COVID-19-associated encephalopathy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Muhammad Adnan Haider, M.B.B.S.[2] Wajeeha Aiman, M.D.[3]

Synonyms and keywords:

Overview

Encephalopathy is an alteration of the level or contents of consciousness due to brain dysfunction and can result from global or focal brain lesions. SARS-CoV-2 which is the member of coronavirus family has caused many neurological complications including encephalopathy. Acute toxic encephalopathy is caused by toxemia, hypoxia and metabolic disorders due the systemic viral infection (viral sepsis).

Historical Perspective

COVID-19, a disease caused by SARS-CoV-2 first emerged in Wuhan, China in December 2019. It then spread so rapidly that it was declared as pandemic in Feb, 2020. It mostly presents with respiratory symptoms like flue, dry cough, fever, fatigue, dyspnea. Although rare but neurological manifestations have been reported throughout the spectrum of COVID-19 pandemic. These neurological symptoms range from headache, anosmia, meningitis, encephalitis, Guillain Berre Syndrome,and stroke. Encephalopathy is rare and few case has been reported with acute encephalopathy during the severe systemic SARS-CoV-2 infection.

Classification

Pathophysiology

  • Severe COVID-19 infection can lead to dysfunction of multiple organs of the body that can lead to hypoxic or metabolic insults to brain and cause encephalopathy.
  • Encephalitis/meningitis are caused by neurotropism of SARS-CoV-2 to brain and meninges through ACE2 receptors.
  • Encephalopathy is caused by hyper inflammation of brain by following three mechanisms;
  • cytokine storm
  • Hypoxic brain injury
  • molecular mimicry

Cytokine storm

  • SARS-CoV-2 causes several neurological complications through production of inflammatory cytokines (mainly IL-6) from glial cells called cytokine storm syndrome.[1]
  • SARS-CoV-2 activates CD4 cells of the immune system and CD4 cells activate macrophages by producing granulocyte-macrophage colony stimulating factors. Actiavted macrophages now produce IL-6.
  • IL-6 is a major cytokine of cytokine storm syndrome and leads to multiple organ failure. This severe organ damage leads to metabolic and toxic changes in the body which causes brain dysfunction and leads to SARS-CoV-2 related encephalopathy.[2]
  • This fact can be supported by the evidence that tocilizumab which is IL-6 antagonist is used in severe COVID-19 infections.[3]

Hypoxic Brain Injury

  • The hall mark of severe COVID-19 infection is dyspnea and hypoxemia due Acute Respiratory distress syndrome (ARDS).[4]
  • This hypoxia and hypoxemia is sometimes enough to cause diffuse brain injury and cause encephalopathy. [5]

Molecular Mimicry

  • Post-infectious encephalomyelitis, an autoimmune demyelinating disease of the brain, can be triggered by the SARS‐CoV‐2 virus.[6]
  • SARS-CoV-2 is considered to have similar antigenic determinants as that of some antigens present on human neuronal cells.
  • Immunological response to the SARS‐CoV‐2 virus cross-react with the myelin autoantigens, resulting in post-infectious encephalomyelitis.[7]
  • Neuropathological findings confirmed vascular and demyelinating pathology in a patient who died from COVID-19.[8]

Causes

  • COVID-19-associated encephalopathy may be caused by SARS-CoV-2.
  • To read more about this virus, click here.

