Pulmonological issues

Abstract

Pediatric leukodystrophies are rare neurodegenerative diseases involving multiple systems. Each form has unique neurologic features but are characterized by encephalopathy with accompanying impairments evidenced in reflexes, muscle tone and movement control. Weakness of expiratory, inspiratory, and upper airway muscles may lead to impaired airway secretion clearance resulting in recurrent respiratory infections, dysphagia, sleep-disordered breathing, restrictive lung disease, and ultimately chronic respiratory insufficiency.

Introduction

The combination of immobility, muscle weakness, skeletal deformity, and swallowing impairment, are leading causes of respiratory deterioration in patients with leukodystrophies.^1,2 Furthermore, impaired secretion clearance can lead to complications including mucous plugging, atelectasis, pneumonia and respiratory failure.

Although leukodystrophies are a heterogenous group of genetic disorders with different clinical presentations and natural courses, they share many common respiratory symptoms and impairments. Given the importance of respiratory health on overall morbidity and mortality, this consensus paper summarizes available literature and expert opinion regarding respiratory health and preventative care relevant to patients with leukodystrophies with the goal of highlighting respiratory evaluation and management strategies. Lacking a leukodystrophy-specific evidence base, some recommendations in this review are extrapolated from other disorders that share a common respiratory physiopathology (e.g., progressive neuromuscular disorders, motor neuron disease).

Sialorrhea and leukodystrophy

The prevalence of sialorrhea (drooling) among those with leukodystrophy is unknown; however, it is commonly reported in case descriptions and is associated with other neurological impairments.^3–5

While drooling is normal in early development, drooling after 4 years of age is considered atypical; for children with neurologic impairment and reduced oral muscular control, it is not considered pathologic until about 6 years of age.⁴ Although often benign, sialorrhea may cause or reveal burdens associated with decreased oral motor function, effective swallow, hydration maintenance, functional interactions, social embarrassment, psychological isolation, and limited access to technology. Some individuals experience barriers due to moisture interfering with technology (e.g., keyboards, switches, speech-generating devices).

Drooling occurs when saliva accumulates in the anterior oral cavity; excess saliva may result from impaired oral sensitivity, infrequent swallowing, muscle weakness, inappropriate postures, diminished cognition, and dysfunctional oral motor control.⁶ Posterior accumulation of saliva is associated with recurrent aspiration and pneumonia.⁷ Extremely uncommon, physiologic hypersecretion may be elicited by medications that increase the activity of muscarinic receptors, such as some tranquilizers, anticonvulsants, and anticholinesterases.³

Often copious oral secretions are noted in the context of poor volitional control of pharyngeal musculature.^8,9 Evidence suggests that children with spasticity produce salivary flow at the same rate as those with typical muscle tone, whereas increased flow rates have been identified with dyskinesia.⁶ As many as 67% of individuals with various confirmed leukodystrophies have reported sialorrhea.¹⁰

Sialorrhea assessment and management

For individuals with leukodystrophy, assess frequency and severity of drooling, skin condition (e.g., maceration, infection), and potential nasal obstruction resulting in mouth breathing (e.g., hypertrophic tonsils/adenoids, allergy) that may exacerbate drooling.¹¹ Self-and caregiver-report inform the impacts on daily living, academic, vocational and social participation. Secretion characteristics are quantified or described to include variations based on time of day or activity, consistency (e.g., thick, mucinous, watery, frothy), color (e.g., brown, yellow, clear), and number of wet bib or clothing changes.¹¹

Considerations for treatment include skin maceration or infection, aspiration, respiratory illnesses, upper airway obstruction by pooled secretions, malodorous secretions, dental caries, gingival issues, impaired neuromotor control of head/tongue, mouth breathing, decreased swallow efficiency, and/or decreased oral sensation.^5,12

Management considerations include nonpharmaceutical, pharmaceutical, and surgical. Each intervention is discussed from the perspective of leukodystrophy management decision making.

Nonpharmaceutical management

Suctioning.

