Skip to content
How It Works
Explore
Ask a Question Resources Pricing
Who It's For
Patients
Decode results, prep for appointments, weigh options.
Caregivers & advocates
Carry the research load for someone you love.
Providers & clinicians
Resources for patients in your practice.
Log In Sign Up
PubMed This is a summary of 43 peer-reviewed journal articles Updated
Neurology

What Treatable Conditions Mimic Fatal Familial Insomnia?

At a Glance

Severe insomnia with rapid cognitive decline does not by itself prove fatal familial insomnia. Doctors urgently look for treatable infections, immune-related brain inflammation, metabolic problems, medication effects, and withdrawal, while testing the PRNP gene helps confirm FFI.

In this answer

3 sections

01

How is FFI Actually Confirmed?

02

Treatable Conditions That Can Overlap with FFI

03

The Diagnostic Workup: What Tests Can and Cannot Tell Us

When to Seek Emergency Care
Do not wait for scheduled outpatient appointments if you or a loved one experience rapidly worsening confusion, a new seizure, an inability to eat or drink safely, severe agitation or hallucinations, fever, or signs of autonomic instability (such as severe changes in heart rate or blood pressure). Likewise, never abruptly stop alcohol, benzodiazepines, or other regularly used sedatives, as sudden withdrawal is a life-threatening medical emergency. Seek immediate emergency medical assessment.

When severe insomnia occurs alongside rapid cognitive decline, abnormal movements, and autonomic symptoms (like a racing heart or sweating), it is frightening. While these symptoms can occur in fatal familial insomnia (FFI), they are not unique to this rare disease [1][2]. Several potentially treatable conditions can overlap substantially with the symptoms of FFI and other rapidly progressive dementias (conditions causing a rapid loss of brain function) [3][4]. Because missing a treatable alternative is a major safety issue, the most critical step a medical team will take is to comprehensively evaluate for these reversible causes [3].

How is FFI Actually Confirmed?

A diagnosis of FFI cannot be made simply by having severe insomnia and a normal MRI or routine spinal fluid test. Confirmation generally requires finding a pathogenic variant in the PRNP gene—classically the D178N mutation combined with methionine at codon 129—identified through specialized genetic testing [5][6]. Because this genetic result has profound implications for biological relatives, genetic counseling is a critical part of the diagnostic process [5].

Treatable Conditions That Can Overlap with FFI

The urgent diagnostic workup typically investigates several categories of overlapping conditions:

Autoimmune Encephalitis

Autoimmune encephalitis occurs when the immune system mistakenly attacks healthy brain cells, causing rapid cognitive decline, sleep disturbances, movement problems, and psychiatric symptoms [7][8]. Several types can resemble FFI:

  • Anti-IgLON5 disease: This condition frequently presents with severe sleep disorders (including sleep apnea, sleepwalking, and excessive daytime sleepiness) alongside movement and swallowing difficulties [9][10].
  • Other neural targets: Antibodies such as LGI1, NMDAR, GABABR, and CASPR2 can also cause rapidly progressive dementia, subtle seizures, and severe behavioral changes [7][11].

Autoimmune encephalitis is potentially treatable with immunotherapies, though neurologic recovery varies [7]. Sometimes, these conditions are triggered by an underlying, hidden tumor (a paraneoplastic syndrome) [12][13]. Finding and treating the tumor is important, though immunotherapy may still be required.

Infections

Certain central nervous system infections are medical emergencies that can cause rapid cognitive decline:

  • HSV and VZV Encephalitis: Herpes simplex virus (HSV) and varicella-zoster virus (VZV) can cause sudden confusion, seizures, and behavioral changes, sometimes without a fever or localized signs [14][15]. If suspected, doctors often start intravenous antivirals (like acyclovir) immediately while waiting for spinal fluid test results [14].
  • Neurosyphilis and HIV: Late-stage syphilis or uncontrolled HIV-associated dementia can mimic prion diseases [16][17].
  • Whipple disease: A rare bacterial infection causing severe cognitive impairment, often accompanied by a fever or chronic diarrhea. Antibiotic treatment is available, and early detection can improve outcomes [18].

