Narcolepsy Treatments and Siddha Remedies

Narcolepsy is a long-term neurological disorder that involves a decreased ability to regulate sleep-wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. About 70% of those affected also experience episodes of a sudden loss of muscle strength, known as cataplexy. Narcolepsy paired with cataplexy is evidenced to be an autoimmune disorder. These experiences of cataplexy can be brought on by strong emotions. Less commonly, there may be vivid hallucinations or an inability to move (sleep paralysis) while falling asleep or waking up. Narcolepsy can occur anytime between early childhood and 50 years typically, however, there is no upper age limit to getting it, with 15 and 36 years of age being the peak time periods when it occurs.

Meaning of Narcolepsy

Narcolepsy is a neurological disorder that affects your ability to wake and sleep. People with narcolepsy have excessive, uncontrollable daytime sleepiness. They may also suddenly fall asleep at any time, during any type of activity.

Narcolepsy Symptoms

There are two main characteristics of narcolepsy: 

• Excessive daytime sleepiness, and
• Abnormal REM sleep.

Excessive daytime sleepiness

Excessive daytime sleepiness occurs even after adequate nighttime sleep. Narcoleptics may not be able to experience the amount of restorative deep sleep that healthy people experience due to abnormal REM regulation – they are not “over-sleeping”.

It can vary in severity and appears most commonly during monotonous situations that don’t require much interaction. Daytime naps may occur with little warning and may be physically irresistible. These naps can occur several times a day. They are typically refreshing, but only for a few hours or less. Drowsiness may persist for prolonged periods or remain constant. A second prominent symptom of narcolepsy is abnormal REM sleep. Narcoleptics are unique in that they enter into the REM phase of sleep at the beginning of sleep, even when sleeping during the day.

Abnormal REM sleep

Narcoleptics typically have higher REM sleep density than non-narcoleptics, but also experience more REM sleep without atonia. Many narcoleptics have sufficient REM sleep but do not feel refreshed or alert throughout the day. This can feel like living their entire lives in a constant state of sleep deprivation.

The classic symptoms of the disorder often referred to as the “tetrad of narcolepsy,” are cataplexy, sleep paralysis, hypnagogic hallucinations, and excessive daytime sleepiness. Other symptoms may include automatic behaviors and night-time wakefulness. These symptoms may not occur in all people with narcolepsy.

Narcolepsy and insomnia

Many people with narcolepsy also have insomnia for extended periods of time. Excessive daytime sleepiness and cataplexy often become severe enough to cause serious problems in a person’s social, personal, and professional life. Normally, when an individual is awake, brain waves show a regular rhythm. After about an hour and a half of NREM sleep, the brain waves begin to show a more active pattern again, called REM sleep (rapid eye movement sleep), when most remembered dreaming occurs. Associated with the EEG-observed waves during REM sleep, muscle atonia is presently called REM atonia.

Narcoleptics can gain excess weight; children can gain 20 to 40 lbs (9 to 18 kg) when they first develop narcolepsy; in adults, the body-mass index is about 15% above average.

Narcolepsy Causes

The mechanism involves the loss of orexin-releasing neurons within the lateral hypothalamus (about 70,000 neurons).

Some research indicated that people with type 1 narcolepsy (narcolepsy with cataplexy) have a lower level of orexin (hypocretin), which is a chemical contributing to the regulation of wakefulness and REM Sleep. It also acts as a neurotransmitter to enable nerve cells to communicate.

In up to 10% of cases, there is a family history of the disorder. Family history is more common in narcolepsy with cataplexy. There is a strong link with certain genetic variants, which may make T-cells susceptible to react to the orexin-releasing neurons (autoimmunity) after being stimulated by infection with H1N1 influenza. In addition to genetic factors, low levels of orexin peptides have been correlated with a history of infection, diet, contact with toxins such as pesticides, and brain injuries due to head trauma, brain tumors, or strokes.

Genetics

The primary genetic factor strongly implicated in the development of narcolepsy involves an area of chromosome 6 known as the human leukocyte antigen (HLA) complex. Specific variations in HLA genes are strongly correlated with the presence of narcolepsy (HLA DQB1*06:02, frequently in combination with HLA DRB1*15:01); however, these variations are not required for the condition to occur and sometimes occur in individuals without narcolepsy. These genetic variations in the HLA complex are thought to increase the risk of an auto-immune response to orexin-releasing neurons in the lateral hypothalamus.

H1N1 Influenza

Type 1 narcolepsy is caused by hypocretin/orexin neuronal loss. 

Genes associated with narcolepsy mark the particular HLA heterodimer (DQ0602) involved in the presentation of these antigens and modulate the expression of the specific T cell receptor segments (TRAJ24 and TRBV4-2) involved in T cell receptor recognition of these antigens, suggesting causality.

Narcolepsy Pathophysiology

Loss of neurons

Orexin, otherwise known as hypocretin, is a neuropeptide that acts within the brain to regulate appetite and wakefulness as well as a number of other cognitive and physiological processes. Loss of these orexin-producing neurons causes narcolepsy and most individuals with narcolepsy have a reduced number of these neurons in their brains. 