Oral, nasopharyngeal, and oropharyngeal suction to remove proximal secretions have the goal of comfort, ease of breathing, and decreased risk of aspiration. For airway protection, a mechanism for physical removal of secretions may provide a helpful means to effectively clear secretions and aspirated material.¹³

The primary suction catheter in use for managing oral secretions is the rigid bulb tip with a portable suction device.¹⁴ For thick secretions, intermittent occlusion of the safety vent hole is suggested to allow greater suction; however, care must be taken as high pressure or prolonged and repeated suctioning may result in trauma to the oral mucosa. Suction catheters with large tips may yield more effective suctioning.¹⁵ Careful education must be provided to caregivers regarding suction procedures to avoid trauma, brady-cardia due to deep suctioning and to maintain airway clearance. Device cleaning is vital as there is a high prevalence of contamination with pathogenic bacteria and fungi (e.g., candida, enteric gram-negative rods, staphylococcus, viridians streptococci, VRE).¹⁶ At present, there are no guidelines regarding optimal frequency of suctioning. There are no trials comparing “as scheduled” versus “as needed” implementation.¹⁷ Of note, nasopharyngeal (NP) suctioning is another common albeit unpleasant procedure for achieving airway clearance with individuals who are unable to clear their own airways by cough or nose-blowing.¹⁸

Pharmaceutical management

Pharmaceuticals used to treat oral and respiratory secretions include anticholinergics, antihistamines, and botulinum toxin injections.^{3,4,10,19–21} Medications prescribed to address other symptoms may also enhance sialorrhea treatment when the side effect profile decreases saliva production.

Anticholinergics.

One anticholinergic with a large evidence base, glycopyrrolate, is used specifically to treat chronic sialorrhea and control respiratory secretions.^4,21–24 For patients with leukodystrophy, the literature is sparse. Excess secretions in Krabbe disease have been appropriately managed with glycopyrrolate.²³ A transdermal scopolamine patch is increasingly used as a treatment for sialorrhea and has been found safe for use by individuals with neuromuscular disorders, cognitive impairment, and neurodegenerative disease.²⁵ Special consideration is required for use of the patch with young children given the fixed dosages from the patch. Atropine and levsin drops may be helpful to treat sialorrhea in children with dysphagia, as the effective dose volume is very small and can be administered into the buccal cavity^3,4,19,26,27

Botulinum Toxin.

A supportive evidence base exists for localized botulinum toxin denervation for reduction of drooling. This treatment yields reduction in saliva without anticholinergic effects. It has also been described as a promising alternative to surgical interventions to resolve excess saliva and drooling for children with neurologic impairment.¹ Effective results are sustained for 6–7 months.⁶ Many children with leukodystrophy receive botulinum toxin injections in other areas of the body for treatment of spasticity, in which case sialorrhea treatment may be simply added to a planned procedure. Similarly, botulinum toxin may be successfully used to treat another commonly noted leukodystrophy-associated condition, bruxism.²⁸

Optimizing Medication Profile.

Considering the therapeutic utility of a side effect to manage sialorrhea may be worthwhile for some; such a strategy may potentially result in reduced polypharmacy by strategically optimizing side effects of an already-prescribed medication (i.e., dry mouth, xerostomia) rather than adding medications that only target sialorrhea. Care is required to appropriately balance medications for everyone. Critically, when secretion production is reduced, some individuals experience changes in saliva consistency that they find difficult to manage (e.g., thick, stringy, tenacious oral and pharyngeal secretions). Conversely, some medications used in management of leukodystrophy symptoms may increase saliva production (e.g., clonazepam). Careful pharmaceutical titration requires management by an interdisciplinary clinical team (e.g., neurologist, pulmonologist, otolaryngologist, pediatrician, pharmacist) to optimize efficacy and safety and to avoid polypharmacy.

Airway clearance.

Individuals with neuromuscular weakness frequently have involvement of the respiratory muscles and the muscles controlling the upper airway. Weakness of expiratory muscles, inspiratory muscles, and upper airway muscles may lead to impaired airway secretion clearance resulting in recurrent respiratory infections, dysphagia, sleep disordered breathing, restrictive lung disease, and finally chronic respiratory insufficiency.²⁹

