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\begin{document}

\title{AMYOTROPHIC LATERAL SCLEROSIS PATIENTS IN OTORHINOLARYNGOLOGY: A
RETROSPECTIVE STUDY}



\author[1]{Jesper Rautiola}%
\author[1]{Hannu Laaksovirta}%
\author[1]{Ahmed Geneid}%
\author[1]{Taru Ilmarinen}%
\author[1]{Petra Pietarinen}%
\author[1]{Teemu Kinnari}%
\affil[1]{Helsinki University Central Hospital}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Abstract OBJECTIVES Given its rarity and the lack of clear clinical
markers, amyotrophic lateral sclerosis (ALS) remains a diagnostic
challenge. Since bulbar-onset ALS (buALS) presents with impaired speech
or swallowing, patients are often primarily referred to an
otolaryngologist (ORL) or phoniatrician. We analyzed the role of such
specialists in ALS diagnostics and treatment. PARTICIPANTS We reviewed
data for all 327 patients treated for ALS through the Hospital District
of Helsinki and Uusimaa (HUS) between 2010 and 2014, focusing
specifically on 110 (34\%) patients presenting with bulbar nerve onset
(buALS). MAIN OUTCOME MEASURES The presenting symptoms, referral to
specialized care, and to a neurology clinic were assessed. Indications
and findings from swallowing studies were reviewed as well as the
incidence of percutaneous endoscopic gastrostomy (PEG) and tracheostomy.
RESULTS Among the 110 patients with buALS, 64 (58\%) were primarily
referred to a neurologist, 28 (25\%) to an ORL, and 5 (5\%) to a
phoniatrician. The most common presenting symptom was dysarthria in 89
patients, (81\%), followed by dysphagia in 26 (24\%). In most cases, an
ORL or phoniatrician suspected a neuromuscular disease; however, in 8
(24\%) cases, the neurological etiology of symptoms was missed. Overall,
49 (45\%) patients underwent a swallowing study and 86 (78\%) patients
underwent PEG placement. CONCLUSIONS Among buALS patients, 30\%
initially consulted an ORL or phoniatrician and 45\% underwent a
swallowing study. Based on our results, swallowing studies rarely lead
to immediate PEG placement. An initial visit to other specialists had no
impact on diagnostic delays or survival. Five keypoints Amyotrophic
lateral sclerosis (or ALS) Motor neuron disease Dysphagia Fiberoptic
Endoscopic Examination of Swallowing (or FEES) Percutaneous Endoscopic
Gastrostomy (or PEG) Level of Evidence: 3%
\end{abstract}%



\sloppy


\textbf{Abstract}

OBJECTIVES

Given its rarity and the lack of clear clinical markers, amyotrophic
lateral sclerosis (ALS) remains a diagnostic challenge. Since
bulbar-onset ALS (buALS) presents with impaired speech or swallowing,
patients are often primarily referred to an otolaryngologist (ORL) or
phoniatrician. We analyzed the role of such specialists in ALS
diagnostics and treatment.

PARTICIPANTS

We reviewed data for all 327 patients treated for ALS through the
Hospital District of Helsinki and Uusimaa (HUS) between 2010 and 2014,
focusing specifically on 110 (34\%) patients presenting with bulbar
nerve onset (buALS).

MAIN OUTCOME MEASURES

The presenting symptoms, referral to specialized care, and to a
neurology clinic were assessed. Indications and findings from swallowing
studies were reviewed as well as the incidence of percutaneous
endoscopic gastrostomy (PEG) and tracheostomy.

RESULTS

Among the 110 patients with buALS, 64 (58\%) were primarily referred to
a neurologist, 28 (25\%) to an ORL, and 5 (5\%) to a phoniatrician. The
most common presenting symptom was dysarthria in 89 patients, (81\%),
followed by dysphagia in 26 (24\%). In most cases, an ORL or
phoniatrician suspected a neuromuscular disease; however, in 8 (24\%)
cases, the neurological etiology of symptoms was missed. Overall, 49
(45\%) patients underwent a swallowing study and 86 (78\%) patients
underwent PEG placement.

CONCLUSIONS

Among buALS patients, 30\% initially consulted an ORL or phoniatrician
and 45\% underwent a swallowing study. Based on our results, swallowing
studies rarely lead to immediate PEG placement. An initial visit to
other specialists had no impact on diagnostic delays or survival.