Endocrine and Metabolic Disorders

Severe chemical imbalances or nutritional deficiencies can profoundly disrupt brain function:

  • Calcium abnormalities: Certain tumors can release proteins (like PTHrP) that cause severe spikes in blood calcium, leading to rapid cognitive decline that may improve with urgent medical correction and tumor treatment [19].
  • Metabolic and nutritional issues: Liver failure, kidney issues, or severe vitamin B12 and thiamine deficiencies can lead to metabolic encephalopathies mirroring a rapid dementia [20][21].

Medications, Toxins, and Substance Withdrawal

Drug interactions, recent medication changes, or toxic exposures can profoundly disrupt cognition [22]. Importantly, sudden withdrawal from alcohol or sedatives can cause delirium tremens, which may involve severe insomnia, autonomic overactivity, and hallucinations (a state called agrypnia excitata that heavily overlaps with FFI symptoms) [1][23]. This withdrawal is a life-threatening emergency requiring urgent, supervised medical care.

Hashimoto-Related Encephalopathy (SREAT)

Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT) is a highly controversial diagnosis [24][25]. It has historically been considered when a patient has encephalopathy (confusion) and high levels of anti-thyroid antibodies [26]. However, anti-thyroid antibodies are relatively common and nonspecific in the general population, and normal thyroid hormone levels neither prove nor disprove the condition [24]. SREAT is strictly a “diagnosis of exclusion,” meaning doctors must rule out all other infectious, metabolic, and neurologic causes before assigning this label [25].

Primary Sleep and Psychiatric Disorders

A careful evaluation must assess for primary sleep or psychiatric contributors [2]. Severe, untreated obstructive sleep apnea can cause sleep fragmentation and cognitive impairment [27]. Severe psychiatric episodes (like major depression) can also cause profound insomnia and cognitive changes, but symptoms should never be attributed solely to a psychiatric or sleep condition until dangerous neurologic and infectious causes have been formally ruled out [2][28].

Other Rapidly Progressive Neurologic Diseases

Other aggressive conditions, such as rapidly progressing Alzheimer’s disease, Lewy body dementia, or intravascular large B-cell lymphoma (a rare cancer inside the brain’s blood vessels) can closely resemble FFI [29][30].

The Diagnostic Workup: What Tests Can and Cannot Tell Us

Because the differential is broad, multiple tests are pursued concurrently by a multidisciplinary team (often including neurology, infectious disease, and sleep specialists) [3].

  • Brain Imaging (MRI): Used to look for strokes, tumors, or inflammation. Some autoimmune mimics show specific inflammatory patterns, but an MRI may be entirely normal in FFI [31][5].
  • Cerebrospinal Fluid (CSF) Analysis: A lumbar puncture tests for white blood cells (pleocytosis) or highly elevated proteins, which generally suggest inflammation, infection, or malignancy [32][22]. However, both FFI and autoimmune encephalitis can present with entirely normal CSF results [33][5]. Specialized prion assays (like RT-QuIC) are highly specific for prion diseases overall but can return a negative result in FFI, meaning a negative test does not perfectly exclude it [34].
  • Autoimmune Studies (Serum and CSF): Doctors may test blood (serum) and CSF for autoantibodies. Positive antibodies—especially in serum alone—do not always prove an autoimmune cause, and a negative panel does not perfectly exclude autoimmune encephalitis [35][36]. Paired testing is helpful but must match the patient’s clinical symptoms [37].
  • Electroencephalogram (EEG): EEG measures the brain’s electrical activity to help detect nonconvulsive seizures [38]. Since seizures can be intermittent, a routine, short EEG might miss them; prolonged or continuous EEG monitoring is sometimes necessary [39].
  • Polysomnography (Sleep Study): A specialized video sleep study can quantify total sleep time, disrupted sleep stages, and motor events [40]. While FFI may show severe sleep architecture disruption (like the loss of normal sleep spindles and slow-wave sleep), these findings overlap with other conditions and cannot definitively diagnose FFI on their own [41].
  • Empiric Treatments: When clinical suspicion is high for certain reversible conditions, specialists might recommend a trial of treatment (such as empiric antiviral therapy for suspected HSV) before all results return [14]. Immunotherapies (like high-dose steroids) carry risks of worsening hidden infections, so specialists carefully weigh the risks and benefits before starting them [42]. A positive response to steroids does not definitively prove an autoimmune diagnosis [43].