Differentiating COVID-19-associated encephalopathy from other Diseases

The symptoms of encephalopathy may overlap with the symptoms of other diseases:

  • Intracranial lesions like tumors, masses, granulomas which are differentiated by the presence of focal neurologic signs and symptoms


Diseases Symptoms Physical Examination Past medical history Diagnostic tests Other Findings
Headache LOC Motor weakness Abnormal sensory Motor Deficit Sensory deficit Speech difficulty Gait abnormality Cranial nerves CT /MRI CSF Findings Gold standard test
Meningitis + - - - - + + - - History of fever and malaise - Leukocytes,

Protein

↓ Glucose

CSF analysis[9] Fever, neck

rigidity

Encephalitis + + +/- +/- - - + +/- + History of fever and malaise + Leukocytes, ↓ Glucose CSF PCR Fever, seizures, focal neurologic abnormalities
Brain tumor[10] + - - - + + + - + Weight loss, fatigue + Cancer cells[11] MRI Cachexia, gradual progression of symptoms
Hemorrhagic stroke + + + + + + + + - Hypertension + - CT scan without contrast[12][13] Neck stiffness
Subdural hemorrhage + + + + + - - - + Trauma, fall + Xanthochromia[14] CT scan without contrast[12][13] Confusion, dizziness, nausea, vomiting
Neurosyphilis[15][16] + - + + + + - + - STIs + Leukocytes and protein CSF VDRL-specifc

CSF FTA-Ab -sensitive[17]

Blindness, confusion, depression,

Abnormal gait

Complex or atypical migraine + - + + - - + - - Family history of migraine - - Clinical assesment Presence of aura, nausea, vomiting
Hypertensive encephalopathy + + - - - - + + - Hypertension + - Clinical assesment Delirium, cortical blindness, cerebral edema, seizure
Wernicke’s encephalopathy - + - - - + + + + History of alcohal abuse - - Clinical assesment and lab findings Ophthalmoplegia, confusion
CNS abscess + + - - + + + - - History of drug abuse, endocarditis, immunosupression + leukocytes, glucose and protien MRI is more sensitive and specific High grade fever, fatigue,nausea, vomiting
Drug toxicity - + - + + + - + - - - - Drug screen test Lithium, Sedatives, phenytoin, carbamazepine
Conversion disorder + + + + + + + + History of emotional stress - - Diagnosis of exclusion Tremors, blindness, difficulty swallowing
Metabolic disturbances (electrolyte imbalance, hypoglycemia) - + + + + + - - + - - Hypoglycemia, hypo and hypernatremia, hypo and hyperkalemia Depends on the cause Confusion, seizure, palpitations, sweating, dizziness, hypoglycemia
Multiple sclerosis exacerbation - - + + - + + + + History of relapses and remissions + CSF IgG levels

(monoclonal bands)

Clinical assesment and MRI [18] Blurry vision, urinary incontinence, fatigue
Seizure + + - - + + - - + Previous history of seizures - Mass lesion Clinical assesment and EEG [19] Confusion, apathy, irritability,

Other differentials

Toxic encephalopathy must also be differentiated from other diseases that cause personality changes, altered level of consciousness and hand tremors (asterixis). The differentials include the following:[20][21][22][23][24][25][26][27][28][29][30]

Diseases History and Symptoms Physical Examination Laboratory Findings
Personality changes Altered level of consciousness Hand tremors (asterixis) Slurred speech Writing disturbances Voice monotonous Impaired memory Elevated blood ammonia Hyponatremia hypokalemia
Hepatic encephalopathy ++ ++ ++ ++ ++ ++ ++ ++ ++ ++
Alcohol intoxication + + -/+ ++ + - + - -/+ -/+
Alcohol withdrawal + + - ++ + - + - -/+ -/+
Uremia ++ ++ + -/+ -/+ -/+ - ++ Hyperkalemia
Wernicke encephalopathy + + -/+ + + + ++ - - -
Toxic encephalopathy from drugs + + -/+ -/+ + -/+ + + -/+ -/+
Altered intracranial pressure + -/+ - -/+ -/+ - -/+ - - -
Intoxication by chemical agents -/+ -/+ -/+ -/+ -/+ - - - -/+ -/+
Malnutrition -/+ - - - -/+ - -/+ - -/+ -/+
Hypoxic brain injury - -/+ - -/+ -/+ -/+ -/+ - - -
Meningitis and encephalitis -/+ -/+ - -/+ + - - - -/+ -
Hypoglycemia -/+ -/+ - -/+ -/+ - - - -/+ -/+

Epidemiology and Demographics

The incidence/prevalence of [disease name] is approximately [number range] per 100,000 individuals worldwide.