\textbf{Five keypoints}

Amyotrophic lateral sclerosis (or ALS)

Motor neuron disease

Dysphagia

Fiberoptic Endoscopic Examination of Swallowing (or FEES)

Percutaneous Endoscopic Gastrostomy (or PEG)

\textbf{Level of Evidence: 3}

\textbf{Introduction}

Amyotrophic lateral sclerosis (ALS), a progressive, neurodegenerative
disease, affects the motor neurons in the cerebral cortex, brainstem,
and spinal cord, resulting in weakness, spasticity, and the progressive
loss of muscular control and function.\textsuperscript{1} In Europe, the
estimated annual incidence of ALS is 2.1--3.8 with a prevalence of
4.1--8.4 per 100~000 person-years.\textsuperscript{2}

Up to 70\% of ALS patients experience spinal nerve onset affecting the
extremities (extALS).\textsuperscript{1} By contrast, 25--30\% of ALS
patients present with impaired speech and/or swallowing, or bulbar nerve
onset ALS (buALS).\textsuperscript{1,3--6} The clinical presentation,
disease course, and prognosis in these subtypes differ. ALS patients
with no evident family history of motor neuron disease, referred to as
``Sporadic ALS'', make up 90--95\% of all ALS
patients.\textsuperscript{1,3--6}

As yet, no curative treatment for ALS is available. Assisted ventilation
is used by a minority of patients. \textsuperscript{7} In Finland from
2017 to 2020, the incidence of tracheostomy-assisted ventilation seems
to have decreased.\textsuperscript{8,9} Prognosis remains poor, with an
expected 3-year survival of 40\% and an 8-year survival of
10\%.\textsuperscript{1,3--6} The progression of symptoms ultimately
leads to respiratory failure, the leading cause of death among ALS
patients.\textsuperscript{5} Survival can vary, partly depending on the
genotype, from less than 1 year to decades.\textsuperscript{10} BuALS is
associated with higher all-cause mortality, greater co-morbidities, and
a lower quality of life.\textsuperscript{1,2,4}

Given the rarity and the lack of clear clinical markers, ALS and buALS
specifically represent diagnostic challenges. Since buALS presents with
dysarthria and dysphagia,\textsuperscript{3} patients may be primarily
referred to an otorhinolaryngologist (ORL) or a phoniatrician.
Furthermore, referral to an ORL, phoniatrician, or a speech-language
pathologist (SLP) is often crucial in order to provide recommendations
for dietary changes, compensatory maneuvers, and supplemental forms of
feeding such as a percutaneous endoscopic gastrostomy (PEG) tube. A
videofluoroscopic swallow study (VFSS) and a fiberoptic endoscopic
examination of swallowing (FEES) are often employed.

This retrospective study aims to characterize ALS patients treated in
the Helsinki metropolitan region during a five-year period (2010--2014).
Specifically, we focused on patients with buALS, their presenting
symptoms, diagnostic delays, and referrals to specialized care. We
analyzed the feasibility of VFSS and FEES in patients with buALS, as
well as the number of patients undergoing PEG and tracheostomy.

\textbf{Materials and Methods}

\textbf{Patients}

We included all patients treated for ALS in the 1.7 million people
Hospital District of Helsinki and Uusimaa (HUS) between 2010 and 2014.
ALS diagnosis was confirmed by a senior neurologist (HL), using the El
Escorial revised version.\textsuperscript{11} Among 388 patients for
whom data were available, 9 (2.3\%) patients were lost to follow-up and
52 (13.4\%) had been erroneously diagnosed with ALS. Thus, our cohort
included a total of 327 patients.

Hospital patient records were reviewed for age at which the first
symptoms of motor dysfunction appeared, gender, time from the
presentation of first symptoms until death, and the incidence of
tracheostomy and PEG. In buALS, we also reported the date of the first
visit to a healthcare provider, to any medical doctor, to specialized
healthcare, and to a neurologist. The presenting symptoms (dysarthria,
dysphagia, breathing symptoms) and findings during clinical and
endoscopic examination (presence of vocal nasality, hoarseness,
dysphagia, and/or fasciculations of the tongue and laryngeal findings
assessed by either ORL, phoniatrician, or SLP) were reported. The first
specialty a patient was referred to (neurology, otolaryngology,
phoniatrics, or internal medicine), referrals to these specialties later
during follow-up, and the date of onset of dysphagia and breathing
symptoms were also reported. Furthermore, we collected the incidence of
instrumental swallowing tests, FEES, or VFSS, as well as their
indications, findings, and conclusions.

