Characterization of Dysphagia and Longitudinal Changes in Swallowing Function in Adults with Niemann-Pick Disease Type C Treated with Miglustat

Abstract

Niemann-Pick disease type C (NPC) is a rare, autosomal recessive neurodegenerative disease, characterized by progressive psychiatric and neurological deficits. Neurological symptoms include cognitive decline and dysphagia. Aspiration pneumonia secondary to dysphagia is a leading cause of death in NPC. Miglustat is currently the only approved disease-specific treatment shown to be effective in stabilizing neurological symptoms. Miglustat has previously been reported to halt or improve early dysphagia and cognitive symptoms. Here we examine the characteristics of dysphagia, the relationship between dysphagia and the presence of cognitive impairment, and longitudinal changes in swallowing function during miglustat treatment in adult-and-adolescent-onset NPC. Retrospective analysis of videofluoroscopic swallow studies (VFSS) was completed for ten adults with NPC (mean age 28.44 years ± 9.34 years). Participants were recruited through the Royal Melbourne Hospital in Australia between 2008 and 2015. The Bethlehem Swallowing Scale and the Penetration-Aspiration Scale were used to quantify VFSS data. Dysphagia was present in 90% of participants at baseline with reduced lingual function and a delayed swallowing reflex as the most common symptoms. Swallow impairment appeared to stabilize during miglustat therapy for periods up to 66 months, with no significant changes in scores (p > 0.05). Data were in accordance with the literature and support the use of miglustat as an efficacious treatment for reducing swallowing impairment and stabilizing cognitive function. Findings provide detailed information on the impairments experienced by patients, give context to events leading to aspiration in NPC and, importantly, inform how management of dysphagia can complement pharmaceutical treatment.

Appendices

Appendix

Case histories.

Participant 1

A 34-year-old female at the time of diagnosis and miglustat treatment commencement. She had a one year history of deficits in executive function and a fine action tremor prior to diagnosis. A clinical exam of her swallow function revealed generalized oromotor weakness and incoordination. No significant pharyngeal dysphagia was observed on her baseline VFSS assessment and there was no history of chest infection. Her bulbar function was within normal limits. She was on an unmodified diet. No further motor symptoms developed over the duration of the study.

Participant 2

A 45-year-old female at the time of diagnosis and miglustat treatment commencement. Neurological symptoms began three years prior to diagnosis with initial changes in her speech and fine motor skills (reduced finger dexterity and tremor). She subsequently developed progressive cognitive decline, gait deterioration, fatigue, dysmetria, and dysarthria. Motor speech impairment was diagnosed as moderate-to-severe ataxic dysarthria, further characterized by imprecise consonants, distorted phonemes and strained vocal quality. There was no history of active psychiatric illness and she maintained insight of her impairments. At the time of baseline assessment, she had developed slowed horizontal saccades and impaired vertical saccades. She developed bilateral hearing loss for higher frequencies requiring hearing aides. Her expressive language was affected by cognitive linguistic deficits, particularly in the areas of attention and word-finding. She displayed fatigue during meals but no pharyngeal deficits were observed during her VFSS assessment.

Participant 3*

A 34-year-old female with a 6 year symptom duration at time of miglustat treatment. She had a positive family history of NPC and her cousin had passed away from NPC. Her NPC-related symptoms included memory impairment, ataxic dysarthria, loss of dexterity of the hands, recurrent falls and changes in personality. A past history of psychiatric symptoms included major depressive disorder and deliberate self-harm (superficial cutting) throughout her twenties. During all VFSS assessments, she required constant prompting to not to talk during mastication. Her baseline VFSS was characterized by premature spillage into the pharynx resulting in silent aspiration. She demonstrated a limited attention span and poor insight into her deficits. No penetration or aspiration of regular fluids was found on a follow-up VFSS 24 months post miglustat commencement. Cognitive function scores were found to be stabilized.

Participant 4*

A 33-year-old female at the time of miglustat treatment commencement. She was diagnosed with NPC at the age of 31 following two years of NPC-related symptoms. Neurological symptoms began with progressive ataxia, gait disturbance, vertical gaze palsy, tremor, ataxic dysarthria, and moderate dysphagia. Language deficits were primarily characterized by word-finding difficulties. Other NPC-related symptoms included psychosis, global cognitive decline, depression, fatigue, and lack of motivation. Her psychosis was treated with Olanzapine and adjunctive Sodium Valproate. She demonstrated adequate insight into her impairments. Brain imaging showed stable mild cerebral and cerebellar atrophy. A modified diet of soft solids and regular fluids was recommended to help with fatiguing during meals. A baseline VFSS did not show any penetration or aspiration of regular fluids. During miglustat treatment, she reported a worsening of her overall mobility but primarily affecting her fine motor control. On follow-up VFSS, at 24 and 48 months post miglustat commencement, she displayed silent aspiration of regular fluids prior to and during the swallow. She died nine year after NPC diagnosis at the age of 40.