Effective cough, an important airway defensive reflex, is essential for removal of mucus and noxious substances from the airways. Coughing is a complex process that requires intact innervation (e.g., vagus) to the pharynx and larynx. Effective coughing requires the ability to inspire adequate volumes of air and forceful contraction of expiratory muscles.³⁰ Children with muscle weakness, including patients with leukodystrophy may develop ineffective cough resulting in impaired secretion clearance due to inability to close the glottis, impaired innervation, and inspiratory or expiratory muscle weakness.³¹ The progression and severity of respiratory problems varies by the type of disorder and age of the patient.³²

Airway evaluation

When evaluating children with leukodystrophy, specific attention is given to their ability to clear secretions and their risk for pneumonia. A thorough history identifies previous respiratory infections, symptoms of aspiration, vocal strength and quality, cough strength and quality, sneeze effectiveness, and chest congestion.^19,32 Although many with leukodystrophy are unable to actively participate in the procedures, objective measures are obtained as possible such as a peak cough flow (PCF), maximal expiratory pressure (MIP) or vital capacity (FVC).

Airway clearance techniques

A variety of medications, treatments, and devices may be considered for airway clearance. These fall largely into two categories: mucus mobilization approaches and mucus extraction techniques.³⁴

Mucus Mobilization.

Mucus mobilization interventions are intended to enhance secretion mobilization and can include bronchodilators and mucolytics as well as intrapulmonary percussion ventilator (IPV) devices, positive expiratory pressure (PEP) devices, postural drainage and high frequency chest wall oscillation.^19,35,36 Mobilization devices can be effective in loosening secretions, but in general must not be used in the absence of mucus extraction techniques when the underlying problem is the inability to cough secretions out of the airway. Secretion mobilization approaches alone are often insufficient, and mucus extraction techniques and devices should be used in conjunction.^32,36

Devices.

Children with leukodystrophy may not generate adequate flow rates to make PEP devices function properly and therefore such devices should be considered individually. Similarly, when it is difficult to position the child for postural drainage, manual chest percussion and postural drainage is not recommended.³⁷ IPV devices (e.g.,. Metaneb, Percussionator) help in reversal of lobar collapse in individuals with neuromuscular disease,³⁸ as well as lead to increased sputum volume, decrease in antibiotic use and hospital length of stay compared to incentive spirometry.² High frequency chest wall oscillation (HFCWO) “vest” are devices that delivers high frequency oscillations to the chest³⁹ resulting in shear forces in the airway that loosen secretions and move them from distal to more proximal airways where they are easier to cough. While evidence for the benefit of HFCWO is limited, case series and small clinical trials suggest clinical improvements.⁴⁰

Medications.

Albuterol, a short acting bronchodilator (i.e., airway smooth muscle relaxant) is reported to increase mucociliary transport and ciliary beat frequency.^41–43 Medications may help to loosen thickened secretions (e.g., hypertonic saline, guaifenesin), though evidence for effectiveness is lacking.⁴⁴

Mucus extraction

There are two main approaches to mucus extraction, manual lung inflation and assisted cough or mechanical insufflation-exsufflation.^33,45 Both manually assisted cough and mechanical insufflation-exsufflation have been shown to substantially increase peak cough flows for patients with reduced respiratory muscle strength.^46–48

It is vitally important to implement respiratory techniques and devices to minimize the risk of aspiration, mucus plugging, and pneumonia. Mechanical insufflation-exsufflation has been shown to improve expiratory flow. Treatment regimens that include mucus extraction techniques have been shown to prolong survival and minimize hospitalization.⁴⁹

Respiratory sleep problems.

People with leukodystrophy have an increased risk for a variety of sleep disorders. One of the most common is obstructive sleep apnea (OSA) that occurs due to respiratory muscle weakness which can impact a patient’s ability to maintain upper airway patency. OSA can occur among individuals with associated facial dysmorphic features (e.g., fucosidosis, mucopolysaccharidosis, multiple sulfatase deficiency).⁵⁰ Disturbance in sleep cycle and poor quality of sleep can also be seen in patients with pain or irritability. Central apnea can also be seen in some leukodystrophies with bulbar involvement.¹⁹

Screening for sleep disordered breathing (SDB)

Symptoms of SDB and nocturnal hypoventilation may include the more classic snoring, witnessed apneas, or gasping respirations to more subtle morning headaches, poor concentration, nocturnal sweating, restlessness, sleep disturbance, fatigue, and poor appetite that can lead to failure to thrive.⁵¹ Patients with symptoms of SBD warrant further evaluation and management, however, many individuals are often asymptomatic.^51–54

