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Table 1. Specialists involved in the care of patients with CLN2 disease as
identified by experts
Expert opinion on the man...
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2016 BDSRA Williams, Adams, Blohm, Cohen-Pfeffer, de los Reyes, Denecke, Drago, Fairhurst, Frazier, Guelbert, Kiss, Kofler, Lawson, Lehwald, Leung, Mikhailova, Mink, Nickel, Shediac, Sims, Specchio, Topcu, von Lobbecke, West, Schulz

Expert Opinion on the Management of CLN2 disease

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2016 BDSRA Williams, Adams, Blohm, Cohen-Pfeffer, de los Reyes, Denecke, Drago, Fairhurst, Frazier, Guelbert, Kiss, Kofler, Lawson, Lehwald, Leung, Mikhailova, Mink, Nickel, Shediac, Sims, Specchio, Topcu, von Lobbecke, West, Schulz

  1. 1. Table 1. Specialists involved in the care of patients with CLN2 disease as identified by experts Expert opinion on the management of CLN2 disease Ruth E. Williams1 , Heather R. Adams2 , Martin Blohm3 , Jessica L. Cohen-Pfeffer4 , Emily de los Reyes5 , Jonas Denecke3 , Kristen Drago6 , Charlie Fairhurst1 , Margie Frazier7 , Norberto Guelbert8 , Szilárd Kiss9 , Annamaria Kofler10 , John Lawson11 , Lenora Lehwald5 , Mary-Anne Leung1 , Svetlana Mikhailova12 , Jonathan W. Mink2 , Miriam Nickel3 , Renée Shediac4 , Katherine Sims13 , Nicola Specchio10 , Meral Topcu14 , Ina von Löbbecke15 , Andrea West16 , Angela Schulz3 1 Evelina London Children’s Hospital, London, UK; 2 University of Rochester School of Medicine, Rochester, NY, USA; 3 University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 4 BioMarin Pharmaceutical Inc., Novato, CA, USA; 5 Nationwide Children’s Hospital, Columbus, OH, USA; 6 Journeycare for Children, Chicago, IL, USA; 7 Batten Disease Support and Research Association (BDSRA), Columbus, OH, USA; 8 Children’s Hospital of Cordoba, Cordoba, Argentina; 9 Weill Cornell Medical College, New York, NY, USA; 10 Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy; 11 Sydney Children’s Hospital, Australia; 12 Russian Regional Pediatric Hospital, Moscow, Russia; 13 Massachusetts General Hospital, Boston, MA, USA; 14 Hacettepe University, Ankara, Turkey; 15 Practice Paediatric Physiotherapy, Hamburg, Germany; 16 Batten Disease Family Association (BDFA), Farnborough, UK Background CLN2 disease (neuronal ceroid lipofuscinosis type 2) is a rare, inherited, pediatric-onset, neurodegenerative lysosomal storage disorder caused by tripeptidyl peptidase 1 (TPP1) enzyme deficiency1-4 It is characterized by language delay, seizures, ataxia, movement disorder, motor deterioration, progressive dementia, blindness, and early death1-4 Only symptomatic, palliative treatment is currently available for CLN2 patients To date, no standard of care or management guidelines exist for this condition ■ Objectives To gain insight into current management strategies specific to CLN2 disease■ Methods In June 2015, 23 disease experts (healthcare professionals and patient advocates) from around the world completed an online survey comprising questions on management of CLN2 disease. A smaller group subsequently met to discuss management practices - Survey respondents were from eight countries: USA, Germany, UK, Italy, Australia, Argentina, Russia, and Turkey - Specialties/sub-specialties represented: neurology/pediatric neurology (11), pediatric palliative care (3), genetics (3), physiotherapy (2), patient advocacy (2), pediatric intensive care/pediatric cardiologist (1), pediatric dietitian (1), neurodisability (1), pediatric pain management (1), pediatrics (1), ophthalmology (1), neuropsychology (1), sleep medicine (1) ■ Results ■ ■ ■ Figure 2. Framework for management of CLN2 disease A multidisciplinary team approach is essential to optimize care for patients and families Antiepileptic drugs (AEDs) are the mainstay for seizure control (Table 2) - Goal is to achieve sufficient seizure control to support function (interactions, mobility, fall prevention) while balancing the side effects (e.g. avoid excessive sedation) - Experts agreed that seizure elimination is not a realistic goal (Figure 1); rather, the aims are to minimize the impact of seizures on the well-being of the child, diminish the most disabling