\textbf{Statistical analysis}

We performed all statistical analyses using the SPSS statistical
software package version 27.0 (IBM Corp., Armonk, NY, USA). Correlations
were calculated using Pearson's correlation analysis, survival rates
were assessed using the Kaplan--Meier method with the log-rank test, and
means were compared using the independent t-test and two-way analysis of
variance (ANOVA), where applicable. We report two-tailed \emph{p} values
whenever possible, and present our findings with 95\% confidence
intervals (CIs) when applicable. The homogeneity and normality of data
between groups were assessed with the Levene's test and the
Shapiro--Wilk's test, respectively.

This study is reported according to the STROBE guidelines.

\textbf{Results}

\textbf{Demographic data and clinical characteristics}

From 327 study patients, 217 (66.4\%) had extALS and 110 (33.6\%) buALS.
We observed a female predominance among ALS patients (189/327, 58\%).
The proportion of women with buALS (73/110, 66\%; \emph{p} \textless{}
0.005) was significantly higher than for extALS (116/217, 53\%;
\emph{p}\textless{} 0.005). Among all 327 ALS patients, 296 (91\%) had
died by the time of data retrieval. In the buALS group, 106 of 110
(96\%) patients had died, compared to 190 of 217 (88\%) patients in the
extALS group. A total of 176 new ALS diagnoses were made during the
5-year study period.

The mean age at symptom onset in the buALS group (66 years) was
significantly higher compared with the extALS group (59 years;
\emph{p}\textless{} 0.001), however in neither group was it associated
with gender. A higher age significantly associated with a shorter
overall survival time (r = -0.333; \emph{p} \textless{} 0.001). Mean
survival was 47 months among all patients (95\% CI 41.5--53.3), 55
months (95\% CI 46.5--63.7) in the extALS group, and 34 months (95\% CI
28.9--38.7) in the buALS group. Thus, survival in the extALS group was
significantly longer (\emph{p} \textless{} 0.005; \emph{Figure 1).} The
clinical characteristics for all study patients as well as a comparison
of buALS and extALS patients appear in Table 1.

\textbf{Presenting symptoms and referral to specialized healthcare among
patients with bulbar-onset ALS}

Among the 110 patients with buALS, 64 (58\%) were primarily referred to
a neurologist, 28 (25\%) to an ORL, 12 (11\%) to internal medicine, and
5 (5\%) to a phoniatrician. Among the 33 patients initially examined by
an ORL or phoniatrician, the mean delay in referral to an academic
neurology center was 56 days (median 26, standard deviation (SD) \selectlanguage{ngerman}± 78,
range 0--337). In 25 (76\%) patients, a clear suspicion of a
neuromuscular disease existed and patients were referred to a
neurologist primarily within one month. Among the remaining 8 (24\%)
patients, the neuromuscular etiology was missed and referral was delayed
for up to 1 year. Several reasons explain these difficulties in
understanding the neurological nature of the disease symptoms and signs.
A tumor was suspected in two patients presenting with constant
supraglottic spasticity, obstruction, and a tense voice. In six
patients, mild symptoms were linked to misleading findings such as a
loose denture, Reinke's edema, vocal fold atrophy, or laryngeal reflux,
while the incipient dysarthria or dysphagia was ignored. In several of
these patients, examination was completed by a less experienced
specialist, including two co-authors, 10 years ago.

Among all buALS patients, the most common presenting symptom was
dysarthria, observed in 89 (81 \%) patients, followed by dysphagia in 26
(24\%) patients, and respiratory difficulties in 7 (6.6\%) patients. A
combination of symptoms was reported in a total of 12 (11\%) patients.

In buALS, the mean time from symptom onset to the first healthcare
provider visit was 4.4 months (range 0--23, SD ± 4.77), 7.1 months
(range 0--55, SD ± 8.43) to a specialist visit, and 8.5 months (range
0--56, SD ± 9.73) to a neurologist referral. In some non-sporadic ALS
patients, disease progression was extremely slow resulting in a long
diagnostic delay. In order to capture the typical course of disease for
buALS, we omitted from our analysis outliers with a delay exceeding 2
years from symptom onset to the first healthcare provider visit.

At some point during follow-up, 48 of 110 (44\%) patients were referred
to an ORL, 17 (16\%) to a phoniatrician, and 102 (94\%) to an SLP. Among
all buALS patients, 3 (3\%) were not referred to any such specialist.
All patients were ultimately referred to an academic neurology center.

The most common finding reported at an ORL, phoniatrician, or SLP
consultation was dysarthria in 100 (91\%) patients, followed by
dysphagia in 94 (85\%), fasciculations of the tongue in 77 (70 \%),
vocal hoarseness in 50 (45\%), and vocal nasality in 44 (40\%) patients.
The most common laryngeal findings were a limitation to the vocal fold
abduction movement in 11 (20\%) patients, vocal fold atrophy in 8
(7.2\%), and laryngeal spasm/vocal cord dysfunction in 2 (1.8\%)
patients.

