at least one grade on Hughes' scale, 64% recovered, 20% had only minor signs or symptoms, and only 4% presented severe disability. Beghi et al. [5] reported a similar prognosis in the epidemiologic survey in Rochester, Minnesota; they observed recovery in 75% (36/48) of patients while 21% (10/48) had minimal residual deficits. Sedano et al. [13] found over 90% of patients recovering or having only minor signs or symptoms at 1 year. The time to recovery was not specified in the Rochester study [5]; Sedano et al. [13] lost a substantial number of cases during follow-up, and prognosis was slightly worse at 6 months, with 54% recovered or with minimal disability.
Other studies on GBS prognosis based on clinical series are those of Winer et al., [21] who found 64% of patients recovered or with grade 1 at Hughes' scale at 1 year; Raphael et al., [22] who found 52% of patients with full muscle strength recovery at 1 year; and Kleyweg et al., [23] who reported 83% of patients with recovery or minor symptoms at 1 year.
The wide variability of the above findings indicates that selection biases may have occurred because these studies were not population-based. Our findings, obtained through the first prospective incidence study on GBS, show that prognosis is better than previously reported. The same may be stated for mortality; our study had a GBS mortality rate of 3%, since in two of five deceased patients, death was due to causes unrelated to GBS; this mortality rate is similar to lowest previously reported values. [3,5,13]
Regarding prognostic indicators, univariate analysis showed that age at onset >or=to40 years, reduced peroneal CMAP amplitude and grading at nadir >or=to4 were significantly associated with a lack of recovery at 6 months. We did not find any significant association with improvement at 30 days, although there were higher odds ratios for age >or=to40 and axonal type of EMG abnormality. We found the improvement at 30 days in 77% of our patients and in 97% at 6 months.
Multivariate analysis showed that age >or=to40 years was a significant predictor of lack of recovery, according to Winer et al. [21] and McKhann et al. [24] Furthermore, in the study of Winer et al., [21] reduced CMAP amplitude significantly predicted poor outcome together with age, notwithstanding the substantial differences in the severity of the population studied (15% of patients requiring ventilation in our study versus 33% in Winer et al. [21]). McKhann et al. [24] found that a reduced CMAP amplitude and need for ventilation were also significantly correlated; this is substantially in agreement with our findings. In fact, although the two latter variables did not reach simultaneous statistical significance in our study, both contributed significantly to independent alternative models, and our study indicates that age is the strongest predictor of outcome in a population-based GBS study.
Lastly, we did not observe differences between PE and IVIg treatments as related to efficacy and side effects, confirming our previous results on the first year of the study. [25] However, this finding should be interpreted cautiously since our numbers are small and we did not evaluate treatment effect within a controlled clinical trial.
Appendix.
The Emilia-Romagna Study Group on Clinical and Epidemiological Problems in Neurology consists of: A. Ravasio, M. Pasquinelli, B. Curro Dossi (Department of Neurology, Rimini); W. Neri, C. Guidi, M. Gessaroli (Department of Neurology, Forli); F. Rasi, R. Fabbri, G. Mazzini (Neurology Service, Cesena); G.G. Rebucci, G. Padoan, C. Callegarini, G. Ciucci, A.R. Guidi (Department of Neurology, Ravenna); G. Facchini, M. Galeotti (Department of Neurology, Lugo); M. Casmiro, G. Bianchedi (Department of Neurology, Faenza); M.R. Tola, V. Govoni, E. Granieri (Institute of Neurology, University of Ferrara); G. Tralli, V. Tugnoli (Department of Neurology, Ferrara); V. Mussuto (Neurology Service, Imola); M. Guarino, G. Azzimondi (Neurology Service, S. Orsola-Malpighi Hospital, Bologna); A. Baldrati, S. Laudadio, T. Sacquegna (Department of Neurology, Maggiore Hospital, Bologna); F. Salvi (Department of Neurology, Bellaria Hospital, Bologna); G. Ambrosetto (Institute of Neurology, University of Bologna), R. D'Alessandro (Institute of Neurology, Neuroepidemiology Unit, University of Bologna); P. Sorgato, V. Ferrari, M. Gentilini, A. Colombo, E. Merelli (Institute of Neurology, University of Modena); V. Miele, V. Lolli, M. Santangelo (Department of Neurology, Carpi); L. Motti, D. Guidetti, F. Solime (Department of Neurology, Reggio Emilia); F. Granella, G. Pavesi, I. Allegri, L. Falco (Institute of Neurology, University of Parma); A. Scaglioni, E. Montanari (Department of Neurology, Fidenza); S. Cammarata, V. Poli (Department of Neurology, Piacenza). Statistician: L. Bassein (Department of Clinical Pharmacology and Therapeutics, S. Orsola-Malpighi Hospital, Bologna). Coordinating members: R. D'Alessandro, M. Guarino, M. Casmiro.
Footnotes
-
Address correspondence and reprint requests to Dr. Roberto D'Alessandro, Institute of Neurology, Neuroepidemiology Unit, via Foscolo 7, 40128 Bologna, Italy.
- Copyright 1997 by Advanstar Communications Inc.
REFERENCES
Letters: Rapid online correspondence
REQUIREMENTS
You must ensure that your Disclosures have been updated within the previous six months. Please go to our Submission Site to add or update your Disclosure information.
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
You May Also be Interested in
Hastening the Diagnosis of Amyotrophic Lateral Sclerosis
Dr. Brian Callaghan and Dr. Kellen Quigg