and life-threatening seizures, and to maintain quality of life (QoL) - As the disease progresses, seizures become refractory, often requiring polytherapy (usually 2-3 AEDs) (Table 2) - Although there are no formal contraindications, some AEDs have a unique adverse event profile in CLN2 patients (e.g. carbamazepine and phenytoin should be used with caution as these may exacerbate myoclonic seizures) or may exacerbate existing symptoms of the disease (e.g. topiramate side effect of speech impairment and psychomotor slowing) ■ ■ ■ ■ Seizure management Table 2. Common medications utilized by experts to treat CLN2-related symptoms Seizures Myoclonus Spasticity Conclusions Although management guidelines for CLN2 disease have not yet been developed, management strategies around the world are consistent among experts A multidisciplinary approach is critical for optimizing care and QoL of patients and families Specific strategies currently exist to effectively manage many of the symptoms of CLN2 disease Although gaps in knowledge remain, this effort to identify common management practices represents an initial step towards development of consensus-based management recommendations References 1. Schulz A et al. NCL diseases – clinical perspectives. Biochim Biophys Acta 2013; 1832:1801-6. 2. Mole SE et al. The Neuronal Ceroid Lipofuscinoses (Batten Disease). 2 ed. Oxford, UK: Oxford University Press; 2011. 3. Steinfeld et al. Late infantile neuronal ceroid lipofuscinosis: quantitative description of the clinical course in patients with CLN2 mutations. Am J Med Genet. 2002;112:347-54. 4. Worgall S et al. Neurological deterioration in late infantile neuronal ceroid lipofuscinosis. Neurology. 2007;69:521-35. Acknowledgements BioMarin Pharmaceutical Inc. provided funding for the survey and meeting and for development of the poster ■ ■ ■ ■ ■ Palliative care and end-of-life care considerations Palliative and hospice care services should be offered to all patients with CLN2 disease; however, it is recognized that access to such care varies across countries/localities and major barriers to care may exist Palliative care is comprehensive and involves all aspects of CLN2 disease management (Figure 2) Experts recommend initiating contact with palliative care team early in the disease Psychological support for the family is essential throughout the course of the disease, and becomes especially critical at the end of life It is important for clinicians to listen to families, encourage advance end-of-life care planning and decision-making, and to respect the wishes of families, including “do not resuscitate” orders ■ Framework for CLN2 disease management Experts share common goals in the care of patients (Figure 2), including: - Maintenance/improvement of QoL of patients and families - Symptom control with prevention and management of complications - Family support - End-of-life care ■ Goals evolve over the progression of the disease (Figure 3) - Early in the disease course, the goal is to maintain function. As the disease progresses, this goal evolves to maintenance of QoL in spite of loss of function - Although the frequency of the interventions varied among experts and are tailored to the individual and the stage of the disease, frequent touch points by the clinical care team may be associated with better outcomes - Early in the disease, symptoms may be easier to control, becoming more refractory as the disease progresses. As the disease evolves, patients are at risk for new complications; for example, once patients are bedridden, secondary complications to immobility occur (e.g. decubitus ulcers, muscle loss) - Integration of palliative care from the time of diagnosis is essential for optimizing the care and QoL of patients and families ■ Importantly, appropriate tools to better assess behavior, sleep and pain in this disease are needed, which may help identify triggers that can lead to an increase or crisis of various movement disorder symptoms such as myoclonus and dystonia ■ ■ ■ ■ ■ ■ ■ ■ Nutritional, gastrointestinal (GI) and secretion management As the disease progresses, swallowing difficulties arise and worsen until oral feeding is not always possible and the risk of aspiration is high Goal of