\textbf{Assessment of swallowing in patients with bulbar-onset ALS}

Among all buALS patients, 49 (45\%) underwent at least one swallowing
function test, FEES in 15 patients and VFSS in 39 patients, with 5
(4.5\%) patients undergoing both tests, and among them 32 (82\%) with
VFSS and 9 (60\%) with FEES had either a strongly suspected or confirmed
ALS at the time of referral. VFSS was indicated by a previous aspiration
in 18 (46\%) patients and 18 (46\%) patients underwent VFSS in order to
evaluate the safety of oral nutrition, whereas 10 (26\%) procedures
served to evaluate an esophageal obstruction. Among patients undergoing
FEES, the corresponding figures are 4 (27\%), 6 (40\%), and 5 (33\%).
The findings of the swallowing function tests appear in Table 2. (Table
2).

Among the VFSS procedures, 8 (21\%) resulted in a recommendation for PEG
placement. None of the FEES procedures resulted in an immediate PEG
recommendation. Outright swallowing interdictions were not provided
based on either test. However, patients undergoing a swallowing function
test more often received PEG at some point (r = 0.207;
\emph{p}\textless{} 0.05). The incidence of PEG placement among all
buALS patients reached 78\% (n = 86): 94\% (n = 46) among those who
underwent a swallowing function test and 66\% (n = 40) among those who
did not.

Among all study patients, 192 of 327 (59\%) underwent PEG placement,
which was more frequent in the buALS group (86/110 patients, 78\%; r =
0.281; \emph{p \textless{}} 0.001) compared to the extALS group
(106/217, 49\%). PEG was associated with a shorter survival time in the
extALS group {[}53 months with PEG (95\% CI 44.1--62.1; \emph{p
\textless{}} 0.001) vs. 57 months without PEG (95\% CI
42.3--72.1;\emph{p \textless{}} 0.05) and a longer survival time in the
buALS group {[}35.6 months (95\% CI 29.9--41.4; \emph{p \textless{}}
0.001) and 26.8 months (95\% CI 18.1--35.5; \emph{p \textless{}} 0.05);
(\emph{Figures 2 \& 3).}

The mean time from symptom onset to death in patients with buALS was not
significantly longer among those primarily referred to a neurologist
compared to those referred to an ORL or phoniatrician. Mean survival in
the buALS patient group was 32 months (95\% CI 27.3--36.9) compared to
33 months (95\% CI 23.0--44.2) and 37 months (95\% CI 25.9--47.4),
respectively, among those initially referred to an ORL and a
phoniatrician.

\textbf{Discussion}

We characterized 176 newly diagnosed ALS patients in the Helsinki
metropolitan region of 1.7 million inhabitants during a 5-year period
(2010--2014). The estimated annual ALS incidence of 2.1 per 100 000
mirrored reports from other European countries. Furthermore, the
proportion of patients with buALS (34\%), the higher mean age at onset
in buALS (66 years) compared with extALS (59 years), and the female
predominance in buALS (66\%) agree with previous
studies.\textsuperscript{12} The strength of our study setting lies in
selecting a retrospective sample, making it possible at the time of data
retrieval to trace the complete course of disease for most patients.

In our study, 48 of 110 patients (44\%) with buALS were not initially
referred to a neurologist. Among 110 patients, 33 (30\%) were initially
referred to an ORL/phoniatrician, typically because of dysarthria or
dysphagia. Practically all patients were referred to a neurologist at
some point, however, in 8 (24\%) patients, an ORL/phoniatrician had
clear difficulties in understanding the nature of the symptoms. The
primary reasons for the diagnostic delay appeared to be the early stage
and mild symptoms of disease, physician inexperience, and, in two
patients, a constant spasticity or hyperfunction in the supraglottic
structures leading to a narrowed airway and tumor suspicion.

ORLs require awareness of the potential symptoms and signs of
bulbar-onset ALS, often presenting with dysarthria or dysphagia.
Clinical findings may include weakness in the facial muscles, palate, or
tongue, as well as fasciculations of the tongue, and a hypernasal or
breathy voice with incomplete vocal fold
closure.\textsuperscript{13}Dysarthria should not be regarded as a sign
of laryngeal pathology. In general, our study confirms Turner et
al.'s\textsuperscript{12} findings that, although half of all buALS
patients being initially referred to other than neurologists, this did
not significantly impact diagnostic delays or survival.

