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Annals of Neurodegenerative Disorders

Cite this article: Karwa KA, Malek AM, Stickler DE (2016) A Pilot Study: Diaphragm Ultrasound in Amyotrophic Lateral Sclerosis. Ann Neurodegener Dis 1(4): 1016.

*Corresponding authorKaren A. Karwa, Staff Physician, Department of Specialty Services, National Jewish Health, 1400 Jackson St, Denver, CO – 80206, USA, Tel: 1 303-388-4061; Email:

Submitted: 02 August 2016

Accepted: 24 October 2016

Published: 26 October 2016

Copyright© 2016 Karwa et al.

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Keywords•Amyotrophic lateral sclerosis•Diaphragm ultrasound•Facial motor weakness•Respiratory function monitoring•Diaphragm thickness

Short Communication

A Pilot Study: Diaphragm Ultrasound in Amyotrophic Lateral SclerosisKaren A. Karwa1,2*, Angela M. Malek3, and David E. Stickler1,4

1Department of Neurology, Medical University of South Carolina, USA2Department of Specialty Services, National Jewish Health, USA3Department of Public Health Sciences, Medical University of South Carolina, USA4Neurology Specialists of Charleston, USA

Abstract

In Amyotrophic Lateral Sclerosis (ALS) there are limitations of respiratory function monitoring in patients with facial weakness. We performed a pilot project to determine if serial change in diaphragm thickening on ultrasound can predict changes in respiratory function in ALS. Five subjects with ALS were recruited from a multidisciplinary ALS clinic in the largest academic medical center in South Carolina. Serial two-dimensional diaphragm ultrasound (DUS), pulmonary function tests and ALS Functional Rating scales were performed at 4-month intervals over a 1-year period. Measurements of diaphragm thickness during inspiration (Tdi) and expiration (Tde) were recorded and the change in thickness (Td) was calculated as the difference between Tdi and Tde. One subject was lost to follow-up; 4 subjects were included in the analysis. Subjects demonstrated a decline in Tdi, Tde and Td over time with variability possibly secondary to technical challenges. DUS may identify decreased contractility and atrophy. This pilot study suggests that DUS may be a potential non-invasive method of evaluating respiratory function in patients with ALS.

ABBREVIATIONSALS: Amyotrophic Lateral Sclerosis; 2D: Two-dimensional;

Td: Diaphragm thickness; Tdi: Diaphragm Thickness during Inspiration; Tde: Diaphragm Thickness during Expiration; Td: Change in Diaphragm Thickness; VC: Vital Capacity; MIP: Maximal Inspiratory Pressure; MEP: Maximal Expiratory Pressure; DUS: Diaphragm Ultrasound; US: United States; FVC: Forced Vital Capacity; ALS-FRS: ALS-Functional Rating Scales; BiPAP: Bi-level Positive Airway Pressure

INTRODUCTIONRespiratory failure is the leading cause of death in individuals

with amyotrophic lateral sclerosis (ALS) [1-3]. Monitoring of respiratory function during the course of the disease is a vital component of multi-disciplinary management of patients with ALS and assists with early diagnosis of respiratory dysfunction. In addition, monitoring of respiratory function results in the earlier use of non-invasive ventilator support that improves survival and quality of life [4]. Most common techniques utilized to monitor respiratory function include pulmonary function tests that measure vital capacity (VC), and maximal inspiratory and expiratory pressures (MIP and MEP) as they are widely available, non-invasive, portable and there exists normal ranges from

prior population data [5-7]. Conventional methods of testing respiratory function are often difficult to interpret in patients with bulbar weakness due to difficulties maintaining a seal around the equipment mouthpiece [5,8,9].

In ALS, changes in diaphragm function are present with advancing disease contributing to symptomatic dyspnea. Changes in ultrasonography characteristics of the diaphragm in ALS include failure to maintain contractile function during maximum respiratory effort and reduced change in diaphragm thickness during respiration [10]. Diaphragm Ultrasound (DUS) two-dimensional (2D) B Mode can measure changes in diaphragm thickness (Td) [11-13], which eliminates the technical limitations encountered by conventional methods of testing in patients with facial motor weakness. Changes in diaphragmatic thickening have been previously used to monitor recovery in individuals with diaphragm paralysis [14]. In a 2007 case series in Japan, DUS has been described in patients with ALS [10]. More recently there have been reports in Italy and Portugal of Td on ultrasound being reflective of respiratory function in patients with ALS [15,16]. It is currently unknown if DUS can be used to serially monitor respiratory function in patients with ALS.

This study is a pilot project conducted to determine if serial ultrasound measurements of diaphragm thickening during

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inspiration and expiration can predict changes in respiratory function in patients with ALS.

