What are the causes of decreased cerebrospinal fluid (CSF) hypocretin levels?

Causes of Decreased CSF Hypocretin Levels

The primary cause of decreased cerebrospinal fluid (CSF) hypocretin levels is narcolepsy type 1, which results from the degeneration of hypothalamic neurons that produce hypocretin/orexin. 1, 2

Primary Causes

Narcolepsy Type 1 (with Cataplexy)

• Most common and well-established cause of low CSF hypocretin
• Characterized by:
  • CSF hypocretin-1 levels below 110 pg/mL (considered diagnostic) 1
  • Strong association with HLA-DQB1*0602 positivity (93% of cases) 1
  • Presence of cataplexy (sudden loss of muscle tone triggered by emotions)
  • Excessive daytime sleepiness
  • Other REM sleep abnormalities (sleep paralysis, hypnagogic hallucinations)

Narcolepsy Without Cataplexy

• Less commonly associated with hypocretin deficiency
• Only a subset of these patients show decreased CSF hypocretin levels 1, 2
• Lower HLA-DQB1*0602 positivity (56%) compared to narcolepsy with cataplexy 1

Secondary (Symptomatic) Causes

Neurological Disorders

1. Brain Tumors

   • Particularly those involving the hypothalamus 3
   • Accounts for approximately 28% of symptomatic narcolepsy cases with potential hypocretin deficiency 3

2. Traumatic Brain Injury

   • Post-traumatic hypersomnia can be associated with intermediate hypocretin levels 4
   • Represents about 16% of symptomatic narcolepsy cases 3

3. Inherited/Genetic Disorders

   • Most common cause of symptomatic narcolepsy (33% of cases) 3
   • Includes Prader-Willi Syndrome (PWS), which can present with lower (though not as low as narcolepsy type 1) CSF hypocretin levels 5

4. Demyelinating Disorders

   • Multiple sclerosis can cause symptomatic narcolepsy with reduced hypocretin levels 3
   • Acute disseminated encephalomyelitis has been reported 3

5. Cerebrovascular Disorders

   • Strokes affecting the hypothalamus 3
   • Normal pressure hydrocephalus may be associated with intermediate hypocretin levels 4

6. Neurodegenerative Disorders

   • Rare cases reported with various neurodegenerative conditions 3

7. Inflammatory/Infectious Conditions

   • Encephalitis affecting the hypothalamus 3

8. Intracranial Hypotension

   • CSF leaks can potentially affect hypocretin levels through altered CSF dynamics 5, 6

Clinical Significance of Decreased CSF Hypocretin

• Hypocretin deficiency identifies a homogenous group of patients with narcolepsy characterized by:

  • Presence of definite cataplexy
  • Severe excessive daytime sleepiness
  • Frequent sleep onset REM periods (SOREMPs) 7

• CSF hypocretin-1 measurement has high specificity (99.1%) and sensitivity (88.5%) for narcolepsy with cataplexy 4

Important Clinical Considerations

• CSF hypocretin-1 levels below 110 pg/mL are considered diagnostic for narcolepsy 1

• Values above 200 pg/mL are considered normal 1

• Intermediate values (110-200 pg/mL) may be seen in:

  • Some cases of narcolepsy without cataplexy
  • Secondary narcolepsy
  • Post-traumatic hypersomnia
  • Normal pressure hydrocephalus 4

• CSF hypocretin measurement is most useful when:

  • Cataplexy is present
  • Multiple Sleep Latency Test (MSLT) is difficult to interpret (e.g., in patients already on psychoactive medications)
  • Other concurrent sleep disorders are present 1

• In symptomatic cases, EDS may sometimes be reversible with improvement of the underlying neurological disorder and corresponding improvement in hypocretin status 3