Selective destruction of the HCRT/OX neurons with preservation of proximate structures suggests a highly specific autoimmune pathophysiology. Cerebrospinal fluid HCRT-1/OX-A is undetectable in up to 95% of patients with type 1 narcolepsy.

The REM stage of sleep

The system which regulates sleep, arousal, and transitions between these states in humans is composed of three interconnected subsystems: the orexin projections from the lateral hypothalamus, the reticular activating system, and the ventrolateral preoptic nucleus. In narcoleptic individuals, these systems are all associated with impairments due to a greatly reduced number of hypothalamic orexin projection neurons and significantly fewer orexin neuropeptides in cerebrospinal fluid and neural tissue, compared to non-narcoleptic individuals. 

Those with narcolepsy generally experience the REM stage of sleep within five minutes of falling asleep, while people who do not have narcolepsy (unless they are significantly sleep-deprived) do not experience REM until after a period of slow-wave sleep, which lasts for about the first hour or so of a sleep cycle.

Disturbed sleep states

In humans, narcoleptic sleep is characterized by a tendency to go abruptly from a waking state to REM sleep with little or no intervening non-REM sleep. The changes in the motor and proprioceptive systems during REM sleep have been studied in both human and animal models.

During normal REM sleep, spinal and brainstem alpha motor neuron hyperpolarization produces almost complete atonia of skeletal muscles via an inhibitory descending reticulospinal pathway. Acetylcholine may be one of the neurotransmitters involved in this pathway. In narcolepsy, the reflex inhibition of the motor system seen in cataplexy has features normally seen only in normal REM sleep.

Narcolepsy Diagnosis

The third edition of the International Classification of Sleep Disorders (ICSD-3) differentiates between narcolepsy with cataplexy (type 1) and narcolepsy without cataplexy (type 2), while the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) uses the diagnosis of narcolepsy to refer to type 1 narcolepsy only. The DSM-5 refers to narcolepsy without cataplexy as hypersomnolence disorder. The most recent edition of the International Classification of Diseases, ICD-11, currently identifies three types of narcolepsy: type 1 narcolepsy, type 2 narcolepsy, and unspecified narcolepsy.

ICSD-3 diagnostic criteria

ICSD-3 diagnostic criteria posit that the individual must experience “daily periods of irrepressible need to sleep or daytime lapses into sleep” for both subtypes of narcolepsy. This symptom must last for at least three months. For a diagnosis of type 1 narcolepsy, the person must present with either cataplexy, a mean sleep latency of fewer than 8 minutes, and two or more sleep-onset REM periods (SOREMPs), or they must present with a hypocretin-1 concentration of less than 110 pg/mL.

A diagnosis of type 2 narcolepsy requires a mean sleep latency of fewer than 8 minutes, two or more SOREMPs, and a hypocretin-1 concentration of more than 110 pg/mL.

DSM-5 narcolepsy criteria

DSM-5 narcolepsy criteria require that the person display recurrent periods of “an irrepressible need to sleep, lapsing into sleep, or napping” at least three times a week over a period of three months. The individual must also display one of the following:

• Cataplexy,
• The hypocretin-1 concentration of less than 110 pg/mL,
• REM sleep latency of fewer than 15 minutes, or
• Multiple sleep latency tests (MSLT) showing sleep latency of fewer than 8 minutes and two or more SOREMPs. 

Narcolepsy Tests

Three tests that are commonly used in diagnosing narcolepsy are polysomnography (PSG), the multiple sleep latency test (MSLT), and the Epworth Sleepiness Scale (ESS). These tests are usually performed by a sleep specialist.

Measuring orexin levels in a person’s cerebrospinal fluid sampled in a spinal tap may help in diagnosing narcolepsy, with abnormally low levels serving as an indicator of the disorder. This test can be useful when MSLT results are inconclusive or difficult to interpret.

Narcolepsy Treatment

Orexin replacement

People with narcolepsy can be substantially helped, but not cured. However, the technology exists in an early form such as experiments in using the pre-pro-orexin transgene via gene editing to restore normal function in mice models by making other neurons produce orexin after the original set has been destroyed, or replacing the missing orexinergic neurons with hypocretin stem cell transplantation, are both steps in that direction for fixing the biology effectively permanently once applied in humans.

Additionally, effective ideal non-gene editing and chemical-drug methods involve hypocretin treatments methods such as future drugs like hypocretin agonists (such as danavorexton) or hypocretin replacement, in the form of hypocretin 1 given intravenous (injected into the veins), intracisternal (direct injection into the brain), and intranasal (sprayed through the nose), the latter being low in efficacy, at the low amount used in current experiments but may be effective at very high doses in the future.

Behavioral

General strategies like people and family education, sleep hygiene and medication compliance, and discussion of safety issues for example driving license can be useful. Regular follow-up is useful to be able to monitor the response to treatment, assess the presence of other sleep disorders like obstructive sleep apnea, and discuss psychosocial issues.