MATERIALS AND METHODSFive patients attending a multidisciplinary ALS Clinic and

carrying a diagnosis of probable or definite ALS according the revised el Escorial criteria were recruited into the study [17]. Subjects included adults aged >18 years with a diagnosis of limb-onset ALS identified during a regularly scheduled clinic visit between September 2012–October 2013. Entry into the study was not dependent on the presence or absence of respiratory symptoms. We excluded patients with bulbar-onset ALS and the presence of dementia in order to get accurate pulmonary function tests. Subjects on mechanical ventilation were excluded from the study. The institutional review board approved this study and all patients gave informed consent. 2D B mode ultrasound measurements of Td were measured in the zone of apposition (the muscular portion) of the diaphragm to the rib cage in each patient [10]. The zone of opposition is parallel to the body axis and thickens and shortens during inspiration. The ultrasound probe was placed 1 inch medial to the anterior axillary line at the bottom of the rib. Subjects were asked to lie on their back for the entire study as most patients with ALS initially develop orthopnea and DUS with patients sitting up may be of limited utility [9].

The diaphragm was identified as a relatively non-echogenic muscular layer bordered by echogenic membranes of diaphragmatic pleura and peritoneum (right) or spleen (left) (Figure 1). We recorded three measurements of Td during inspiration and expiration on each side during tidal breathing. An average of the three recordings of maximal Td on inspiration and expiration during tidal breathing was calculated and used as the diaphragm thickness on inspiration (Tdi) and expiration (Tde), respectively. The change in diaphragm thickness (Td) was measured as the difference between Tdi and Tde. Serial DUSs were performed at 4-month intervals over a 1-year period during routine visits to a multidisciplinary ALS Clinic. As part of the routine ALS Clinic evaluation forced vital capacities (FVC) and ALS-Functional Rating Scales (ALS-FRS) were obtained. Of the 5 subjects, 1 was lost to follow-up; therefore, 4 subjects were included in the analysis. Three subjects were examined 4 times over a year of participation; however, one subject missed one follow up visit. The subjects were examined for changes over time and a relationship between the changes in the ALS-FRS and FVC were examined (Figure 2,3). Descriptive analysis was performed on the above data.

RESULTS AND DISCUSSION

Case 1

60-year-old Caucasian female diagnosed with ALS 2 years ago based on revised el Escorial criteria. Patient initially developed left foot drop, progressed to bilateral lower extremity weakness (subsequently wheelchair bound) with progressive distal predominant upper extremity weakness bilaterally, generalized hyperreflexia however no bulbar dysfunction at the time presentation. On serial DUS monitoring, Tdi and Tde were both decreased over the 1-year period suggestive of gradual

Figure 1 Ultrasound image measuring diaphragm thickness on expiration during tidal breathing on the right side.

Figure 2 Forced vital capacity (FVC) and ALS Functional Rating Scale (ALSFRS) by change in right side diaphragm thickness at 4-month intervals over a 1-year period.

weakness and atrophy (Table 1). Td in right diaphragm showed a decrease from 3.4mm at baseline to 1.2 mm at 1 year and Td in left diaphragm decreased respectively from 2.2mm to 1.5mm. However, at the second visit, left Td increased to 2.7mm but subsequently decreased to 1.5mm at the third visit. This decrease

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Figure 3 Forced vital capacity (FVC) and ALS Functional Rating Scale (ALSFRS) by change in left side diaphragm thickness at 4-month intervals over a 1-year period.

Table 1: Serial measurements of change in diaphragm thickness ( Td), forced vital capacity (FVC) and ALS Functional rating scale (ALS FRS) in patients enrolled in the study

Patient Time Right Right Right Left Left Left FVC ALSTdi Tde Td Tdi Tde Td (L) FRS