management is to maintain good nutritional status (supplementing with formula/vitamins/minerals as needed), appropriate growth and prevention of nutritional deficiencies When the child is still taking food orally, feeding/swallowing should be assessed frequently and risk of aspiration monitored - Parents should be advised on food and liquids consistency, positioning, and monitoring Tube feeding (nasogastric or gastric tube) is recommended when aspiration risk is high, when the child can no longer swallow or struggles to eat (dysphagia), when weight loss/nutritional deficiencies are observed, or when the family struggles to feed their child Timing of tube feeding has cultural variations: some clinics/regions initiate tube feeding early in the disease (e.g. to give medications) and to allow the child to enjoy favorite foods Other commonly seen complications that require management are constipation and gastro-esophageal reflux Experts recommend pharmacologic (Table 2) and non-pharmacologic therapies to manage secretions (suctioning, oral care, speech/feeding/physical therapies, corn whiskers tea) Experts reported that cardiorespiratory failure and sepsis secondary to pneumonia due to aspiration are the most common causes of death in these children, thus aggressive management and prevention of aspiration as much as possible is recommended ■ ■ Social and educational strategies and interventions Maintaining regular school attendance and social interaction are extremely valuable to ensure children remain integrated into the community - School as well as home environments should be adapted to accommodate cognitive and behavioral impairments and physical disabilities Use of alternative and augmentative communication methods such as symbols, gestures, and aids may be helpful in managing speech/language impairment ■ ■ ■ Physical, occupational, speech and holistic therapy interventions Physical, occupational and speech therapies are recommended to be initiated early and performed frequently by carers under supervision from professional therapists: experts recommend at a minimum 2-3 times a week for therapists to teach caregivers to do exercises at home Because affected children lose skills rapidly, early use of adaptive devices is recommended to support/prolong function and independence - Ability to sit and stand upright may be maintained through use of therapy chairs and standing devices; these devices also support the functioning of muscles involved in eating and speaking - Standing devices may be used to treat spasticity and dystonia - Orthoses may be used to provide stability Many experts agreed that the use of holistic therapies (music, swim, hippotherapy and reiki) could be effective in decreasing anxiety, pain and boredom ■ ■ ■ Ophthalmological considerations No therapies currently exist to treat ophthalmological manifestations Optical coherence tomography (OCT) is useful and is recommended as an assessment to establish the extent of retinal degeneration Use of retina-toxic medications (or any other agents that have direct toxicity to the retina) should be avoided (e.g. hydroxychloroquine, thioridazine, vigabatrin) ■ ■ ■ ■ ■ ■ Pain management Pain in children with CLN2 can derive from multiple sources, including musculoskeletal causes (e.g. spasticity, dystonia), GI symptoms (constipation, reflux, dysmotility), urine retention, corneal abrasions and skin breakdown(s)/sores. Effective treatment requires an accurate determination of the source(s) of pain It is also important to distinguish pain from other causes of discomfort, for example the child may be experiencing fear, anxiety, loneliness or boredom that may manifest as grunting and may be confused with pain Pain is assessed by the majority of experts/clinics, but there is no standardized tool for doing so Currently, the most useful pain assessment tool is parents’ perception - It is important to discuss pain regularly with parents/caregivers and to highly value their perceptions as they know their child the best Experts recommend various medications (Table 2) and other interventions to relieve pain (holistic therapies, positioning aids, physiotherapy and heat) Pain management is a very important goal, especially at the end of life to