Pharmacology minutiae of antiepileptic drugs

from E Ramsey at AAN

1.  Enzyme induding drugs (Phenytoin, carbamazepine and lamotrigine) cause eighty percent or more reduction of many drugs including statins, (except one), so need to way increase dose of statin. Ditto for calcium channel blockers (think nimodipine after SAH),  antidepressants, erectile dysfunction drugs (all of them), and HAART therapy.

2.  Carbamazepine is related to weight gain almost as much as valproate

3.  Topiramate helps blood pressure and insulin sensitization needing readjustment of insulin

4.  Dilantin will not be absorbed with high pH such as pepcid or protonix

5.  LTG or TOP levels will increase two or three fold if you wean off an inducer like PTN due to decreased clearance

6.   Warfarin metabolism with Dilantin is variable, up or down, depending on genetics.

7.  Drugs that lower seizure threshold include theophylline, antihistamines, stimulants, antipsychotics, narcotics, hormones, antibiotics (PCN, metronidazole, lindane), antidepressants (SSRI, TCA's), baclofen, oral hypoglycemics, some immunosuppressants

8.  CBZ induces CYP34, and ethinyl estradiol is a substrate, hence lower bc pill levels.  

Saline bullets (and hypertonic saline) for increased intracranial pressure.

Saline bullets are not FDA approved but rather a novel effective way to lower increased intracranial pressure acutely.  The idea was proposed by Geoffrey Ling MD at a lecture based on his experience in the military.  The advantage is that hypertonic saline, in this case a saline bullet, does not promote diuresis just creates a gradient that treats increased ICP.  Per Dr. Ling, a saline bullet of 23 % NaCL, 30 cc, decreases ICP by 50 % and sustains the decrease for about eight hours.  It needs to be given through a central line.  The 23 percent saline infusion is available in every pharmacy as a basis for TPN and needs to be cannibalized from that cart since not likely to be available from pharmacy for stated purpose of controlling ICP.  Once the goal is achieved Ling uses a 3 percent saline infusion at 75 cc per hour, of half NaCl and half Naacetate

Pearls CSF and alternate forms of meningitis: PCR for TB, CMV,enterovirus, VZV, toxo meningitis

HSVE
1.  In CSF , PCR has sens/spec of 98 and 94 % respectively, and stay positive for a long time in one third.
2. In cases of false negative, treat with acyclovir anyway for ten days if clinical suspicion is high and consider repeating LP at 48 hours.

CMV
1.   PCR is 79 % sensitive, 95 % specific

toxo
1  PCR in CSF is 42 % sensitive, 100 % specific

enterovirus
1.  more sensitive than viral culture

mycoplasma pn
1.need to check IgM and IgM is CSF: serum

HSVE
1.  Antibody is positive at tn days in half
Tests:
immunocompetent-- initially test with PCR for HSVE, VZV, and enterovirus
immunocompromised -- add  EBV and CMV PCR and HHV6 and HHV7
Consider quantitative CSF: blood esp HIV patients

TB meningitis diagnostic test pearls

H/t Wendy Ziai and John Lewin Neurol Cl May 2008

1. CXR and ppd may be negative in half of cases, and typical  CSF profile may not be present especially in immunosuppressed patients. 

2. AFB in CSF is positive in only 30 % (maybe able to increase to 70 % with meticulous and repeated sampling), culture is only positive in 40-70 %, and may require weeks to have a result.

3.  CSF adenosine deaminase (ADA) activity is a biochemical marker that may help.  At a cutof of 6.97 iu/L it is fairly sensitive and specific  (85 % and 88 % respectively).  ADA is useful in third world countries and poorly equipped labs  (Gautam et al., Nepal Med Coll, 2007). 

4.  Molecular  nucleic acid amplification kits   have sensitivity 60-83 % and specificity of 98 % and should be first line to rule out (Dinnes et al. Health Care Tech  2007)

5. PCR is fastest and most sensitive tests but is not good enough to rule out TB meningitis.

6.  Measurement of interferon gamma  in CSF compared with PCR is more sensitive (70 v 65 %) and has specificity of 94 %.  Interferon gamma plus PCR has 80 % sensitivity.

7.  In general careful bacti is as good as molecular in initially diagnosing TB meningitis although molecular stays positive longer with treatment.

8.  TB is prevalent in indigent urban nonwhite populations with a high rate of HIV infection (Arch Int Med 1996).  Presentation is fever, malaise, headache and personality changes, leading in 2-3 weeks to classic signs such as headache, meningismus, vomting, confusion and focal neurologic findings.  Occassionally it presents like acute bacterial infefctions.

9. MRI classic triad for TB meningitis is basal meningeal enhancement, hydrocephalus, and supratentorial and brainstem infarctions; hydrocephalus can be communicating or noncommunicating.

10.  Outcome scoring system is called Weisfelt system and is calculated one hour after admission based on six variables: age, heart rate, GCS, cranial neuropathies, CSF WBC, Gram stain findings.

Ventriculitis pearls and a few more meningitis pearls

Ventriculitis
1.  Occurs in 30 % of adult meningitis cases, 90  % of neonatal cases.  Often thought of as a late occurrence in refractory meningitis but can occur as primary event also.

