Guidelines on Hereditary Leukodystrophies
Treatment: General Introduction
Since there is currently no cure for congenital leukodystrophy, the aim of treatment is to alleviate the distress caused by its various symptoms. Specialist pediatricians, internists, neurologists, respirologists, and orthopedic surgeons work as a team with nurses and different therapists, and preventive and psychosocial strategies must be considered throughout the acute and chronic disease stages. Central nervous system symptoms include intellectual disability, dysautonomia, epilepsy, and involuntary movements. Visceral symptoms include disorders of the respiratory, digestive, circulatory, urinary, musculoskeletal, and sensory organs, which are treated to prevent them from inconveniencing patients.
1. Developmental delay and intellectual disability
In many cases, no particular problems are evident at birth and the disorder is only noticed when developmental delay, intellectual disability, or learning disability becomes evident. Because motor disability is present alongside intellectual disability, many children receive the same care and education as that provided for children with cerebral palsy, the most common similar condition. The greatest difference from cerebral palsy is the clear appearance of developmental regression. In cases of adult onset, dementia-like symptoms and other mental symptoms are the first to be noticed. Because in most cases the disease is expected to progress, preparations must consider the patient's lifestyle, employment, financial support, and future plans.
2. Dysautonomia
Despite being very common, the latent and mild symptoms if dysautonomia often go unnoticed. The organs affected include the digestive system (constipation, fecal incontinence), urinary system (enuresis, urinary incontinence), circulatory system (arrhythmia, orthostatic hypotension), and temperature regulation (hypohidrosis). Treatment is symptomatic, but it is important that its presence is recognized.
3. Epilepsy
Because controlling epileptic seizures is difficult in many cases, the aim of treatment is to prevent injury, encephalopathy, aspiration, hospitalization, and other negative consequences of seizures. The actual treatment depends on the type of seizure involved. For partial seizures, carbamazepine (10–20 mg/kg twice daily) is the first-line drug, followed by second-line drugs including levetiracetam (40–60 mg/kg twice daily), lamotrigine (1–15 mg/kg twice daily), topiramate (5–9 mg/kg twice daily), zonisamide (4–8 mg/kg twice daily), valproic acid (10–30 mg/kg 2–3 times daily), or clobazam (0.2–1 mg/kg twice daily). For full seizures, the first-line drug is valproic acid or phenobarbital (2–5 mg/kg 1–2 times daily), followed by second-line drugs including lamotrigine, topiramate, zonisamide, and clobazam.
4. Dystonia and spasticity
Dystonia is the involuntary persistent simultaneous contraction of the flexor and extensor muscles that causes twisting or an abnormal posture. Dystonia is evoked by voluntary movement, emotion, and uncomfortable stimuli, among other causes, and causes the affected individual pain and musculoskeletal impairment. Spasticity is a hypertonic condition that is mainly due to an increased phasic stretch reflex. Pain and movement impairments can be managed with physiotherapy and regular stretching exercises. Drug treatments for generalized hypertonia and dystonia include eperisone (1–4 mg/kg three times daily), diazepam (0.1-0.3 mg/kg 1–3 times daily), baclofen (0.1–0.3–0.6 mg/kg 1–3 times daily), dantrolene (0.5–3 mg/kg 2–3 times daily), tizanidine (0.05–0.1–0.15 mg/kg 1–3 times daily), or phenobarbital (2–5 mg/kg 1–2 times daily). In severe cases, other methods such as baclofen intrathecal injection and deep brain stimulation may be used. Botox (1–3 U/kg) may be used to treat localized dystonia and spasticity (no more than once every 3 months).
5. Respiratory and eating disorders
In very severe cases, laryngopharyngeal dysfunction may make patients prone to dysphagia and aspiration pneumonia from an early stage, for which close monitoring is essential. Patients who are unable to ingest food by mouth may be fed via a nasogastric tube or a gastrostoma; if gastroesophageal reflux is present, then fundoplication is also performed. X-ray scanning is used to analyze swallowing function, and the use of enteral nutrition enables patients to receive the correct nutritional and fluid intake more safely. Non-invasive positive pressure ventilation via a mask and the use of a mechanical respirator are useful for other muscle disorders and may be considered for patients with these diseases depending on their symptoms. If pneumonia or other bronchial infections or suffocation by sputum repeatedly occur despite these measures, artificial ventilation via a tracheotomy may be required. In patients with abnormal muscle tension or hyperesthesia, however, the increased amount of secretions and the effort required to look after the ventilator may not necessarily benefit the patient's condition and their use should be considered with caution.