(mm) (mm) (mm) (mm) (mm) (mm)1 Baseline 6.8 3.4 3.4 5.7 3.5 2.2 3.09 40

4 months 5 3.3 1.7 5.7 3.1 2.6 2.84 338 months 4 2.8 1.2 4.3 2.7 1.6 2.4 33

1 year 4 2.8 1.2 4 2.4 1.6 2.09 302* Baseline 4.7 2.5 2.2 5.6 2.3 3.3 4.7 38

4 months 4.7 1.5 3.2 4.9 2.4 2.5 4.2 388 months 3.1 2.2 0.9 3.5 2.7 0.8 4.2 33

3 Baseline 4.8 3.2 1.6 4.1 3.1 1 2.65 334 months 3.3 2.1 1.2 3.4 2.2 1.2 2.91 338 months 3 1.8 1.2 3.7 2.5 1.2 2.38 33

1 year 7.9 4.3 3.6 5.5 3.4 2.1 2.72 334 Baseline 4 2.7 1.3 3.3 2.2 1.1 2.8 32

4 months 4.2 2.8 1.4 3.7 2.6 1.1 2.8 268 months 3.3 2.4 0.9 2.7 1.6 1.1 1.48 21

1 year 3.3 2.2 1.1 2.5 1.8 0.7 1.51 20*Patient 2 completed only 3 visitsAbbreviationsTdi: Diaphragm Thickness during Inspiration; Tde: Diaphragm Thickness during Expiration; Td: Change in Diaphragm Thickness; FVC: Forced Vital Capacity; ALS-FRS: ALS-Functional Rating Scales

in Td occurred in conjunction with a slight reduction in FVC from 3.09L at initial visit to 2.09L at 1 year, however the patient did not report any respiratory symptoms. ALS-FRS also declined from 40 to 30 over 1 year however the patient did not report orthopnea. This case showed a decrease in Td on Tdi, Tde and Td over 1 year with the exception of an increase in left Td at the second visit.

This is suggestive of decline in muscle contractility with early findings of diaphragm atrophy prior to symptom onset and significant decline in FVC. This brings to light the possibility that DUS may pick up early changes in respiratory muscle even prior to pulmonary function testing; however, clinical utility of this observation is unclear and warrants further studies.

Case 2

49-year-old Caucasian male diagnosed with ALS 3 years ago based on revised el Escorial criteria. He developed weakness in his right hand followed by progressive upper extremity weakness since 2008, with preserved bulbar function and lower extremity strength. Serial DUS monitoring was performed for 8 months and showed a decrease in Tdi bilaterally with relative preservation of Tde (Table 1). Right Td decreased from 2.2mm at baseline to 0.9mm at 8 months, and left Td decreased respectively from 3.3mm to 0.8mm. This change is indicative of decreased contractility of diaphragm in ALS. Right Td increased from 2.2mm to 3.2mm at second visit, which is difficult to explain, as we do not know enough about Td in ALS however there is concern that it may have been due to a technical error. FVC showed mild reduction from 4.7L to 4.2L at the baseline and 8 months, respectively, and the patient denied any respiratory symptoms. ALS-FRS declined slowly from 38 to 33 over 8 months.

Case 3

63-year-old African American male diagnosed with ALS 1

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year ago based on revised el Escorial criteria. Patient had been symptomatic for 3 years prior to diagnosis and was a slow progressor. He initially presented with a perception of left foot slapping and subsequently had progressive weakness of all four extremities with distal predominant weakness and hyperreflexia. Patient had a low FVC (2.65L at initial visit and 2.72L at final visit) and ALS-FRS (unchanged at 33) at time of enrollment which remained stable over 1 year. Bilateral Tdi, Tde and Td were all low from the initial study with a slight decline over 8 months (Table 1). Right Td decreased from 1.6mm at baseline to 1.2mm at 8 months and left Td remained about the same from 1mm at initial visit to 1.2mm at 8 months. These findings are suggestive of decreased muscle contractility and changes in diaphragm prior to symptoms onset. On the final visit at 1 year patient had an increase in Tdi, Tde and Td (Right – 3.7mm, Left - 2.2mm), which raises questions about testing error.

Case 4

75-year-old Caucasian female diagnosed with ALS 1 year ago based on revised el Escorial criteria. She initially developed weakness and atrophy of right hand, with progressive motor weakness, dysphagia, and hyperreflexia. Patient also had poor baseline ALS-FRS of 32. She was on Bi-level Positive Airway Pressure (BiPAP) on enrollment in the study. Patient had low values of Tdi, Tde, Td with a slight decline over time (right Td 1.3mm at baseline decreased to 1.1mm at 1 year and similarly left Td decreased from 1.1mm to 0.9mm – refer to table 1). Of note patient initially used BiPAP intermittently; however, by 8 months she was orthopneic and needed a BiPAP to sleep at at night. She also required percutaneous endoscopic gastrostomy tube placement 2 weeks prior to last study. In this case we have a patient whose functional status is low to begin with and we are able to see thin diaphragm with poor change in Tdi.

It is important to identify respiratory muscle weakness in ALS as early intervention can improve survival and quality of life [4,5]. In current clinical practice, conventional methods of monitoring respiratory function are often difficult to interpret in patients with ALS given facial muscle weakness. A definitive way to diagnose respiratory muscle weakness would involve needle electromyography of diaphragm, which is not only invasive but also carries a risk of complications. DUS is a noninvasive method of measuring respiratory muscle strength. Further, assessing change in Td during tidal breathing is independent of patient effort. This has a significant role to play in clinical practice in patients with ALS. In addition to ALS patients having facial muscle weakness, patients with dementia also have difficulty following commands and maintaining a tight seal around the mouthpiece.