Common questions in this guide

What treatable illnesses can look like fatal familial insomnia?
Autoimmune encephalitis, including anti-IgLON5 disease, infections such as herpes simplex or varicella-zoster encephalitis, metabolic or nutritional problems, medication or toxin effects, and alcohol or sedative withdrawal can resemble FFI. Severe sleep apnea, psychiatric illness, and some other rapidly progressive neurologic diseases can also produce overlapping symptoms, so clinicians use a broad evaluation.
How is fatal familial insomnia confirmed?
Symptoms such as severe insomnia, cognitive decline, or a normal MRI cannot confirm FFI. Confirmation generally depends on specialized testing that identifies a pathogenic PRNP gene variant, classically D178N with methionine at codon 129; genetic counseling is important because the result may affect biological relatives.
Can a normal MRI or spinal fluid test rule out FFI or autoimmune encephalitis?
No. MRI and routine cerebrospinal fluid results can be normal in FFI, and autoimmune encephalitis can also have normal cerebrospinal fluid, so doctors interpret these tests alongside symptoms, antibody testing, EEG, and other results. Abnormal white blood cells or very high protein may suggest infection, inflammation, or cancer, but normal findings do not settle the diagnosis.
What tests are used to investigate FFI-like symptoms?
Clinicians may use brain MRI, a lumbar puncture with cerebrospinal fluid testing, blood and spinal-fluid antibody tests, EEG monitoring, a video sleep study, and PRNP genetic testing. Testing is often coordinated by neurology with infectious disease, sleep, and other specialists, and prolonged EEG may be needed if seizures are intermittent.
When should someone with possible FFI symptoms seek emergency care?
Get emergency medical help for rapidly worsening confusion, a new seizure, inability to eat or drink safely, severe agitation or hallucinations, fever, or major changes in heart rate or blood pressure. Do not abruptly stop alcohol, benzodiazepines, or other regular sedatives, because withdrawal can be life-threatening and requires supervised treatment.
Does a positive antibody test or improvement with steroids prove autoimmune encephalitis?
No. An antibody found only in blood may be nonspecific, a negative antibody panel does not completely exclude autoimmune encephalitis, and improvement after steroids is not definitive proof. Specialists compare test results with symptoms and exclude infections and other causes before deciding on immunotherapy.
Could Hashimoto-related encephalopathy explain these symptoms?
Steroid-responsive encephalopathy associated with autoimmune thyroiditis, or SREAT, is a controversial diagnosis. High thyroid antibody levels alone do not prove it, and normal thyroid hormone levels do not settle the diagnosis; doctors consider SREAT only after infectious, metabolic, medication-related, and other neurologic causes have been excluded.

Related questions

What Do PRNP D178N and Codon 129 Mean for FFI Risk? FFI vs. Sporadic Fatal Insomnia: What's the Difference? What Do Polysomnography and FDG-PET Show in Suspected FFI? Why Do Sleeping Pills Fail in FFI, and How Is It Treated? How Is Fatal Familial Insomnia Diagnosed vs Other Causes?
Show more
Does a PRNP Mutation Guarantee Fatal Familial Insomnia? What Should I Expect Before and After FFI Genetic Testing? How Is Genetic Testing Arranged for FFI Relatives? How Is Swallowing Managed in Fatal Familial Insomnia? How Does FFI Testing Affect Privacy, Insurance, and Work? Can FFI Cause Central Fever? When Is It an Emergency? Can You Have FFI With a Negative PRNP Genetic Test? Can You Join FFI Research Without Learning Your PRNP Status? How Are Dehydration and Hyponatremia Monitored in FFI? How Are FFI Agitation, Hallucinations, and Dreams Managed? How Are FFI Jerks, Stiffness, and Walking Problems Treated? How Are Stridor and Breathing Problems Treated in FFI? How Are FFI Sweating, Fast Heart Rate, and Fever Managed? Should Children Have Predictive Genetic Testing for FFI?

Get notified when new evidence is published on Fatal familial insomnia.

We monitor PubMed for new peer-reviewed studies on this topic and email a short summary when something meaningful changes.

References

References (43)
  1. 1

    Fatal familial insomnia and Agrypnia Excitata: Autonomic dysfunctions and pathophysiological implications.