6. Urinary system dysfunction
This is a common and important comorbidity. The symptoms usually comprise urinary incontinence or dysuria, which increase the risk of bacterial urinary tract infection. Urinary tract infections cause pain and discomfort and may require in-hospital treatment when serious. If a patient has a history of multiple urinary tract infections, a urologist should be involved in their management. Dysautonomia, neurogenic bladder, and constipation also entail secondary risks. If atonic bladder with dysuria is present, intermittent self-catheterization or indwelling catherization with a urethral catheter should also be considered.
7. Scoliosis and hip dislocation
Scoliosis is progressive and affects both cardiopulmonary function and quality of life. Its prevention is important, and it should be checked upon at every examination. If it is suspected, it should be confirmed on X-rays and corrected with a brace. Surgery should be considered once the Cobb angle exceeds 40–50°. Hip dislocation may be caused by hypotonia, rigidity, seizures, brittle bones, or other conditions and is made more likely because the femur is readily adducted, internally rotated, and flexed. It may be necessary to use a night-time brace to retain it in the abducted position. In severe cases, orthopedic surgery may be performed to extend or transect the iliopsoas muscle.
8. Bone loss and fracture
Factors such as lack of movement, little exposure to sunlight, and poor nutrition increase the risk of bone loss and fracture. A number of anti-epileptic drugs and the long-term use of proton pump inhibitors to prevent reflux esophagitis are also believed to increase the risk of bone demineralization and fracture. To prevent fractures, blood calcium and vitamin D levels must be regularly evaluated, and regular bone mineral density measurements by DEXA or other techniques is also recommended.
9. Visual, hearing, and speech impairments
Leukodystrophy causes visual impairment via damage to the cerebral white matter and retina, cataracts, and glaucoma. Hearing is similarly impaired due to damage to the cerebral cortex. If patients exhibit a sudden impairment in communication ability, hearing tests should be performed. Electronic communication tools can help facilitate communication in children with visual or hearing impairments.
10. Sleep disturbance
Although sleep disturbances are common, it is often not obvious to others. There are many possible causes, including pain, behavioral problems, a side effect of the use of multiple drugs, glossoptosis causing obstructive respiratory disturbances, and dysautonomia due to cerebral damage. Start by creating an environment conducive to sleep. Melatonin, the safest and best tolerated drug treatment, may be effective. As a next option, the benzodiazepines zolpidem and temazepam may also be used, but as their effects may also include hypersomnia, glossoptosis due to hypotonia, and increased secretions, they should be introduced and continued cautiously.
References
- Helman G, Van Haren K, Bonkowsky JL, Bernard G, Pizzino A, Braverman N, Suhr D, Patterson MC, Ali Fatemi S, Leonard J, van der Knaap M, Back SA, Damiani S, Goldma SA, Takanohashi A, Petryniak M, Rowitch D, Messing A, Wrabetz L, Schiffmann R, Eichler F, Escolar ML, Vanderver A; GLIA Consortium. Disease specific therapies in leukodystrophies and leukoencephalopathies. Mol Genet Metab 2015; 114: 527-536.
- Van Haren K, Bonkowsky JL, Bernard G, Murphy JL, Pizzino A, Helman G, Suhr D, Waggoner J, Hobson D, Vanderver A, Patterson MC; GLIA Consortium. Consensus statement on preventive and symptomatic care of leukodystrophy patients. Mol Genet Metab 2015; 114: 516-526.
- Adang LA, Sherbini O, Ball L, Bloom M, Darbari A, Amartino H, DiVito D, Eichler F, Escolar M, Evans SH, Fatemi A, Fraser J, Hollowell L, Jaffe N, Joseph C, Karpinski M, Keller S, Maddock R, Mancilla E, McClary B, Mertz J, Morgart K, Langan T, Leventer R, Parikh S, Pizzino A, Prange E, Renaud DL, Rizzo W, Shapiro J, Suhr D, Suhr T, Tonduti D, Waggoner J, Waldman A, Wolf NI, Zerem A, Bonkowsky JL, Bernard G, van Haren K, Vanderver A; Global Leukodystrophy Initiative (GLIA) Consortium. Revised consensus statement on the preventive and symptomatic care of patients with leukodystrophies. Mol Genet Metab 2017; 122: 18-32.
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