What is the management and treatment of Kleine-Levine (KLS) syndrome?

Management and Treatment of Kleine-Levin Syndrome

Lithium is the recommended treatment for Kleine-Levin syndrome (KLS) in adults to reduce episode frequency, despite very low quality evidence, and requires intensive serum monitoring twice weekly during initial treatment until stabilization. 1

Acute Episode Management

During active episodes, treatment options are limited and largely supportive:

• Stimulants (amphetamines) may reduce somnolence in approximately 40% of cases during acute episodes, though evidence is limited. 2
• Neuroleptics and antidepressants show poor benefit for acute symptom management. 2
• Intravenous methylprednisolone has been studied but lacks sufficient evidence for formal recommendations, though may reduce duration of prolonged episodes (>30 days). 1, 3
• Armodafinil has been reported effective in isolated case reports but lacks systematic evidence. 4

Prophylactic Treatment to Prevent Relapses

Lithium is the only medication with demonstrated efficacy for preventing KLS relapses, showing a 41% response rate compared to 19% with medical abstention. 2 The American Academy of Sleep Medicine provides a conditional recommendation for lithium use versus no treatment. 1

Critical Lithium Safety Requirements

Lithium toxicity occurs at doses close to therapeutic concentrations, making this a high-risk medication requiring specific infrastructure:

• Serum lithium concentrations must be measured twice per week during acute treatment phase until patient and levels are stabilized. 1, 5, 6
• Facilities for prompt and accurate serum lithium determination must be accessible before initiating therapy. 1
• Regular monitoring of clinical state, lithium levels, electrolytes, and renal function is mandatory throughout treatment. 6

Common Adverse Effects and Toxicity Signs

The most common adverse effects reported in KLS patients include:

• Tremor
• Polyuria-polydipsia
• Diarrhea
• Subclinical hypothyroidism 1

Early signs of lithium toxicity include tremor, nausea, diarrhea, and polyuria-polydipsia. 5, 6 No serious adverse events or lithium toxicity were reported in the open-label KLS study, though this reflects very low quality evidence. 1

Critical Drug Interactions and Contraindications

• NSAIDs must be avoided as they increase lithium levels and precipitate toxicity. 5, 6
• Lithium should be temporarily suspended during intercurrent illness, planned IV radiocontrast administration, bowel preparation, or prior to major surgery. 5, 6
• Adequate hydration must be maintained, especially during illness. 6
• Lithium may cause fetal harm based on animal and limited human studies; the risk-benefit balance differs for pregnant and breastfeeding women. 1

Hemodialysis Indications for Severe Toxicity

Urgent hemodialysis is indicated with serum levels ≥3.5 mEq/L and significant symptoms, or with any level accompanied by significant cardiovascular compromise. 5, 6

Medications Without Proven Benefit

Carbamazepine and other antiepileptics (except oxcarbamazepine in isolated case reports) show no benefit for KLS relapse prevention. 2, 4

Disease Course and Monitoring

KLS typically:

• Affects predominantly males (64-68%) with median onset at age 15 years 2, 7
• Lasts a median of 8 years with approximately 7 episodes of 10 days duration, recurring every 3.5 months 2
• Episodes become progressively milder and less frequent before resolving in most patients 8
• One-third of patients experience prolonged episodes (>30 days) with more severe immediate and long-term consequences 7
• 20-40% develop long-term mild cognitive impairment or mood disorders requiring regular cognitive and psychiatric assessment during asymptomatic periods 3

Common Pitfalls

The most critical pitfall is misdiagnosis as a psychiatric condition (mental disorders represent the most frequent differential diagnosis), leading to inappropriate treatment with antidepressants or antipsychotics that show poor efficacy. 2, 7 The key distinguishing feature is sudden severe hypersomnia (>18 hours/day of sleep) that is recurrent, combined with derealization and apathy during episodes with complete normality between episodes. 3