Juvenile neuronal ceroid lipofuscinosis (JNCL, CLN3 disease) is a neurodegenerative disease with an incidence of 2–5 per 100,000 (1, 2). Debut occurs at 5–7 years of age, most often as a rapid progressive loss of vision leading to blindness within 2–4 years. The disease propagation continues with loss of cognition, speech, motor abilities, and development of epilepsy and behavioral challenges. Death occurs in the early thirties (3). Typical time course relative to onset of specific clinical symptoms or milestones appears in Table 1. In addition to epilepsy, recurrent episodes of an anxious, fearful behavior, which occur in more than half of post-adolescent JNCL patients and may be related to premature death (4), cause great parental concern (5). As can be seen from Table 1, it is a relatively late symptom of the disease. In addition to a frightened facial appearance while clinging to the bed or chair, the young JNCL patients demonstrate increased atypical muscle activity, excessive sweating, increased body temperature and blood pressure, tachycardia, tachypnea and often show non-sustained multi-directional nystagmus, pupil dilation and a decreased awareness (4–7). The episodes might start without obvious reason, but typically the episodes occur when the patients are being left alone by their caregivers, or are exposed to stimuli that are either non-nociceptive (lifting the patient against gravity, i.e., from bed to a chair/wheelchair) or only minimally nociceptive (bathing, brushing teeth) or when they hear loud sounds (4–7). The episodes initially last for seconds or minutes and occur often in clusters. The rate of episodes increases during the later stages of the disorder and may last up to hours and days (4–7). Phenotypically, the episodes thus resemble the seizures which normally are seen following acute traumatic brain injuries (TBI), known as paroxysmal sympathetic hyperactivity (PSH), and believed to be caused by a disconnection syndrome between sympathetic inhibitory regions (insula, cingulate cortex) and sympathetic activating centers (hypothalamus and brainstem) (8–14).

The attacks develop in the late teens during a phase of the disease where the cognitive developmental age of the affected patients is around, or even below 2 years of age (15); i.e., at a mental developmental age when individuals do not have the cognitive ability to encounter a normal anxiety response. Instead, the anxious behavior has to be perceived as an exaggerated form of a developmental “natural fear”-response, i.e., the fear similar to what happens when healthy toddlers are left alone, feel discomfort or are exposed to stimuli as loud sounds, unknown person or start rising from the ground (16–18). Based on present knowledge of triggering factors, the neural anxiety/fear circuit, its afferent and efferent pathways and the documented CLN3 disease-impact on these tracks, the current study presents and discusses a rational approach and strategy how to treat and/or prevent the attacks.

PubMed was searched for articles written in the English language and published between Jan 1, 1970, and April 1, 2023 using the search terms “ceroid,” “lipofuscin” “Batten,” “juvenile NCL,” “NCL,” “CLN3,” “neurodegeneration”; “Parkinson’s disease”; “dementia”; “Alzheimer”; “anxiety”; “fear”; “autonomic dysfunction”; “dysautonomia”; “paroxysmal sympathetic hyperactivity”; “sympathetic nervous system”; “parasympathetic nervous system”; “heart rate variability”; “vagal stimulation”; “heart and brain.” The final reference list was generated on the basis of relevance to the topic covered.

Clinical as well as preclinical research suggests that anxiety and fear emerge from alterations in a set of highly interconnected neural circuits, of which the amygdala, ventral hippocampus, and medial prefrontal cortex are key nodes (17–19).

In addition to the lack of visual stimuli and the resulting difficulties it entails, patients with JNCL have a disturbed somatosensory modulation leading to a reduced threshold for pain; an allodynia (22). Since repeated skin stimulation shows increase in responsiveness and an increased thalamocortical excitability has been demonstrated in the sensorimotor cortex of JNCL patients (23), the pain most probably is of a central rather than a peripheral origin (22).

So far, there exists no human imaging, histological, or functional studies with a specific focus on the neural anxiety/fear circuit in JNCL. Recently, a top-down CLN3 disease propagation has been proposed (24), with starting point in the internal layers of the retina followed by a secondary spreading through the connectome to the hemispheres, the brainstem, and via medulla to the peripheral nerves. Accordingly, conventional magnetic resonance imaging (MRI) studies have shown a progressive cerebral, cerebellar, and hippocampal atrophy (25–27), whereas functional studies using positron emission tomography (PET) and Single photon emission computed tomography (SPECT) in adolescent and adult JNCL patients have demonstrated thalamic, nigrostriatal and striatal dysfunction as well (28, 29). Using a Cln3 knockout (Cln3^Delta-ex1-6) mice model, an increased anxiety-related behavior has been demonstrated in older mice (30). Grünewald and co-workers suggested that the co-occurrence of severely affected inhibitory and excitatory synaptic transmission in the amygdala, hippocampus and loss of GABAergic interneurons thereby fosters an imbalance of network inhibition and excitation (30). The present studies thus point to changes due to degenerative processes in CLN3 disease that also are believed to be important in the patho-etiology of PSH following TBI (5, 13, 14).