    Baldelli L, Provini F

    Autonomic neuroscience : basic & clinical 2019; (218()):68-86 doi:10.1016/j.autneu.2019.02.007.

    PMID: 30890351
  2. 2

    Plasma neurofilament light chain as a biomarker for fatal familial insomnia.

    Hermann P, Canaslan S, Villar-Piqué A, et al.

    European journal of neurology 2022; (29(6)):1841-1846 doi:10.1111/ene.15302.

    PMID: 35212083
  3. 3

    Rapidly Progressive Dementia.

    Geschwind MD

    Continuum (Minneapolis, Minn.) 2016; (22(2 Dementia)):510-37 doi:10.1212/CON.0000000000000319.

    PMID: 27042906
  4. 4

    Rapidly progressive dementias - aetiologies, diagnosis and management.

    Hermann P, Zerr I

    Nature reviews. Neurology 2022; (18(6)):363-376 doi:10.1038/s41582-022-00659-0.

    PMID: 35508635
  5. 5

    Genetic prion disease: D178N with 129MV disease modifying polymorphism-a clinical phenotype.

    Tan TH, Stark RJ, Waterston JA, et al.

    BMJ neurology open 2020; (2(2)):e000074 doi:10.1136/bmjno-2020-000074.

    PMID: 33681799
  6. 6

    Dysfunction of the cardiac parasympathetic system in fatal familial insomnia: a heart rate variability study.

    Cui Y, Huang Z, Chu M, et al.

    Sleep 2023; (46(4)) doi:10.1093/sleep/zsac294.

    PMID: 36472576
  7. 7

    Autoimmune Encephalitis Resembling Dementia Syndromes.

    Bastiaansen AEM, van Steenhoven RW, de Bruijn MAAM, et al.

    Neurology(R) neuroimmunology & neuroinflammation 2021; (8(5)) doi:10.1212/NXI.0000000000001039.

    PMID: 34341093
  8. 8

    Anti-dipeptidyl-peptidase-like protein 6 encephalitis, a rare cause of reversible rapid progressive dementia and insomnia.

    Zhou Q, Zhu X, Meng H, et al.

    Journal of neuroimmunology 2020; (339()):577114 doi:10.1016/j.jneuroim.2019.577114.

    PMID: 31775073
  9. 9

    Clinical manifestations of the anti-IgLON5 disease.

    Gaig C, Graus F, Compta Y, et al.

    Neurology 2017; (88(18)):1736-1743 doi:10.1212/WNL.0000000000003887.

    PMID: 28381508
  10. 10

    Case Report: Neuropsychological Findings in IgLON5 Antibody Disorder.

    El Shazly J, Juenemann M, Gerriets T, Tschernatsch M

    Frontiers in neurology 2021; (12()):632497 doi:10.3389/fneur.2021.632497.

    PMID: 33633675
  11. 11

    Improving the antibody-based evaluation of autoimmune encephalitis.

    McCracken L, Zhang J, Greene M, et al.

    Neurology(R) neuroimmunology & neuroinflammation 2017; (4(6)):e404 doi:10.1212/NXI.0000000000000404.

    PMID: 29075658
  12. 12

    The expanded clinical spectrum of anti-GABABR encephalitis and added value of KCTD16 autoantibodies.

    van Coevorden-Hameete MH, de Bruijn MAAM, de Graaff E, et al.

    Brain : a journal of neurology 2019; (142(6)):1631-1643 doi:10.1093/brain/awz094.

    PMID: 31009048
  13. 13

    Update on the diagnosis of encephalitis.

    Arbizu J, Gállego Pérez-Larraya J, Hilario A, et al.

    Revista espanola de medicina nuclear e imagen molecular 2022; (41(4)):247-257 doi:10.1016/j.remnie.2022.05.003.

    PMID: 35701317
  14. 14

    Subacute Herpes Simplex Type 1 Encephalitis: Case Report With Literature Review.

    Elshony H, Idris A, Al-Ghamdi A, et al.

    The neurologist 2021; (26(5)):178-184 doi:10.1097/NRL.0000000000000343.

    PMID: 34491935
  15. 15

    Rapidly progressive dementia: An eight year (2008-2016) retrospective study.

    Anuja P, Venugopalan V, Darakhshan N, et al.

    PloS one 2018; (13(1)):e0189832 doi:10.1371/journal.pone.0189832.