relieve suffering and to maintain QoL ■ ■ Management of sleep disturbance Sleep disturbance greatly impairs QoL of children with CLN2 and their families but may not be well addressed or managed Behavioral strategies (e.g. establishing bedtime and routine) and medications (e.g. melatonin, chloral hydrate) may be helpful valproic acid, clobazam, levetiracetam, lamotrigine, zonisamid and phenobarbital; most commonly used was valproate in various add-on combinations lamotrigine, zonisamid, phenobarbital, levetiracetam, valproate baclofen, tizanidine, THC, diazepam, phenobarbital Dystonia Secretions Pain tizanidine, baclofen, benzodiazepines, trihexyphenidyl inhaled, ipratropium bromide, atropine, glycopyrolate scopolamine (hyoscine) simple analgesia (acetaminophen, NSAIDs); stronger analgesics (methadone, morphine, hydromorphone); other (gabapentin, clonidine, pregabalin, amitriptyline) ■ ■ ■ ■ Medication should be re-evaluated periodically, especially when there is a new emerging symptom or acute change (e.g. valproate is used successfully early in the disease, although there are anecdotal reports of dystonic crisis that resolved once it was discontinued) For appropriate medication selection, it is important to distinguish epileptic seizures from non-epileptic events, including non-epileptic movements (dystonia, dyskinesia, chorea, tremor) and pain, boredom and fear Some types of ketogenic diet may have a role in the treatment of refractory epilepsy Figure 2 presents a framework for overall care of patients with CLN2 ■ ■ ■ Management of movement disorder (myoclonus, dystonia, spasticity) Myoclonus (epileptic and non-epileptic) is a hallmark manifestation of CLN2 disease In general, these neurological symptoms are difficult to control and the collective goals are to diminish their frequency and severity, maintain range of motion, posture and function, prevent pain, and maintain QoL Pharmacological treatment of movement disorder in CLN2 disease is shown in Table 2 Physical therapy and other interventions [ankle foot orthosis, adaptive equipment (gait-trainers, therapy chair, lateral pillow, neck support and vests, etc.)] are adjuvant strategies used to treat these symptoms ■ Future directions 274 ©2016 BioMarin Pharmaceutical Inc. All rights reserved.Presented at the 12th Annual WORLD Symposium: 29 February – 4 March, 2016, San Diego, CA Quality of Life (child and family) Medical Management Family Support End-of-Life Care Symptom management (seizures, myoclonus, spasticity, pain, etc.) Nutritional care and growth Early interventional therapies (PT, OT, speech/feeding) Prevention and management of complications General pediatric care ■ ■ ■ ■ ■ Maintain participation in school, community and home activities as long as possible Maintain ambulation and independence Maintain means of communication Maintain comfort ■ ■ ■ ■ Psychosocial and transition support Family education Early palliative care team engagement Home nursing Connection with advocacy groups and other support services ■ ■ ■ ■ ■ Early and frequent discussions Multidisciplinary team Grief support/counseling ■ ■ ■ Figure 1. Frequency of seizures in treated CLN2 patients as reported by experts 21% 7% 64% Figure 3. Goals of care evolve as the disease progresses Maintenance of function to support QoL as disease progresses Maintenance of QoL as disease progresses Quality of Life Ongoing symptom management. Prevention and management of complications (e.g. respiratory, immobility, nutrition) Symptom management Medical Management Early discussions of what the future looks like Implement palliative care concept with multidisciplinary support for the patient, the parents and the family These activities become more important Psychosocial support Transition support End-of-Life Care Family Support Cardiologist Dentist Dietitian Epileptologist Gastroenterologist Genetic counselor Home nursing Neurodevelopmental therapist Neurologist/pediatric neurologist Neurodisability expert Neuro-muscular specialist Occupational therapist Ophthalmologist Orthopedist Pain therapist Palliative care team Pediatrician Physical therapist Psychologist Respiratory therapist/Pulmonologist Sleep therapist Social worker Speech/feeding therapists Daily Weekly Monthly