Myopathies Associated with Decreased Hypocretin in CSF
Guillain-Barré syndrome (GBS) is the most well-documented myopathy associated with decreased hypocretin (orexin) levels in cerebrospinal fluid, with myotonic dystrophy type 1 also showing evidence of hypocretin deficiency in patients with excessive daytime sleepiness.
Guillain-Barré Syndrome and Hypocretin
GBS has been clearly linked to decreased hypocretin levels in CSF:
- Studies have found undetectably low hypocretin-1 levels (<100 pg/mL) in approximately 25% of GBS patients 1
- Moderate reductions in hypocretin-1 levels have been observed in an additional 39% of GBS patients 1
- Low hypocretin levels in GBS typically occur early in the disease course and are associated with upper CNS level abnormalities 1, 2
GBS is characterized by:
- Progressive bilateral weakness of arms and legs
- Absent or decreased tendon reflexes in affected limbs
- Relatively mild sensory symptoms and signs
- Cranial nerve involvement (especially bilateral facial palsy)
- Autonomic dysfunction 3
Myotonic Dystrophy Type 1
Myotonic dystrophy type 1 has also shown evidence of hypocretin deficiency:
- Significantly lower hypocretin-1 levels compared to controls (p<0.001) 4
- Some patients with myotonic dystrophy type 1 and excessive daytime sleepiness have hypocretin-1 levels in the range observed in narcolepsy (<110 pg/mL) 4
- Others show intermediate levels (110-200 pg/mL) 4
Clinical features include:
- Myotonia
- Muscle weakness
- Cataracts
- Endocrine dysfunction
- Intellectual impairment
- Excessive daytime sleepiness 4
Other Potential Myopathies and Neurological Disorders
While not as well documented as GBS and myotonic dystrophy, other conditions that may affect both muscle function and hypocretin levels include:
- Miller-Fisher syndrome (a variant of GBS) - moderate reduction in hypocretin-1 levels observed in some patients 1
- Chronic inflammatory demyelinating polyneuropathy (CIDP) - rare cases with reduced hypocretin levels 1
- Neurodegenerative diseases with myopathic components:
- Alzheimer's disease
- Huntington's disease
- Parkinson's disease 5
Pathophysiological Mechanisms
The exact mechanisms linking myopathies to hypocretin deficiency are not fully understood, but may include:
- Autoimmune processes targeting hypocretin-producing neurons (as in narcolepsy)
- Inflammatory processes affecting the hypothalamus
- Disruption of neural pathways involving hypocretin signaling
- Genetic factors affecting both muscle function and hypocretin production 6
Clinical Implications
When evaluating patients with myopathies and suspected hypocretin deficiency:
- Consider measuring CSF hypocretin-1 levels, particularly in patients with:
- Excessive daytime sleepiness
- Sleep-onset REM periods
- Unexplained fatigue or fluctuating symptoms
- Be aware that hypocretin deficiency may contribute to sleep disturbances in these patients
- The timing of hypocretin measurement may be important, as levels can fluctuate during the disease course, particularly in GBS 1
Diagnostic Considerations
For accurate assessment of hypocretin status:
- Lumbar CSF measurement is the most widely used technique
- Levels <110 pg/mL are considered low (narcolepsy range)
- Levels between 110-200 pg/mL are considered intermediate
- Levels >200 pg/mL are considered normal 6
Understanding the relationship between myopathies and hypocretin deficiency may help guide treatment approaches for associated sleep disturbances and potentially improve quality of life in affected patients.