OR

In [year], the incidence/prevalence of [disease name] was estimated to be [number range] cases per 100,000 individuals worldwide.

OR

In [year], the incidence of [disease name] is approximately [number range] per 100,000 individuals with a case-fatality rate of [number range]%.


Patients of all age groups may develop [disease name].

OR

The incidence of [disease name] increases with age; the median age at diagnosis is [#] years.

OR

[Disease name] commonly affects individuals younger than/older than [number of years] years of age.

OR

[Chronic disease name] is usually first diagnosed among [age group].

OR

[Acute disease name] commonly affects [age group].


There is no racial predilection to [disease name].

OR

[Disease name] usually affects individuals of the [race 1] race. [Race 2] individuals are less likely to develop [disease name].


[Disease name] affects men and women equally.

OR

[Gender 1] are more commonly affected by [disease name] than [gender 2]. The [gender 1] to [gender 2] ratio is approximately [number > 1] to 1.


The majority of [disease name] cases are reported in [geographical region].

OR

[Disease name] is a common/rare disease that tends to affect [patient population 1] and [patient population 2].

Risk Factors

There are no established risk factors for COVID-19-associated encephalopathy.

Screening

There is insufficient evidence to recommend routine screening for COVID-19-associated encephalopathy.

Natural History, Complications, and Prognosis

If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].

OR

Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].

OR

Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with [disease name] is approximately [#]%.

Diagnosis

Diagnostic Study of Choice

The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met: [criterion 1], [criterion 2], [criterion 3], and [criterion 4].

OR

The diagnosis of [disease name] is based on the [criteria name] criteria, which include [criterion 1], [criterion 2], and [criterion 3].

OR

The diagnosis of [disease name] is based on the [definition name] definition, which includes [criterion 1], [criterion 2], and [criterion 3].

OR

There are no established criteria for the diagnosis of [disease name].

History and Symptoms

The case reported with COVID-19 associated encephalopathy are analyzed in the table below :

Patient No. Early symptoms Later presentation GCS Lab. Findings Specific Tests Imaging studies
CBC CSF MRI/CT scan

Physical Examination

Patients with [disease name] usually appear [general appearance]. Physical examination of patients with [disease name] is usually remarkable for [finding 1], [finding 2], and [finding 3].

OR

Common physical examination findings of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

The presence of [finding(s)] on physical examination is diagnostic of [disease name].

OR

The presence of [finding(s)] on physical examination is highly suggestive of [disease name].

Laboratory Findings

An elevated/reduced concentration of serum/blood/urinary/CSF/other [lab test] is diagnostic of [disease name].

OR

Laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].

OR

[Test] is usually normal among patients with [disease name].

OR

Some patients with [disease name] may have elevated/reduced concentration of [test], which is usually suggestive of [progression/complication].

OR

There are no diagnostic laboratory findings associated with [disease name].

Electrocardiogram

There are no ECG findings associated with [disease name].

OR

An ECG may be helpful in the diagnosis of [disease name]. Findings on an ECG suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

X-ray

There are no x-ray findings associated with [disease name].

OR

An x-ray may be helpful in the diagnosis of [disease name]. Findings on an x-ray suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no x-ray findings associated with [disease name]. However, an x-ray may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

Echocardiography or Ultrasound

There are no echocardiography/ultrasound findings associated with [disease name].

OR

Echocardiography/ultrasound may be helpful in the diagnosis of [disease name]. Findings on an echocardiography/ultrasound suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no echocardiography/ultrasound findings associated with [disease name]. However, an echocardiography/ultrasound may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

CT scan

There are no CT scan findings associated with [disease name].