Our study also aimed to evaluate the feasibility of VFSS and FEES in
buALS patients. A recent systematic review concluded that several
assessment strategies are employed in neuromuscular diseases, depending
on the center, the country, and local protocols. In our study, 18 of 39
patients (46\%) presented with aspiration in VFSS and 5 of 15 (33\%) in
FEES.

An obvious advantage of FEES, performed in 14\% of buALS patients, is
that patients may receive recommendations for modifying food consistency
and therapeutic strategies, and compensatory maneuvers can be evaluated
during examination with visual feedback. However, a recommendation for
complete tube feeding after VFSS or FEES in our study patients remained
extremely uncommon. Thus, the usefulness of VFSS, performed on 35\% of
buALS patients, remains questionable.

In our study, 86 of 110 patients (78\%) with buALS underwent PEG
placement, similar to reports from previous
studies.\textsuperscript{12}PEG associated with a longer survival period
among buALS patients in our study, possibly associated with improvement
in nutritional status. This finding was reversed in the extALS patient
group, possibly related to the fact that among this ALS subtype the
swallowing symptoms usually appear late. Those who underwent swallowing
studies were also slightly more likely to undergo PEG placement, which
may be related to the shared indications in both. However, the driving
force in proceeding with PEG placement was rarely a swallowing study.
More likely, the decision was forced by increasing aspiration.

Moreover, median survival among our patients, 55 months in extALS versus
34 in buALS, agrees with previous studies.\textsuperscript{7,12}Survival
in extALS is typically longer, since bulbar affision represents a major
cause of morbidity and mortality in ALS patients and occurs fairly late
in the limb-onset disease subgroup.

In our study, 8 (2.4\%) patients were treated with a tracheostomy. This
also agrees with the low overall tracheostomy incidence in
Finland.\textsuperscript{8} Since invasive mechanical ventilation brings
about the risk of entering a complete locked-in state, this option
requires a timely consultation with an experienced specialist and a
profound consideration of end-of-life treatment
options.\textsuperscript{1,14,15}

\textbf{Conclusions}

Based on our findings, the diagnosis and treatment of ALS in Finland
agree with results from earlier studies. Primary diagnostics are
performed quickly and efficiently and do not depend on the specialty of
the initial physician a patient consults. Gastric tubes are commonly
placed and appear to improve survival among buALS patients. Swallowing
studies rarely provided clear recommendations when considering feeding,
thereby casting doubt on their usefulness. Invasive ventilation remains
a rarity among all ALS patients in Finland.

Authors declare that they have no conflicts of interest.

\textbf{References}

The data that support the findings of this study are available on
request from the corresponding author. The data are not publicly
available due to privacy or ethical restrictions.

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8. Kotanen P, Kreivi HR, Vainionpää A, Laaksovirta H, Brander P, Siirala
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14. Andersen PM, Borasio GD, Dengler R, et al. Good practice in the
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\emph{Table 1: Clinical characteristics of study patients, overall and
within groups. The p values are provided in the right-hand column for
the difference between groups, and in the respective cells for the
intragroup difference. P values are provided only for statistically
significant differences.}

\emph{Table 2. Significant findings from the swallowing function tests.}

\emph{Figure 1. Comparison of survival among extALS and buALS
patients}(\emph{p} \textless{} 0.005)\emph{.}

\emph{Figure 2. Cumulative survival in the extALS group, depending on
whether PEG placement was performed.}

\emph{Figure 3. Cumulative survival in the buALS group, depending on
whether PEG placement was performed.}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1-Cumulative-survival-extALS-vs-buALS-BW-PDF/Figure-1-Cumulative-survival-extALS-vs-buALS-BW-PDF}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2-Cumulative-survival-PEG-vs-no-PEG-BW-PDF/Figure-2-Cumulative-survival-PEG-vs-no-PEG-BW-PDF}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3-Cumulative-survival-PEG-vs-no-PEG-buALS-BW/Figure-3-Cumulative-survival-PEG-vs-no-PEG-buALS-BW}

\end{center}
\end{figure}

\textbf{Hosted file}

\verb`Table 1 Clinical Characteristics (1).docx`  available at \url{https://authorea.com/users/472796/articles/563357-amyotrophic-lateral-sclerosis-patients-in-otorhinolaryngology-a-retrospective-study}

\textbf{Hosted file}

\verb`Table 2 Findings of SFTs (1).docx`  available at \url{https://authorea.com/users/472796/articles/563357-amyotrophic-lateral-sclerosis-patients-in-otorhinolaryngology-a-retrospective-study}

\selectlanguage{english}
\FloatBarrier
\end{document}