    PMID: 29346380
  16. 16

    [Rapidly progressive dementia by late neurosyphilis (general paresis). Case report].

    Atzin-Vela GA, González-Rodríguez CH, Chable-Guerrero FA, Bernal-González HS

    Revista medica del Instituto Mexicano del Seguro Social 2024; (62(5)):1-6.

    PMID: 39578093
  17. 17

    Human immunodeficiency virus-associated dementia complex with positive 14-3-3 protein in cerebrospinal fluid: A case report.

    He YS, Qin XH, Feng M, et al.

    World journal of clinical cases 2024; (12(12)):2065-2073 doi:10.12998/wjcc.v12.i12.2065.

    PMID: 38680258
  18. 18

    Rapidly progressive dementia and intractable diarrhea: a teaching case report and a systematic review of cognitive impairment in Whipple's disease.

    Manini A, Querzola G, Lovati C, Pantoni L

    Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 2022; (43(2)):907-926 doi:10.1007/s10072-021-05844-5.

    PMID: 34981284
  19. 19

    PTHrP-Producing Renal Cell Carcinoma Presenting as Rapidly Progressive Cognitive Impairment: A Case Report.

    Yano F, Sawada N, Tanaka N, et al.

    IJU case reports 2026; (9(1)):e70142 doi:10.1002/iju5.70142.

    PMID: 41567516
  20. 20

    Treatable causes of adult-onset rapid cognitive impairment.

    Wang S, Zhang J, Liang J, et al.

    Clinical neurology and neurosurgery 2019; (187()):105575 doi:10.1016/j.clineuro.2019.105575.

    PMID: 31715517
  21. 21

    Rapidly Progressive Dementia in an Elderly Male: Perseverance Becomes the Key to a Rare Diagnosis.

    Negi A, Prabhu MM

    Cureus 2023; (15(10)):e47231 doi:10.7759/cureus.47231.

    PMID: 38021635
  22. 22

    Rapidly Progressive Dementia.

    Day GS

    Continuum (Minneapolis, Minn.) 2022; (28(3)):901-936 doi:10.1212/CON.0000000000001089.

    PMID: 35678409
  23. 23

    Agrypnia excitata: a human model to explore the derailment of sleep-wake cycle integrated control.

    Mutti C, Baldelli L, Cortelli P, et al.

    Journal of sleep research 2025; (34(2)):e14324 doi:10.1111/jsr.14324.

    PMID: 39223838
  24. 24

    Thyroid antibodies: the end of an era?

    Rodenbeck SJ, Clardy SL

    Brain communications 2021; (3(2)):fcab030 doi:10.1093/braincomms/fcab030.

    PMID: 34159318
  25. 25

    Hashimoto Encephalopathy With Status Epilepticus.

    Sliwinska A, Fumuso P, Stringer B, et al.

    Cureus 2020; (12(12)):e11857 doi:10.7759/cureus.11857.

    PMID: 33409091
  26. 26

    A Case of Euthyroid Steroid-Responsive Encephalopathy With Subacute Dementia.

    John R, Datta A, Ovallath S

    Cureus 2021; (13(9)):e17689 doi:10.7759/cureus.17689.

    PMID: 34513537
  27. 27

    Stridor during sleep: description of 81 consecutive cases diagnosed in a tertiary sleep disorders center.

    Silva C, Iranzo A, Maya G, et al.

    Sleep 2021; (44(3)) doi:10.1093/sleep/zsaa191.

    PMID: 32954431
  28. 28

    A fatal familial insomnia patient newly diagnosed as having depression: A case report.

    Yukang T, Jiaquan L, Xiaoling L, et al.

    Medicine 2021; (100(41)):e27544 doi:10.1097/MD.0000000000027544.

    PMID: 34731156
  29. 29

    Rapidly progressive dementia due to intravascular lymphoma: A prion disease reference center experience.

    Bentivenga GM, Baiardi S, Righini L, et al.

    European journal of neurology 2024; (31(1)):e16068 doi:10.1111/ene.16068.

    PMID: 37738529
  30. 30

    From parasomnia to agrypnia excitata - An illustrative case on diagnostic approach.

    Fong SL, Dy Closas AMF, Lim TT, et al.