OR

[Location] CT scan may be helpful in the diagnosis of [disease name]. Findings on CT scan suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no CT scan findings associated with [disease name]. However, a CT scan may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

MRI

There are no MRI findings associated with [disease name].

OR

[Location] MRI may be helpful in the diagnosis of [disease name]. Findings on MRI suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no MRI findings associated with [disease name]. However, a MRI may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

Other Imaging Findings

There are no other imaging findings associated with [disease name].

OR

[Imaging modality] may be helpful in the diagnosis of [disease name]. Findings on an [imaging modality] suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

Other Diagnostic Studies

There are no other diagnostic studies associated with [disease name].

OR

[Diagnostic study] may be helpful in the diagnosis of [disease name]. Findings suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

Other diagnostic studies for [disease name] include [diagnostic study 1], which demonstrates [finding 1], [finding 2], and [finding 3], and [diagnostic study 2], which demonstrates [finding 1], [finding 2], and [finding 3].

Treatment

Medical Therapy

There is no treatment for [disease name]; the mainstay of therapy is supportive care.

OR

Supportive therapy for [disease name] includes [therapy 1], [therapy 2], and [therapy 3].

OR

The majority of cases of [disease name] are self-limited and require only supportive care.

OR

[Disease name] is a medical emergency and requires prompt treatment.

OR

The mainstay of treatment for [disease name] is [therapy].

OR

The optimal therapy for [malignancy name] depends on the stage at diagnosis.

OR

[Therapy] is recommended among all patients who develop [disease name].

OR

Pharmacologic medical therapy is recommended among patients with [disease subclass 1], [disease subclass 2], and [disease subclass 3].

OR

Pharmacologic medical therapies for [disease name] include (either) [therapy 1], [therapy 2], and/or [therapy 3].

OR

Empiric therapy for [disease name] depends on [disease factor 1] and [disease factor 2].

OR

Patients with [disease subclass 1] are treated with [therapy 1], whereas patients with [disease subclass 2] are treated with [therapy 2].

Surgery

Surgical intervention is not recommended for the management of [disease name].

OR

Surgery is not the first-line treatment option for patients with [disease name]. Surgery is usually reserved for patients with either [indication 1], [indication 2], and [indication 3]

OR

The mainstay of treatment for [disease name] is medical therapy. Surgery is usually reserved for patients with either [indication 1], [indication 2], and/or [indication 3].

OR

The feasibility of surgery depends on the stage of [malignancy] at diagnosis.

OR

Surgery is the mainstay of treatment for [disease or malignancy].

Primary Prevention

There are no established measures for the primary prevention of [disease name].

OR

There are no available vaccines against [disease name].

OR

Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].

OR

[Vaccine name] vaccine is recommended for [patient population] to prevent [disease name]. Other primary prevention strategies include [strategy 1], [strategy 2], and [strategy 3].

Secondary Prevention

There are no established measures for the secondary prevention of [disease name].

OR

Effective measures for the secondary prevention of [disease name] include [strategy 1], [strategy 2], and [strategy 3].

