How can Levodopa cross the blood-brain barrier, while Dopamine cannot?

Exogenous Dopamine is unable to cross the tight junctions of the endothelial cells in the blood-brain barrier (BBB). Dopamine has no clinically significant endogenous transporter on the blood-brain barrier and is otherwise too polar of a molecule to move through the lipid membrane. Levodopa, however, utilizes a receptor on the BBB known as Large amino acid transporter (LAT)  which allows it to be transported across the blood-brain barrier and decarboxylated into Dopamine.

l-dopa-crossing-bbb

REFERENCES

  1. Tsuji A. Small Molecular Drug Transfer across the Blood-Brain Barrier via Carrier-Mediated Transport Systems. NeuroRx. 2005;2(1):54-62.
  2. Laterra J, Keep R, Betz LA, et al. Blood—Brain Barrier. In: Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.
  3. Kageyama T, Nakamura M, Matsuo A, Yamasaki Y, Takakura Y, Hashida M, Kanai Y, Naito M, Tsuruo T, Minato N, Shimohama S. The 4F2hc/LAT1 complex transports L-DOPA across the blood-brain barrier. Brain Res. 2000 Oct 6;879(1-2):115-21.

Dementia with Lewy bodies: Why to avoid Haldol

Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia in the elderly (accounting for 15-20% on autopsy- => alpha-synuclein deposition). 

It is characterized as clinically:

  1. fluctuating cognitive impairment
  2. visual hallucinations
  3. extrapyramidal motor symptoms (parkinsonism)

WHY AVOID HALDOL? Individuals suffering from DLB have a reduction in post-synaptic dopaminergic (D2) receptor activity. Hence when given D2-receptor antagonists, particularly traditional neuroleptic agents (i.e haldol), it can provoke severe neuroleptic sensitivity reactions (catatonia, decreased LoC, muscle rigidity)  in up to 50% of DLB patients.

NOTE: consider new generation anti-psychotics (Quetiapine is preferred by some LBD experts).

REFERENCES

  1. McKeith I, Mintzer J, Aarsland D, Burn D, Chiu H, Cohen-Mansfield J, et al. Dementia with Lewy bodies. Lancet Neurol. 2004;3:19–28.
  2. Mosimann UP, McKeith IG. Dementia with Lewy bodies—diagnosis and treatment. Swiss Med Wkly. 2003;133:131–42.

Why Steroids before Antibiotics in Bacterial Meningitis?

Studies have demonstrated that patients with pneumococcal meningitis had reduced mortality (14 versus 34 percent placebo) and hearing loss (ototoxicity) when dexamethasone was given shortly before (~20mins) or concurrently with first dose antimicrobial therapy.

NOTE: Patients who did not have pneumococcal meningitis (i.e meningococcal meningitis) had significantly lower rates of mortality (4 vs. 9 percent placebo), regardless of dexamethasone therapy. Also, patients are unlikely to benefit from steroids if they are started AFTER initiation of antimicrobial therapy.

REFERENCES

  1. de Gans J, van de Beek D, European Dexamethasone in Adulthood Bacterial Meningitis Study Investigators. Dexamethasone in adults with bacterial meningitis. N Engl J Med. 2002;347(20):1549.
  2. Brouwer MC, McIntyre P, Prasad K, van de Beek D. Corticosteroids for acute bacterial meningitis. Cochrane Database of Systematic Reviews 2015, Issue 9. Art. No.: CD004405. DOI: 10.1002/14651858.CD004405.pub5
  3. Lutsar I, Friedland IR, Jafri HS, Wubbel L, Ahmed A, Trujillo M, McCoig CC, McCracken GH Jr. Factors influencing the anti-inflammatory effect of dexamethasone therapy in experimental pneumococcal meningitis. J Antimicrob Chemother. 2003;52(4):651.

Alcohol Withdrawal & GABA: Mechanism

MECHANISM: Abrupt withdrawal is thought to reduce inhibitory neurotransmission and enhance excitatory neurotransmission.alcohol-withdrawal-mechanism

  • Caused by the effects of alcohol on GABA receptors (enhances γ-aminobutyric acid)
  • Constant consumption of alcoholic beverages will down regulate these GABA-receptors in order to maintain homeostasis!
  • There is a counter up regulation of excitatory neurotransmitters (i.e Glutamate) => Think of it like a see-saw trying to balance! (see image) 
    • When alcohol is no longer consumed
    • Down-regulated GABA receptor complexes are so insensitive to GABA that the typical amount of GABA produced has little effect
  • Compounded with the fact that GABA normally inhibits action potential formation (there are not as many receptors for GABA to bind to aka Tachyphylaxis); sympathetic activation is unopposed!!! (i.e tachycardia, hypertension, tremulousness, and hyperreflexia)

REFERENCES

  1. Bayard M, McIntyre J, Hill KR, Woodside J Jr. Alcohol withdrawal syndrome. Am Fam Physician. 2004 Mar 15;69(6):1443-50.
  2. Chapter 5. Environmental and Nutritional Pathology. Pathology: The Big Picture. Walter L. Kemp, Dennis K. Burns, Travis G. Brown. Copyright © 2008 by The McGraw-Hill Companies, Inc. All rights reserved.

ADLs (DEATH) and IADLs (SHAFT)

ADLS (Activities of daily living): Often used to assess functional status; Mostly used for elderly or chronically ill patients.

D– DRESSING
E– EATING
A– AMBULATION
T– TOILET USE with or without help?
H– HYGIENE

IADLs (Instrumental activities of daily living): Not a necessity for survival; but important to an individual’s independence. 