Participant 5*

A 32-year-old male at the time of miglustat treatment commencement who was diagnosed with NPC six years prior. Initial neurological symptoms were progressive ataxia, dystonia, gait disturbance, dysphagia, ataxic dysarthria, dysmetria and vertical saccades. He described himself as clumsy throughout childhood; however, there were no academic problems evident until the onset of psychiatric symptoms (auditory hallucination) at the age of 16. He developed significant decline in his cognitive and neurological function following diagnosis. Speech became unintelligible, he displayed limited insight into his deficits, and was diagnosed with dementia secondary to NPC. A baseline VFSS found severe oropharyngeal dysphagia characterized by prolonged mastication, generalized weakness, and incoordination resulting in frank silent aspiration of regular fluids. He was subsequently placed on a modified diet of moderately thick fluids and pureed solids. On a second VFSS at eighteen months post miglustat treatment, no signs of penetration or aspiration were observed with regular fluids, but mastication of solids remained prolonged. At age 37, a PEG was inserted to improve caloric intake secondary to feeding difficulties. He died six months later of respiratory failure.

Participant 6*

An 18-year-old male at the time of diagnosis and miglustat treatment commencement. Past medical history was significant for neonatal jaundice following a cesarean birth, longstanding history of impaired movement coordination, learning difficulties, unilateral (right) hearing impairment, and alcohol abuse. His parents were both carriers of NPC and he had a brother (participant 7) who also had a diagnosis of NPC. His NPC-related symptoms included hepatosplenomegaly, vertical gaze palsy, dysphagia, non-fluent aphasia, ataxic dysarthria, ataxic gait, dystonia, and cognitive impairment. His dysarthria was described as moderate in severity with reduced articulatory precision, vocal volume, intonation, and respiratory support. Language was characterized by word-finding difficulties, agrammatism, and delayed auditory processing. Ataxia of the upper limbs affected his written communication His gait disturbance deteriorated over time with a high risk for falls reported by his physical therapist. Cognitive function also progressively declined, primarily affecting his memory, attention span, and mood. He had limited awareness and ability to implement strategies for his speech, language and swallowing impairments. A baseline VFSS noted a fatigue effect, consistent with clinical swallow investigations, leading to penetration of regular fluids. No change in dysphagia or cognitive function was found during a follow-up assessment 24 months later.

Participant 7*

A 21-year-old male at the time of miglustat treatment with a two year disease duration of NPC-related symptoms. He had a positive family history of NPC. His past medical history was significant for cognitive impairment, mild developmental delay, and ADHD with social functioning difficulties. As a young adult, he displayed poor social cognition and limited capacity to manage his own finances. Psychiatric behaviors included coprolalia, a gambling disorder, and violent behaviors both in public and at home. Excessive alcohol intake exacerbated psychiatric symptoms. Other NPC-related symptoms included ataxic dysarthria, splenomegaly, dyslipidemia, bilateral vertical gaze palsy, and horizontal saccades. Distractibility, impulsivity, and limited awareness affected his swallow safety; however, no physical swallowing deficits were reported on any of his instrumental swallowing studies.

Participant 8*

A 21-year-old female at the time of miglustat commencement. She was diagnosed with NPC at age 19 and had a positive family history. She was noted to have had learning difficulties with impaired intellectual function, reduced auditory processing, and hypernasal speech throughout childhood. As an adult, she had difficulty maintaining employment due to limited verbal communication skills and declining cognitive function. Assessment of cognitive function found significant impairment of all domains except language. Psychiatric symptoms included depression and hallucinations (visual and auditory). She also exhibited slowed vertical supranuclear gaze palsy particularly with downward gaze on saccadic testing. Dysphagia was characterized by generalized oropharyngeal weakness and velopharyngeal insufficiency with nasal emissions. She was unable to clear aspirated material (regular fluid bolus) secondary to motor weakness during her baseline VFSS. On follow-up VFSS, 12 months post miglustat commencement, no aspiration events occurred. Overall cognitive function scores had also improved.

Participant 9

A 16-year-old male with a 10 year history of cognitive decline and dementia at time of miglustat commencement. A family history of neurodegenerative disorders on his paternal side was reported. He had progressively become withdrawn and apathetic throughout childhood with limited spontaneous verbal expression. A sudden worsening of symptoms occurred at age 16 and was characterized by very minimal speech output, choreoathetoid movement, vertical gaze palsy and a significant gait disturbance. Verbal speech was limited to echolalia. A clinical swallow examination found oromotor weakness exacerbated by cognitive deficits. Specifically, he was overfilling the oral cavity leading to anterior spillage and requiring multiple swallows for clearance. VFSS confirmed piecemeal deglutition and delayed swallow initiation leading to posterior leakage into the vallecula prior to swallow initiation was occurring.

Participant 10

A 34-year-old male at baseline VFSS assessment with a 15 year history of symptom onset. He was not on miglustat treatment. A family history was unknown. His NPC-related symptoms included dysphagia, bilateral hearing loss requiring the use of hearing aids, global cognitive impairment, ataxia of upper and lower limbs with subsequent gait disturbance, dysarthria, and vertical gaze palsy. His executive functioning skills had progressively declined over the past 10 years. He used gait aids to alleviate his gait disturbance and frequent falls. He was largely dependent for most motor needs due to severely impaired dexterity. A clinical swallow examination noted moderate oropharyngeal weakness and incoordination with no overt signs of aspiration. On VFSS, he silently aspirated all regular fluid trials and had severe piriform residue with soft and solid consistencies. Minced and moist solids with single sips of mildly thick fluids were determined the safest oral diet. A year later, he developed aspiration pneumonia requiring a hospital admission. He died at age 39 of respiratory failure.

* Indicates participant included in longitudinal analyses; VFSS -Videofluoroscopic swallow study.