References

  1. Wang F, Nie J, Wang H, Zhao Q, Xiong Y, Deng L; et al. (2020). "Characteristics of Peripheral Lymphocyte Subset Alteration in COVID-19 Pneumonia". J Infect Dis. 221 (11): 1762–1769. doi:10.1093/infdis/jiaa150. PMC 7184346 Check |pmc= value (help). PMID 32227123 Check |pmid= value (help).
  2. Chen C, Zhang XR, Ju ZY, He WF (2020). "[Advances in the research of mechanism and related immunotherapy on the cytokine storm induced by coronavirus disease 2019]". Zhonghua Shao Shang Za Zhi. 36 (6): 471–475. doi:10.3760/cma.j.cn501120-20200224-00088. PMID 32114747 Check |pmid= value (help).
  3. Zhang C, Wu Z, Li JW, Zhao H, Wang GQ (2020). "Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality". Int J Antimicrob Agents. 55 (5): 105954. doi:10.1016/j.ijantimicag.2020.105954. PMC 7118634 Check |pmc= value (help). PMID 32234467 Check |pmid= value (help).
  4. Buckner FS, McCulloch DJ, Atluri V, Blain M, McGuffin SA, Nalla AK; et al. (2020). "Clinical Features and Outcomes of 105 Hospitalized patients with COVID-19 in Seattle, Washington". Clin Infect Dis. doi:10.1093/cid/ciaa632. PMC 7314181 Check |pmc= value (help). PMID 32444880 Check |pmid= value (help).
  5. Vashisht R, Duggal A (2020). "Respiratory failure in patients infected with SARS-CoV-2". Cleve Clin J Med. doi:10.3949/ccjm.87a.ccc025. PMID 32409443 Check |pmid= value (help).
  6. Parsons T, Banks S, Bae C, Gelber J, Alahmadi H, Tichauer M (2020). "COVID-19-associated acute disseminated encephalomyelitis (ADEM)". J Neurol. doi:10.1007/s00415-020-09951-9. PMC 7260459 Check |pmc= value (help). PMID 32474657 Check |pmid= value (help).
  7. Nalleballe K, Reddy Onteddu S, Sharma R, Dandu V, Brown A, Jasti M; et al. (2020). "Spectrum of neuropsychiatric manifestations in COVID-19". Brain Behav Immun. doi:10.1016/j.bbi.2020.06.020. PMC 7297688 Check |pmc= value (help). PMID 32561222 Check |pmid= value (help).
  8. Reichard RR, Kashani KB, Boire NA, Constantopoulos E, Guo Y, Lucchinetti CF (2020). "Neuropathology of COVID-19: a spectrum of vascular and acute disseminated encephalomyelitis (ADEM)-like pathology". Acta Neuropathol. 140 (1): 1–6. doi:10.1007/s00401-020-02166-2. PMC 7245994 Check |pmc= value (help). PMID 32449057 Check |pmid= value (help).
  9. Carbonnelle E (2009). "[Laboratory diagnosis of bacterial meningitis: usefulness of various tests for the determination of the etiological agent]". Med Mal Infect. 39 (7–8): 581–605. doi:10.1016/j.medmal.2009.02.017. PMID 19398286.
  10. Morgenstern LB, Frankowski RF (1999). "Brain tumor masquerading as stroke". J Neurooncol. 44 (1): 47–52. PMID 10582668.
  11. Weston CL, Glantz MJ, Connor JR (2011). "Detection of cancer cells in the cerebrospinal fluid: current methods and future directions". Fluids Barriers CNS. 8 (1): 14. doi:10.1186/2045-8118-8-14. PMC 3059292. PMID 21371327.
  12. 12.0 12.1 Birenbaum D, Bancroft LW, Felsberg GJ (2011). "Imaging in acute stroke". West J Emerg Med. 12 (1): 67–76. PMC 3088377. PMID 21694755.
  13. 13.0 13.1 DeLaPaz RL, Wippold FJ, Cornelius RS, Amin-Hanjani S, Angtuaco EJ, Broderick DF; et al. (2011). "ACR Appropriateness Criteria® on cerebrovascular disease". J Am Coll Radiol. 8 (8): 532–8. doi:10.1016/j.jacr.2011.05.010. PMID 21807345.