In many cases, planned regular short naps can reduce the need for pharmacological treatment of the EDS, but only improve symptoms for a short duration. A 120-minute nap provided benefit for 3 hours in the person’s alertness whereas a 15-minute nap provided no benefit. Daytime naps are not a replacement for nighttime sleep. Ongoing communication between the health care provider, person, and family members is important for the optimal management of narcolepsy.

Medications for narcolepsy

Central nervous system

The main treatment of excessive daytime sleepiness in narcolepsy is central nervous system stimulants such as methylphenidate, amphetamine, dextroamphetamine, modafinil, and armodafinil. In late 2007 an alert for severe adverse skin reactions to modafinil was issued by the FDA. Pemoline was previously used but was withdrawn due to toxicity.

Non-stimulant drug

Another drug that is used is atomoxetine, a non-stimulant, and a norepinephrine reuptake inhibitor (NRI), which has no addiction liability or recreational effects. Other NRIs like viloxazine and reboxetine has also been used in the treatment of narcolepsy. Additional related medications include mazindol and selegiline.

Sodium oxybate

Another FDA-approved treatment option for narcolepsy is sodium oxybate, also known as sodium gamma-hydroxybutyrate (GHB). It can be used for cataplexy associated with narcolepsy and excessive daytime sleepiness associated with narcolepsy. Several studies also showed that sodium oxybate is effective to treat cataplexy.

Solriamfetol – A new molecule

Solriamfetol works by inhibiting the reuptake of the monoamines via the interaction with both the dopamine transporter and the norepinephrine transporter.

This mechanism differs from that of the wake-promoting agents modafinil and armodafinil. Solriamfetol also differs from amphetamines as it does not promote the release of norepinephrine in the brain.

Selective serotonin reuptake inhibitors

Narcolepsy has sometimes been treated with selective serotonin reuptake inhibitors and tricyclic antidepressants, such as clomipramine, imipramine, or protriptyline, as well as other drugs that suppress REM sleep. Venlafaxine, an antidepressant that blocks the reuptake of serotonin and norepinephrine, has shown usefulness in managing symptoms of cataplexy, however, it has notable side effects including sleep disruption. 

Narcolepsy among Children

Common behavioral treatments for childhood narcolepsy include improved sleep hygiene, scheduled naps, and physical exercise.

These medications include central nervous system stimulants such as methylphenidate, modafinil, amphetamine, and dextroamphetamine. Other drugs, such as sodium oxybate or atomoxetine, may also counteract sleepiness. Medications such as sodium oxybate, venlafaxine, fluoxetine, and clomipramine may be prescribed if the child presents with cataplexy.

Herbal remedies for Narcolepsy

Ayurveda offers various herbal combinations for the treatment of narcolepsy which are safe, effective, and do not cause side effects.

Brahmi Capsules

Brahmi is a wonderful herb known for its functions such as sound sleep, calming emotional imbalance, and also improves concentration and alertness. It is known by the name brain tonic in Ayurveda. It is also known to support the body’s natural healing process and healthy blood circulation. These are prepared from the pure extract of the herb Bacopa monnieri and are very useful for patients suffering from narcolepsy.

Dose: 1 capsule twice daily.

Gotukola Capsules

The botanical name of Gotukola is Centella asiatica. It has neuroprotective properties. The Gotukola herb has a calming action on the mind. It helps in making the mind resistant to worrying and overthinking. It also restores mental energy and vitalizes the neurons by reducing oxidative stress in the brain. Gotukola also strengthens the functioning of the connective tissues in the body. It also improves the strength of the veins and enhances the flow of blood and nutrients to the brain.  Thus, gotukola capsules are quite effective for patients suffering from narcolepsy.

Dose: 1 capsule twice daily.

Punarnava Capsules

Ayurveda’s Punarnava Capsules are prepared from the extract of Boerhavia diffusa.  Punarnava is a well-known herb in Ayurveda. It is cooling in nature and helps in relaxing nerves as well. It makes the body new again, so the name Punarnava. These capsules also cause sound sleep without causing any side effects.

Dose: 1 capsule twice daily.

Ashwagandha Capsules

Ashwagandha (Withania somnifera) is a well-known Ayurvedic herb and it has been used for the treatment of stress for ages. Excessive neuron activity leads to the sleep disorders such as narcolepsy. Ashwagandha induces a calming anxiolytic effect. It produces calming, anti-anxiety, anti-convulsive, and highly stabilizing effects.  It contains various active components that have effects on Central Nervous System (CNS) and act as anti-stress agents.

Dose: 1 capsule twice daily.

Amalaki Rasayan Capsules

Amalaki Rasayan Capsules of Ayurveda are prepared from Amla or Indian gooseberry with a very specific process. Amla is the richest source of Vitamin C. Vitamin C is rich in antioxidant properties and aid in combating free radicals. It is also one of the most powerful rejuvenating herbs used by mankind for ages. These capsules help in keeping the body fit and active.

Dose: 1 capsule twice daily after meals with water.

Siddha remedies for Narcolepsy

Reference: https://en.wikipedia.org/wiki/Narcolepsy