Previous studies have shown that 2D B mode ultrasound can be used for measuring diaphragm thickening [11-13]. Sequential DUS has been shown to be a useful for diagnosis of diaphragm paralysis and for monitoring recovery [14]. A Japanese case series performed DUS in 3 patients with ALS and revealed that ultrasound may be a useful tool in diagnosing diaphragm involvement in patients with ALS [10]. In addition, changes in diaphragm thickening have been shown to correlate well with changes in vital capacity [14]. In another study in Japan, DUS was compared with conventional methods of respiratory monitoring in 36 patients with ALS and 19 healthy controls. Td

correlated with percent VC, which demonstrated that DUS could provide additional information for respiratory assessment in patients with ALS [9]. In Portugal it has been demonstrated that ultrasound thickness of diaphragm correlates with functional motor units assessed by phrenic nerve motor nerve conduction studies in ALS patients [9]. There is data from Italy supporting correlation between ultrasound thickness of diaphragm and global respiratory alterations in patients with ALS [9].

Our study is the first study to use DUS as a method of serially evaluating respiratory function in patients with ALS in the U.S. We recruited 5 patients with limb-onset ALS, of which 4 participated and were monitored every 4 months for a period of 1 year. This data pool is insufficient for statistical analysis; however, we did observe a decline in Tdi, Tde and Td in these patients. Cases 1 and 2 had a decline in both Tdi, Tde, Td over time suggestive of a neurodegeneration and atrophy of diaphragm muscles. Case 3, however was a slow progressor and despite the decrease in Tdi, Tde and Td with time patient did not worsen significantly clinically. Case 4 demonstrates a patient with a poor baseline and respiratory involvement with steady clinical worsening and corresponding low values of Tdi, Tde and Td. The limitations in the study are the small number of patients enrolled who differed in their site of disease onset and rate of progression and for which not all time points were available and lack of a control group, and thus the inability to draw meaningful conclusions from this pilot study. However, important benefits of this study include provision of preliminary data for hypothesis generation and design of a larger study. In addition, this is the first published report of serial measurements of changes in diaphragm thickening, to our knowledge. Another limitation we faced was technical challenges related to errors in measurement given that the Td did not show a steady decline, as one would expect. For example, Td initially increased and subsequently decreased in Case 1 on the left and Case 2 on the right. It is unclear if it was due to technical error versus a normal variation of findings, as we do not have existing data of values of Td in ALS. Case 3 also demonstrates the possibility of testing error at last visit, as patient clinically was a slow progressor with low values of Tdi, Tde and Td at first three visits; however, the Td approximately doubled at 1 year. There currently exists data for normal value s of diaphragm thickness by 2D ultrasound [12] however there is a lack of data related to Td in patients with ALS. It is unclear if we should be expecting a temporary variability in Td early in the course of the disease prior to a steady decline in thickness.

Larger randomized controlled trials and validation studies are needed to gather data about Td in ALS prior to adopting this methodology into clinical practice. However this study demonstrates feasibility of an inexpensive non-invasive method of potentially monitoring respiratory muscle strength independent of patient effort. Further, DUS has previously been demonstrated to be a highly sensitive and specific tool in diagnosing neuromuscular dysfunction [18,19]. With widespread standardization of this technique, DUS can potentially be adopted as a tool to serially monitor respiratory function in multidisciplinary ALS clinic. Prior studies have looked at diaphragm training in patients with ALS; however, there is insufficient evidence that training leads to actual muscle strengthening. One experimental group has shown improved

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survival in ALS patients with inspiratory training although further trials are warranted [20]. However, if one could detect early changes in Td, diaphragm exercises would be a potential early intervention in patients with ALS.

CONCLUSIONFindings from our pilot study include a decline in Tdi, Tde and

Td over time suggesting that DUS may be a potential non-invasive method of evaluating respiratory function in patients with ALS although the observed variability was possibly secondary to technical challenge. DUS has potential utility in clinical practice as an additional tool to help physicians with decisions on initiation of non-invasive ventilator support in patients with ALS. It also has the potential to be used as a measure of respiratory dysfunction in ALS patients in clinical trials. Further studies are needed to describe normal values of Td in patients with ALS as well as to validate the methodology in this population.

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Karwa KA, Malek AM, Stickler DE (2016) A Pilot Study: Diaphragm Ultrasound in Amyotrophic Lateral Sclerosis. Ann Neurodegener Dis 1(4): 1016.

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