In the absence of ideal predictors for SDB, vital capacity (VC) is the most predictive measure currently implemented. For patients who can perform spirometry, a VC less than 40 percent predicted is highly suggestive of nocturnal hypoventilation with hypercapnia.^55–58 With VC less than 40% predicted, individuals may already have chronic respiratory failure. With a goal of identifying patients before progressing to chronic respiratory failure, screening patients with VC less than 60 percent predicted is a sensitive marker of SDB.^57,59

For asymptomatic patients who cannot perform a pulmonary function test, screening for SBD relies on history and physical exam. Moreover, using available questionnaires like Sleep-Disordered Breathing in Neuromuscular Disease Questionnaire (SiNQ-5) may be beneficial. Further testing should be considered when patients develop deterioration in baseline muscle strength.⁶⁰

Diagnosing sleep disordered breathing in leukodystrophies

The gold standard for assessment of SDB is polysomnography (PSG).^52,61,62 A complete PSG with accompanying measurement of CO2 values (end tidal or transcutaneous) is the test of choice. Nocturnal pulse oximetry can be considered as a screening test in the absence of access to PSG.⁶³ There are no standardized definitions as to what constitutes an abnormal oximetry in the context of hypoventilation. The presence of clusters of desaturations, or a “saw tooth pattern”, can be a sign of early obstructive apnea or hypopneas in REM sleep in NMD.^64,65

Initiating respiratory support

While data specific to patients with leukodystrophies is sparse, the long term benefits of respiratory support in another class of neurodegenerative disorders is well established. Respiratory support for nocturnal respiratory failure has demonstrated multiple benefits including decreased mortality, unplanned hospitalizations, and daytime hypercarbia along with overall daytime symptom improvement.⁶¹ For the leukodystrophies, the benefit and optimum timing for the initiation of ventilatory support is unknown. Delayed initiation can increase the risk for worsened pulmonary function, nutritional deterioration, and progressive respiratory failure.⁶⁶

Daytime respiratory failure, characterized by awake hypercarbia with or without accompanying hypoxia, tends to develop slowly and usually follows the appearance of nocturnal hypoventilation and/or recurrent episodes of respiratory exacerbation in patients with neuromuscular disorders.⁶⁷ The development of daytime hypercarbia is an indication for the initiation of ventilatory support, if not already initiated. Left untreated, awake hypercarbia is associated with a poor prognosis.⁶⁸

Non-invasive ventilatory support

Non-invasive ventilation (NIV) is the most common modality of ventilatory support in patients with neuromuscular disorders and SDB.⁶⁹ The main goals of NIV support are: a) to rest the respiratory muscles; b) to improve the sensitivity of the respiratory center to CO₂; c) to improve pulmonary mechanics, and d) to improve sleep architecture.

Nocturnal NIV allows the muscles to rest and recover with a subsequent improvement in inspiratory muscle function and gas exchange during the day.^70,71 It also prevents hypoventilation, thus restoring the sensitivity of the respiratory center to CO₂ and improving ventilation and gas exchange during the day.^61,71 Furthermore, it has also been proposed that NIV improves lung function through the recruitment of atelectatic areas, increasing lung compliance and improving ventilation-perfusion relationships

NIV improves sleep architecture and reduces sleep fragmentation, thus improving overall sleep efficiency. Moreover, NIV improves the most common symptoms of SBD such as hyper-somnolence, fatigue, morning headache, cognitive dysfunction and dyspnea, mostly related with sleep disruption secondary to apneas.^61,62

The success of treatment with NIV depends on several factors including: correct patient selection, appropriate medical indication, the patient’s ability to cooperate, adequate support (including nursing), a proper fitting interface, and family education.

Non-invasive ventilation modes and settings.

For a child with a compromised respiratory system, alveoli may not adequately inflate due to weakness of respiratory muscles, airway obstruction, injury to lung tissue leading to hypoventilation. The type of NIV generally recommended for neuromuscular patients is bilevel positive airway pressure (BiPAP). BiPAP provides constant positive pressure at two different pressure settings, one for inspiration and one for expiration.