S– SHOPPING
H– HOUSEKEEPING
A– ACCOUNTING
F– FOOD PREPARATION
T– TRANSPORTATION

REFERENCES

  1. Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW. Studies of illness in the aged: the index of ADL: a standardized measure of biological and psychosocial function. JAMA 1963;185:914-919
  2. Noelker, L.S.; Browdie, R. (2014). “Sidney Katz, MD: a new paradigm for chronic illness and long-term care”. The Gerontologist 54 (1): 13–20.

What are the Reversible Causes of Dementia? (mnemonic)

VERY common question on internal medicine wards, and important to recognize as early as possible! The mnemonic commonly used is “DEMENTIA”

Drugs

Ears and Eyes (i.e Deafness or Blindness)

Metabolic Derangement (i.e Chronic Hypercalcemia, Hypo and hyper thyroidism, Adrenal insufficiency)

Emotional (Depression)

Nutrition (i.e B12 deficiency, also B1, B6) Normal pressure hydrocephalus

Trauma (i.e Subdural hematoma), Tumor (i.e Neoplasm or Intracranial abscess)

Infection (i.e Neurosyphilis, Encephalitis (limbic, HIV, herpes), Lyme’s disease, Whipple’s disease)

Alcohol (i.e Wernicke encephalopathy) – but also consider other recreation drug use!

REFERENCES

  1. Protocols in Primary Care Geriatrics. John P. Sloan, M.D. 2nd edition. Springer Publishing 1996
  2. Draper B. Aust N Z J Psychiatry. 1991 Dec; 25(4):506-18.
  3. Tripathi M, Vibha D. Reversible dementias. Journal of Psychiatry. 2009;51(Suppl1):S52-S55.

When to administer Tissue Plasminogen Activator (tPA)

tPA is considered a gold standard for treatment of patients with ischemic strokes.

Mechanism: Works by dissolving clots and restoring/improving blood perfusion to part of the brain that was previously impeded.

Important: Differentiate ischemic and hemorrhagic stroke by administering CT scan. tPA will not be useful in hemorrhagic strokes as decreased perfusion to brain is result of intracranial bleeding as opposed to a vascular obstruction.

When to give: Must be given within 3-4.5 hours from onset of stroke symptoms. *NOTE: it is from the time the patient was last asymptomatic, hence if a patient awakes with stroke symptoms, they were last asymptomatic whatever time they fell asleep.

How is it administered: IV

REFERENCES

1. Davis SM, Donnan GA (June 2009). “4.5 hours: the new time window for tissue plasminogen activator in stroke”. Stroke 40 (6): 2266–7. 

2. Fonarow GC, Zhao X, Smith EE, et al. Door-to-Needle Times for Tissue Plasminogen Activator Administration and Clinical Outcomes in Acute Ischemic Stroke Before and After a Quality Improvement Initiative. JAMA. 2014;311(16):1632-1640. doi:10.1001/jama.2014.3203. 

VITAMINS- Causes for Seizures

  • Vascular (Stroke, Hemorrhage, AV Malformation, Malignant Hypertension)
  • Infection (Meningitis, Abscess, Encephalitis)
  • Trauma
  • Auto-immune (CNS, Vasculitis)
  • Metabolic (Hyponatremia, Hypocalcemia, Hypogylcemia, Hypomagnesemia, drug overdose/withdrawal)
  • Idiopathic
  • Neoplasm
  • pSychogenic

References

  1. https://www.nlm.nih.gov/medlineplus/ency/article/003200.htm

What are the signs of Pseudo seizures (Psychogenic Nonepileptic Seizures)?

Controversial topic, and do not refer to them as Pseudo seizures to staff/neurology. The correct terminology is Psychogenic Nonepileptic Seizures.

SIGNS to suspect:

  1. Waxing and weaning
  2. Eye closure
  3. Side to side movement
  4. Time >3mins [very soft sign]
  5. Crying
  6. Out of phase movement
  7. Pelvic thrusting
  8. The “teddy bear sign” (adults and older teenagers who bring toy stuffed animals into hospital)

REFERENCES

  1. Chapter 16. Epilepsy and Other Seizure Disorders. Adams and Victor’s Principles of Neurology, 10

Why CT before LP in Suspected Meningitis?

Traditional thinking was if there is a space occupying lesion, it may result in increased ICP. When you perform a LP, it will drop pressure at the site of the LP => creating a pressure gradient and result in cerebral herniation.

Hence it is very common to request computed tomography (CT) to rule out space occupying lesions with +/- mass effect before lumbar puncture (LP).

This has become a contentious subject. Many will argue that a normal CT doesn’t reliably rule out the risk of herniation post LP. Hence its diagnostic utility in patients without any signs of raised ICP (i.e Papilledema, focal neurologic signs, seizures, GCS <12, Cushing triad) or risk factors (i.e immunocompromise, history of CNS disease, seizures) is questionable. The clinical findings and patient history should always be considered when deciding on CT before LP in the setting of suspected meningitis.

RULE OF THUMB: you should never delay antibiotics to do a CT then LP in the setting of meningitis. Treat empirically!!!

References

  1. Rodrigo Hasbun, M.D., James Abrahams, M.D., James Jekel, M.D., and Vincent J. Quagliarello, M.D. Computed Tomography of the Head before Lumbar Puncture in Adults with Suspected Meningitis. N Engl J Med 2001; 345:1727-1733.
  2. Gopal, A et al. Cranial computed tomography before lumbar puncture: a prospective clinical evaluation. ARCH INTERN MED. Dec 1999; 159:2681-2685