2.  Commonly occurs with EVD or VP shunt, less commonly if EVD management protocols are strictly adhered to.

3.  Hemorrhagic CSF is considered a risk factor

4.  Gram positive organisms such as Staph aureus and Staph epidermidis are most common, but gram negative organisms also occur.  (E coli, Klebsiella, Acinetobacter, pseudomonas species.

5.  Cell index is ratio of WBC: RBC in CSF:Serum.  Its used in ventriculostomy cases with IVH to consider infection.  It is one normally and in ventriculitis patients without infection.  In 7 patients with definite ventriculitis, index rose 3 days before diagnosis of ventriculitis and declined with antibiotic treatment (Pfauler et al. Acta Neurchir 2004)

CSF in meningitis
5.  Common practice is to perform CT first, then LP, then begin therapy.  These practices lead to delay in antimicrobial treatment which actually is worse for patient than risk of performing lumbar puncture.  In many cases antibiotics should be given before CT because even a delay of a few hours can be catastrophic.   Aronin et al. ANn Int Med 1998.

6.  Delay of LP is not needed if the following factors are not present:  immunosuppression, ( to R/O toxo or lymphoma), alteration in mentation, focal deficits, seizures, pappilledema, ocular palsies, bradycardia or irregular respirations, sedation or muscle paralysis.   see Mellor DH. Arch Dis Children 1992.

7.  CSF findings in bacterial meningitis WBC> 1000 (60 %) and > 100 (90%); CSF glc < 40 (50 %) but CSF : serum glc < 0.4 80 % sensitive and 98 % specific. 

8.  Blood cultures are positive in about 50 % of cases of bacterial meningitis, but touch preparation of the rash is positive in 70 % on Gram stain.

9.  CSF lactate is not helpful in community acquired meningitis but is helpful in postop neurosurgical cases.  A cutoff of 4 mmol/L lactate in CSF is superior to measuring the glucose CSF: serum ratio.  88 % sensitive, 98 % specific, ppv 96 %, npv 94 %.

10.  Latex agglutination CIE is useful only for certain organisms and in patients with pretreatment of antibiotics and negative cultures.

11.  C reactive protein is sensitive for bacterial meningitis in some pediatric population esp. with CSF profile c/w meningitis but negative gram stain. 

12.  Procalcitonin levels differentiate bacterial and virla meningitis in kids (cutoff > 5, 94 %  sensitive, 100 % specific).  Also in adults ( cutoff > .2 ng/mL , sensitivity and specificity 99 %) .  Moreover the levels decline rapidly, within 24 hours, and may be useful to monitor the effectiveness of the treatment.   (Gendrel et al, Clin Inf Dis 1997, Viallon et al, Clin Inf Dis 1999, ibid. Crit Care 2005).  PCT levels remain normal in ventriculitis and do not help in that situation.

13.  Real time PCR is emerging but disadvantage include a lack of sensitivity, lack of sensitivity to antibiotics result, false negatives and contamination issues.

Infratentorial abscess after bacterial meningitis

Presents with a subacute meningitis and and neck stiffness and decreased consciousness.  It occurs after surgery for otitis, mastoiditis, and sinusitis.  Delay in detection occurs due to CT missing the diagnosis, leading to a high mortality.  MRI with DWI can differentiate this condition from reactive subdural effusion,  which is important due to the risk of hydrocephalus, the need for antibiotics and sometimes surgery (should have low threshold to explore). 
See van de Beek, et al.  Neurology 2007, and Wong et al., AJNR 2004. 

Neurocritical infection/ meningitis pearls

1.  Bacterial meningitis damage is half mediated by toxins, half by inflammatory response

2.  Classic triad of headache, fever, and neck stiffness is NOT sensitive for meningitis.  However, 90 + % of patients have 2 of the following four symptoms:  ha, neck stiffness, fever and mental status changes.14 % of patients are comatose on admission, and 34 % have focal deficits. Only 30 % have nuchal rigidity. Fever is often missing in elderly, immunosuppressed and the partly treated groups.  Overall fever is present in 71-77 % of cases, neck stiffness in 48 %, headache in 87-92 %, nausea and vomiting in 74 %, photophobia 57 %, seizures 5-23 %, focal signs <30 %, rash 11 %.  (see van de Beck, NEJM 2006:354:44-53; Durand NEJM 1993; 321:21-28; Thomas et al, Clin Inf Dis 2002; 35:46-52).  Latter article reveals Kernig's and Brudzinski's signs are NOT reliable and have a positive predictive value in the 20s and sensitivity of less than 10 percent.  Older patients >60 in Dutch study had less fever and neck stiffness and more encephalopathy as a presenting sign. 

In infants, signs can be subtle, bulging fontanelle and seizures is not sensitive (Klein, Pediatrics, 1986), and an LP is warranted(?controversial) in patients with first simple febrile seizure. The presentation is usually fever, lethargy, irritability, respiratory distress, jaundice, reduced food intake, vomiting and diarrhea. 