The inspiratory positive airway pressure (IPAP) and rate are adjusted to deliver adequate ventilatory support and expiratory positive airway pressure (EPAP) helps to maintain patency of the upper airway. The settings are titrated based on individual patient’s needs. Ideally, a titration study is performed to assess key polysomnographic parameters (pressures and gas exchange) so that these are integrated into decision making.

For children with leukodystrophy, it is recommended that a backup rate is set, as they may be unable to trigger the device due to muscular weakness.^72–74 The starting backup rate is equal to or slightly less than the spontaneous sleeping respiratory rate, and can be calculated by subtracting 2–4 breaths from the patient’s awake respiratory rate.^66,72–75

Contraindications to and considerations for NIV

There are a few important considerations prior to the initiation of NIV⁷⁶:

• Behavioral problems that could compromise adherence to therapy

• Skin lesions/trauma at the site of mask apposition

• Inability for a community-based durable medical equipment provider (DME) or hospital to provide or manage this type of support

• NIV use of more than 16 h per day. Prolonged use may increase the risk of complications and side effects such as skin breakdown, mid-face hypoplasia, and possibly increase the risk of morbidity.

• Patient/parent discussions about switching to invasive ventilation with a tracheostomy are indicated, as this is a quality of life decision.

• Bulbar muscle weakness associated with swallowing dysfunction which will increase the risk of aspiration

• The only absolute contraindication is respiratory failure that is not controlled by NIV.

Invasive mechanical ventilation with tracheostomy

As many leukodystrophies are progressive and without targeted options, the decision to explore ventilatory options should be carefully made between the family and their care team. Additional important considerations include the overall disease prognosis and course. In this section, we discuss invasive support modalities that may be discussed when appropriate.

Use of noninvasive ventilation (NIV) has gained popularity over invasive ventilation via tracheostomy to correct hypoventilation and sleep-disordered breathing in patients with neuromuscular weakness in the last two decades.^76–79 Nonetheless, invasive mechanical ventilation via tracheotomy (IMV-T) remains the recommended mode of respiratory support in cases of respiratory insufficiency or failure with NIV. It is also a preferred option for children who require continuous ventilatory assistance, patients for whom continuous nasal ventilation may interfere with age-appropriate development, and when lacking suitable interfaces.

IMV-T is considered for patients with extra thoracic airway obstruction preventing adequate airflow through the natural airway; patients with glottic dysfunction that predisposes to recurrent aspiration and interferes with cough clearance; patients who develop recurrent pneumonia despite the use of aggressive cough augmentation; lack of health care providers experienced in use of continuous NIV, and if this is the patient’s preference.^44,77–83

A lack of suitable interfaces and machines with adequate trigger and cycle sensitivities may also be a contributing factor for the use of IMV-T over NIV among the smallest and weakest patients.^72–74,84 A tracheostomy can provide possible benefits including reduced risk of aspiration (when using cuffed tubes), improved secretion clearance, possibility for airway inspection, reduction of dead space and a reduction of resistive loads by 50 – 80 percent.^79,80

Potential side effects from tracheostomy include tracheo-bronchomalacia, traumatic fistula formation between trachea and innominate artery or trachea and esophagus, and hemorrhage resulting from erosion of the tracheostomy tube into the jugular artery.⁸⁵⁻¹⁰⁷ Other disadvantages of tracheostomies include more complex and costly care, loss of glottic control, difficulty vocalizing, gram negative bacterial colonization, occlusion of the tube by secretions, granuloma formation within the airway, and inadvertent displacement of the tube.⁸⁵⁻¹⁰⁸ The incidence of pneumonia has been described as low despite marked colonization,⁷⁴ as was hospitalization rate.⁸⁶

It is crucial for physicians having discussions with the family to know that the approach to patients with leukodystrophy is not uniform.

Summary.

Children with leukodystrophy are impacted by poor muscle tone, limited cognitive function, and impaired motor abilities that can lead to increased risk of life-threatening complications, such as aspiration pneumonias and respiratory compromise. With no current cure, the symptoms are managed by a skilled team of medical professionals in partnership with the family. Management of respiratory function includes a range of systems, including dysfunctional swallowing (dysphagia), sialorrhea, secretion mobilization and extraction, supportive ventilation, and evolving plans of care.