Experts Create New Guidelines for Optimal CLN2 Disease Management

A group of experts has created a set of guidelines to best manage late infantile Batten disease, also known as CLN2. 

Although effective strategies exist, clinicians currently lack common management guidelines to best respond to the disease’s symptoms. Multidisciplinary approaches and consensual practice guidelines are key to achieving optimal care, researchers said.

The study, “Management Strategies for CLN2 Disease,” was published in the journal Pediatric Neurology.

Late infantile Batten disease is a serious, inherited disease in children, typically appearing between the ages of 2 and 4. It is characterized by seizures, loss of motor skills and cognitive ability, and a reduced life expectancy. It is caused by mutations in the TPP1 gene, which encodes for an enzyme called tripeptidyl peptidase 1 (TPP1).

CLN2 disease management is complex. Treatment approaches are limited to symptomatic and supportive care, and patients require a multidisciplinary approach due to the diversity and severity of symptoms. The families of patients also need considerable psychosocial support. Therefore, specific guidance “is necessary to ensure that patients and families receive appropriate care,” researchers said.

To improve CLN2 disease management, researchers created a set of guidelines based on literature and the opinions of clinicians and patient advocates with extensive experience in CLN2. This is the first comprehensive effort to date to compile consensual recommendations to guide this management.

Sponsored by BioMarin, which produced the first approved therapy for CLN2 disease, Brineura, researchers surveyed 24 healthcare professionals — including several specialists — as well as patient advocates from eight countries. Later, a smaller group subsequently met to discuss current management practices.

Management evolves as the disease progresses. Priority shifts from early diagnosis and maintenance of function during the initial stages to maintaining quality of life at a later stage.

An ideal care team should include physicians, nurses, therapists, dietitians, psychologists, social workers, and counselors. But the values of patients and families “should be central in all decision-making processes,” the study’s authors wrote.

Early diagnosis

A major obstacle to optimal care is the time required for CLN2 disease diagnosis. A delay of two to three years after the first symptoms appear leaves most patients with significant disabilities already at the time of diagnosis.

Delays are due to a lack of disease awareness and to the non-specificity or the misinterpretation of initial symptoms.

“New-onset unprovoked seizures in combination with a history of early language delay in a child aged 2-4 years should prompt suspicion of CLN2 disease,” researchers said.

Electroencephalography (EEG) to detect seizures and magnetic resonance imaging (MRI) of the brain can also help at this early stage.

Definitive diagnosis can be obtained by testing for deficient enzyme activity of TPP1 and genetic testing for mutations of the TPP1 gene. Tissue biopsies may be used when molecular testing is unavailable.

Seizures

Common antiepileptic drugs are recommended, but in cases where multiple medications are needed to manage treatment-resistant seizures, the number of antiepileptics should be kept to a minimum to reduce side effects.

Antiepileptics should be selected with caution and re-evaluated periodically as they may exacerbate disease symptoms, such as seizures, speech impairment, and psychomotor decline. These antiepileptics include carbamazepine, phenytoin, and topiramate.

A ketogenic diet, which is high in fats and low in carbs, may be used as long as caregivers are aware of the difficulties in implementing the diet’s regimen and patients are monitored for side effects. This type of diet changes the source of the body’s energy from carbohydrates to fats, and promotes the use of ketone bodies — compounds produced during the metabolism of fats — as a source of energy, which is thought to have an antiepileptic effect.

Movement disorders, physical and occupational therapies

Myoclonus, the sudden and involuntary twitching of muscles, is a hallmark of CLN2 disease, but several other types of movement problems may appear. Antiepileptics are preferred for treating myoclonus. Physical therapy and orthopedic equipment such as ankle-foot orthoses, neck support, and vests can help alleviate motor symptoms and complications.

Treatment should be implemented early and tailored to the child’s abilities and the family’s goals. Two to three physical therapy sessions per week are recommended, including interventions to stretch the muscles, stabilize pressure in the joints, reduce muscle rigidity, and improve posture.

For managing speech and communication problems, the use of symbols and gestures may be helpful. This should be initiated early so the child can maintain meaningful communication and social interactions after the loss of speech.

Other complementary therapies, such as hippotherapy, hydrotherapy, and music therapy, may aid in relieving anxiety and pain and provide comfort, social interaction, and amusement, the guidelines state.

Feeding and nutritional balance 

As children progressively lose their ability to eat, they are at a higher risk of aspirating oral secretions, which may lead to severe lung infections and cardiorespiratory failure.

Thus, caregivers should attentively monitor children during meals, and treatment with medicines and nonpharmacologic interventions, such as suctioning, oral care, physiotherapy, and corn silk tea, are recommended.

Tube feeding is advised when the risk of aspiration is high, the child struggles to eat, or when weight loss or nutritional deficiencies occur.

Preventive treatment for constipation should also be implemented, including an adequate intake of liquids and fibers, stool softeners, agents to improve intestinal motility, and laxatives.

Breathing problems

At late stages of the disease, children may develop life-threatening breathing problems that are preventable with vaccination against infectious agents, regular clearing of lung mucus, and bronchodilator medicines.

Sleep disturbance

Good sleep habits and strategies to promote falling and staying asleep — such as music, massage, weighted blankets, and medications such as melatonin — may help treat sleep difficulties, which are thought to affect a majority of patients with CLN2 disease.

Vision loss

Visual deterioration worsens with advancing age, ultimately leading to vision loss. No treatments are available yet to prevent this disease symptom, but experts recommend avoiding medications that are toxic to the retina, such as hydroxychloroquine, thioridazine, and vigabatrin. They also noted that evidence is lacking to support the beneficial effects of using polarized sunglasses or antioxidants.

Pain and distress

Identifying the cause of pain and other sources of discomfort is important to achieving optimal treatment. To assess pain, particularly when children can no longer speak, tools may be used including the Batten’s Observational Pain Scale.

Pain relief may be achieved with medication and nonpharmacologic interventions including complementary therapies, positioning aids, weighted blankets, physiotherapy, and heat.

Social and educational interventions

In addition to the above-mentioned strategies to promote children’s communication, maintaining school attendance as long as possible is advised to prevent social isolation and provide sensory stimulation.

Behavioral symptoms

Patients often present problems such as anxiety and agitation. Interventions should prevent the triggers of these negative behaviors (situations, settings, people), and relieve pain and sleep difficulties. Use of antipsychotic drugs is not recommended, due to the risk of movement disorders as side effects.

End-of-life care

Maintenance of quality of life, with a particular focus on the prevention of pain and the promotion of comfortable breathing, should be a priority at the end of life.

Psychosocial support for the family is also particularly critical at this stage. “It is important for clinicians to listen to families, encourage advanced end-of-life care planning and decision making, and respect the wishes of families,” researchers wrote.

“Effective strategies currently exist to manage many of the symptoms,” the team added. But improved tools are needed for assessing these symptoms.

“[A]s new research and therapies become available, it will be imperative to establish and then regularly revise consensus-based management guidelines,” the researchers concluded.