    Parkinsonism & related disorders 2023; (109()):105332 doi:10.1016/j.parkreldis.2023.105332.

    PMID: 36948111
  31. 31

    Cerebral amyloid angiopathy-related inflammation: current status and future implications.

    Wu JJ, Yao M, Ni J

    Chinese medical journal 2021; (134(6)):646-654 doi:10.1097/CM9.0000000000001427.

    PMID: 33625036
  32. 32

    Improving Early Recognition of Creutzfeldt-Jakob Disease Mimics.

    Lazar EB, Porter AL, Prusinski CC, et al.

    Neurology. Clinical practice 2022; (12(6)):406-413 doi:10.1212/CPJ.0000000000200097.

    PMID: 36540139
  33. 33

    Novel Surrogate Markers of CNS Inflammation in CSF in the Diagnosis of Autoimmune Encephalitis.

    Jiang JX, Fewings N, Dervish S, et al.

    Frontiers in neurology 2019; (10()):1390 doi:10.3389/fneur.2019.01390.

    PMID: 32116981
  34. 34

    Diagnosis of prion diseases by RT-QuIC results in improved surveillance.

    Rhoads DD, Wrona A, Foutz A, et al.

    Neurology 2020; (95(8)):e1017-e1026 doi:10.1212/WNL.0000000000010086.

    PMID: 32571851
  35. 35

    CSF findings in patients with anti-N-methyl-D-aspartate receptor-encephalitis.

    Wang R, Guan HZ, Ren HT, et al.

    Seizure 2015; (29()):137-42.

    PMID: 26076857
  36. 36

    Seroprevalence of neuronal antibodies in diseases mimicking autoimmune encephalitis.

    Vaisvilas M, Petrosian D, Bagdonaite L, et al.

    Scientific reports 2024; (14(1)):5352 doi:10.1038/s41598-024-55995-6.

    PMID: 38438516
  37. 37

    Autoimmune encephalopathies presenting as dementia of subacute onset and rapid progression.

    Banks SA, Sechi E, Flanagan EP

    Therapeutic advances in neurological disorders 2021; (14()):1756286421998906 doi:10.1177/1756286421998906.

    PMID: 33796145
  38. 38

    Creutzfeldt-Jakob Disease Presenting as Expressive Aphasia and Nonconvulsive Status Epilepticus.

    Mahboob HB, Kaokaf KH, Gonda JM

    Case reports in critical care 2018; (2018()):5053175 doi:10.1155/2018/5053175.

    PMID: 29666711
  39. 39

    Heidenhain Variant of Sporadic Creutzfeldt-Jakob Disease with a Variety of Visual Symptoms: A Case Report with Autopsy Study.

    Hisata Y, Yamashita S, Tago M, et al.

    The American journal of case reports 2023; (24()):e938654 doi:10.12659/AJCR.938654.

    PMID: 36905109
  40. 40

    Clinical Features and Sleep Analysis of Chinese Patients with Fatal Familial Insomnia.

    Wu L, Lu H, Wang X, et al.

    Scientific reports 2017; (7(1)):3625 doi:10.1038/s41598-017-03817-3.

    PMID: 28620158
  41. 41

    Fatal familial insomnia presenting with agrypnia excitata and very low atonia index level: A case report and literature review.

    Yang TW, Park B, Kim KT, et al.

    Medicine 2018; (97(18)):e0646 doi:10.1097/MD.0000000000010646.

    PMID: 29718878
  42. 42

    Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT): Characteristics, treatment and outcome in 251 cases from the literature.

    Laurent C, Capron J, Quillerou B, et al.

    Autoimmunity reviews 2016; (15(12)):1129-1133 doi:10.1016/j.autrev.2016.09.008.

    PMID: 27639840
  43. 43

    Creutzfeldt-Jakob disease mimicking Hashimoto's encephalopathy: steroid response followed by decline.

    Wu TC, Zhao F, Liang Y, et al.

    Open life sciences 2025; (20(1)):20251245 doi:10.1515/biol-2025-1245.

    PMID: 41883393

This page explains how clinicians evaluate treatable conditions that can resemble FFI for informational purposes only and does not constitute medical advice. Rapid confusion, seizures, unsafe swallowing, severe agitation, hallucinations, fever, major heart-rate or blood-pressure changes, or sedative withdrawal require urgent medical assessment.