The efferent pathways of the anxiety-fear circuit include autonomic, neuroendocrine, and skeletal-motor responses. As described, activation of the autonomic nervous system occurs fast, and since the immediate consequence is an increase in heart rate, an important pivot must be the balance between the activating sympathetic system and the inhibiting parasympathetic system. Variations of heart-rate variability (HRV) can be used as a proxy for the activity of the autonomic nervous system (5, 31). In JNCL, a significant age-dependent decrease of the parasympathetic activity has been documented without any accompanying age-related change of the neural and neuro-hormonal sympathetic activities (5, 31). Beyond 18–20 years of age the activity of parasympathetic activity is very low (5), and when an adolescent or adult JNCL patient, having a developmental cognitive level equal to a 1–2-year-old child, experiences the sensation of fear, the markedly autonomic imbalance with a dominance of sympathetic activity leaves the ascending noradrenergic system originated from the locus ceruleus (LC) without its normal parasympathetic counterbalance, the fear response will be exaggerated in relation to the stimulus at hand.

The lack of increase in the neural and neuro-hormonal induced sympathetic activity in JNCL with increasing age (5, 31) indicates that a major stimulating role of neuro-endocrine pathways of the anxiety/fear circuit is weak or absent. However, so far, there exist no investigations of the adrenergic hormone or transmitter levels during the attacks in JNCL patients, and therefore a neuro-endocrine impact cannot be totally excluded. In PSH following TBI, median values of the Adrenocorticotropic Hormone (ACTH) and cortisol concentrations are moderately elevated whereas the neurotransmitter concentrations (noradrenaline, epinephrine, dopamine) are significantly increased to levels that nearly equalize the increase regarded as diagnostic in patients with suspected pheochromocytoma (32). Although some of the clinical symptoms of pheochromocytoma (palpitations, diaphoresis and paroxysmal hypertension) are identical to the episodic fearful symptoms in JNCL, others are quite different, like for instance paleness in form of a blotchy or mottled skin color which is a common symptom of pheochromocytoma and caused by adrenergic constriction of the skin blood vessels. In JNCL, on the contrary, the skin is warm, red, and flushing. Anxiety and muscle activity, especially tremor, can be seen in patients with pheochromocytoma, but they do not have an anxious behavior or atypical muscle activity of the same high intensity as in JNCL.

Heart rate variability studies in PSH related to TBI have shown both a higher sympathetic excitatory activity and a lower parasympathetic activity in patients with TBI when compared to controls in general (no TBI), and that during several months after their brain injury. Of note, no differences in heart rate variability were found when TBI patients with and without symptoms of PSH was compared (33, 34). In PSH following TBI, the attacks may even occur when the patients are still sedated and unable to feel fear. In addition, in the majority of TBI patients, the episodes are transient and is phased out within 1–2 weeks (35). In others it persists several months, is related to severity and propagation of the brain damage and a bad prognosis (12–14). In JNCL, the attacks disappear when the patients sleep or are sedated, worsen in frequency, length and often also in intensity over the years. Additionally, in JNCL the sympathetic-parasympathetic imbalance seems more related to a severe decrease in the parasympathetic neural activity than an increase in the neuro-humeral sympathetic activity demonstrated in TBI (33, 34). Therefore, despite many phenotypic similarities, including the allodynia, atypical motor activity and seizure-like appearance there may nevertheless be individual patho-etiological autonomic differences between the well described PSH following TBI and the PSH-like, non-epileptic episodes seen in adolescent and adult JNCL patients.

The key node of the regulatory control of the skeletal muscle is the central nucleus of the amygdala (CeA) (17, 20), which, by mingling of the emotional processing and the balance between the sympathetic and parasympathetic activity, stimulates various midbrain regions or nuclei responsible for different aspects of the fear/anxiety response, including skeletal muscle responses like freezing or escape, startling and respiratory movements. In JNCL, the motor activity is primarily an increase in atypical motor activity, including shivering and a dystonic positioning similar to the abnormal motor activity seen in PSH following TBI (13, 14).

In summary, patients with JNCL have a disturbed somatosensory modulation leading to a reduced threshold of pain; degeneration within the central neural anxiety/fear circuit leading to an imbalance of the central network inhibition and excitation pathways; and finally, an, with advancing age, increasing imbalance between the sympathetic and parasympathetic neural activity resulting in a significant dominance of the sympathetic branch beyond early adolescence.

Theoretically, there are thus 3 points of attack when trying to treat or prevent the episodes: (1) increase in threshold of discomfort impact; (2) modulation of the imbalance of central network inhibition and excitation, and (3) restoring the balance between the sympathetic and parasympathetic neural systems. In relation to the latter, it is important to note that low parasympathetic activity by itself is accompanied by increased anxiety readiness in children (35) and that low parasympathetic activity decreases nociceptive sensitivity and is accompanied by an increase in visceral pain and a generalized somatosensory allodynia (36). A restoring of the sympathetic-parasympathetic balance may thus have a dual effect.

The author confirms being the sole contributor of this work and has approved it for publication.

This work was funded by Legacy of Emanuel Poulsen.

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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