  14. Lee MC, Heaney LM, Jacobson RL, Klassen AC (1975). "Cerebrospinal fluid in cerebral hemorrhage and infarction". Stroke. 6 (6): 638–41. PMID 1198628.
  15. Liu LL, Zheng WH, Tong ML, Liu GL, Zhang HL, Fu ZG; et al. (2012). "Ischemic stroke as a primary symptom of neurosyphilis among HIV-negative emergency patients". J Neurol Sci. 317 (1–2): 35–9. doi:10.1016/j.jns.2012.03.003. PMID 22482824.
  16. Berger JR, Dean D (2014). "Neurosyphilis". Handb Clin Neurol. 121: 1461–72. doi:10.1016/B978-0-7020-4088-7.00098-5. PMID 24365430.
  17. Ho EL, Marra CM (2012). "Treponemal tests for neurosyphilis--less accurate than what we thought?". Sex Transm Dis. 39 (4): 298–9. doi:10.1097/OLQ.0b013e31824ee574. PMC 3746559. PMID 22421697.
  18. Giang DW, Grow VM, Mooney C, Mushlin AI, Goodman AD, Mattson DH; et al. (1994). "Clinical diagnosis of multiple sclerosis. The impact of magnetic resonance imaging and ancillary testing. Rochester-Toronto Magnetic Resonance Study Group". Arch Neurol. 51 (1): 61–6. PMID 8274111.
  19. Manford M (2001). "Assessment and investigation of possible epileptic seizures". J Neurol Neurosurg Psychiatry. 70 Suppl 2: II3–8. PMC 1765557. PMID 11385043.
  20. Meparidze MM, Kodua TE, Lashkhi KS (2010). "[Speech impairment predisposes to cognitive deterioration in hepatic encephalopathy]". Georgian Med News (181): 43–9. PMID 20495225.
  21. Kattimani S, Bharadwaj B (2013). "Clinical management of alcohol withdrawal: A systematic review". Ind Psychiatry J. 22 (2): 100–8. doi:10.4103/0972-6748.132914. PMC 4085800. PMID 25013309.
  22. Roldán J, Frauca C, Dueñas A (2003). "[Alcohol intoxication]". An Sist Sanit Navar. 26 Suppl 1: 129–39. PMID 12813481.
  23. Seifter JL, Samuels MA (2011). "Uremic encephalopathy and other brain disorders associated with renal failure". Semin Neurol. 31 (2): 139–43. doi:10.1055/s-0031-1277984. PMID 21590619.
  24. Handler CE, Perkin GD (1983). "Wernicke's encephalopathy". J R Soc Med. 76 (5): 339–42. PMC 1439130. PMID 6864698.
  25. Kim Y, Kim JW (2012). "Toxic encephalopathy". Saf Health Work. 3 (4): 243–56. doi:10.5491/SHAW.2012.3.4.243. PMC 3521923. PMID 23251840.
  26. Hartmann A, Buttinger C, Rommel T, Czernicki Z, Trtinjiak F (1989). "Alteration of intracranial pressure, cerebral blood flow, autoregulation and carbondioxide-reactivity by hypotensive agents in baboons with intracranial hypertension". Neurochirurgia (Stuttg). 32 (2): 37–43. doi:10.1055/s-2008-1053998. PMID 2497395.
  27. Kumar N (2011). "Acute and subacute encephalopathies: deficiency states (nutritional)". Semin Neurol. 31 (2): 169–83. doi:10.1055/s-0031-1277986. PMID 21590622.
  28. Chiu GS, Chatterjee D, Darmody PT, Walsh JP, Meling DD, Johnson RW; et al. (2012). "Hypoxia/reoxygenation impairs memory formation via adenosine-dependent activation of caspase 1". J Neurosci. 32 (40): 13945–55. doi:10.1523/JNEUROSCI.0704-12.2012. PMC 3476834. PMID 23035103.
  29. Peate I (2004). "An overview of meningitis: signs, symptoms, treatment and support". Br J Nurs. 13 (13): 796–801. doi:10.12968/bjon.2004.13.13.13501. PMID 15284663.
  30. Abdelhafiz AH, Rodríguez-Mañas L, Morley JE, Sinclair AJ (2015). "Hypoglycemia in older people - a less well recognized risk factor for frailty". Aging Dis. 6 (2): 156–67. doi:10.14336/AD.2014.0330. PMC 4365959. PMID 25821643.


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