Immunocompromised patients have the triad only 21 % of time, due to less immune response and greater propensity to get atypical organisms. 

3.  Predictors of bacterial v. viral meningitis include one of the following indicators of severity:  altered consciousness, focal deficits, seizures, and shock.  Non predictors include CSF glc< 2, CSF protein > 2 (Brivet et al, Intensive Care Med 2005).

4.  Predictors of mortality include seizures (34 v. 7 %)  and decreased level of consciousness on admission (26 v. 2 %). 

5.  An unusual presentation of brainstem HSVE in an immunocompromised patient included diplopia, dysarthria, and ataxia .

6.  HSVE also causes radiculitis in immunocompromised (lumbosacral) and most cases of recurrent meningitis (previously called Mollaret's meningitis).
 
7.  WNV in CNS includes movement disorders with myoclonus, postural tremor and cerebellar signs in addition to polio like features.  Death can occur due to respiratory depression.

8.  Presentation of cerebral abscess includes neck stiffness only in 20 % often only shows increased ICP.  Seizures occur in up to 40 %.  Focal specific symptoms such as aphasia occur but are variable.

9. Cranial epidural abscess presents with ha, fever, nausea and usually does not lead to neurologic complications due to neurosurgery>meningitis, with organisms often Strep, Staph and polymicrobial

10.  Subdural empyema occurscausing altered level of consciousness, fever, seizures, septomthrombophlebitis, venous infarcts and more complicated course.  Sources include paranasal sinuses, hematogenous spread due to emissary veins in subdural space, and postoperative extension due to epidural abscess.

11. Peripheral lab clues:  amylase increased in mumps, cold agglutination titers in mycoplasma, CXR  abnormal could be associated with mycoplasma, legionella or lymphocytic chorionic meningitis.

12. Cancer patients much less commonly have the triad (56 % fever, 47 % headaches, 35 % altered mental status, 14 % nuchal rigidity, 14 % completely asymptomatic, and may be related to frequency of a range of neurosurgical procedures (Safdieh, Neurology 2008).


13. Novel lab tests to help diagnose bacterial meningitis include: CSF lactate> 4.2 (nonspecific and only sensitive in acute setting), CRP (normal level has high negative predictive value) and serum procalcitonin level (newest marker) (see Tunkel Clin Inf Dis 2004; Sormunen, J Ped 1999; Viallon et al, Clin Inf Dis 1999 and others).

14. Third generation cephalosporins sterilize the CSF within 2 hours in all patients; in one third by one hour. Latex agglutination and PCR techniques are useful in these situations.

Blast TBI and other TBI pearls

1.  Battlefield injury without breach of cranium thought to have different pathology than standard CHT or penetrating injury.  Its due to a concussive pressure wave. 

2.  Battle armor and helmets, and medical care on the scene have reduced the kill wounded ration to less than 1:10, v 1:4 in WWII. 

3.  Secondary injury factors are the focus of treatment. 

4.  Mild , moderate and severe TBI is defined by GCS.  Mild is 13 or above, moderate is 8-13, and severe is < 8.

5.  Second impact syndrome has a high mortality, up to 50 % but the mechanism is not well understood

6.  Early mgmt recommendations include avoiding hypotension and hypooxygenation in addition to ABC. 

7. The role of hemicraniectomy is being studied in the RESCUE trial

8.  Indications for ICP monitoring include abnormal CT scan, hypotension (SBP < 90), or age > 40.

9.  Hypertonic saline boluses may be as effective as mannitol.  Give through a central line.  2-3 % hypertonic saline through a peripheral line is given half NACL, half Na acetate. 

10. Pseudoaneurysms and vasospasm are very common.

status epilepticus pearls

1,  Among patients with convulsive SE that stops, 14 % have ongoing  subclinical status and 48 % have ongoing intermittent seizures (DeLorenzo et al., Epilepsia 1998)

2.  Risk factors for increased mortality in SE include higher age, intubated, length of time till treated

3.  Fever contributes to cerebellar injury, and neuromuscular blockade prevents (Meldrum 1973 Arch Neurol)

4.  Among eleven patients with SE who died acutely, 8 had contraction band necrosis of cardiac muscle, and died due to initial catechol release Manno et al. Ann Neurol 2005)

5.  Neuron specific enolase (NSE) is unvestigated as a marker for neuronal injury in prolonged SE

6.  The VA cooperative study (Treiman et al, NEJM, 1998) looked at overt status and found the efficacy of each of the following regimens in stopping SE:  lorazepam, 65 %, phenobarbital 58 %, diazepam plus phenytoin, 56 % ,and phenytoin alone 44 %.  Subjects who failed the first drug responded to the second drug (7 %) and the third drug (2.3 %) at a low rate.  The only significant difference statistically was between lorazepam and phenytoin.

7.  Inttravenous valproate may be as good or better than phenytoin or fos-phenytoin ( Aggarwal et al, Seizure, 2007) both as a first line and second line agent (Misra Neurology 2006). If used with phenytoin, it may increase the free level of the drug, paradoxically causing increased seizure.  Antibiotics such as merepenem and amikacin may cause a dramatic fall off in the blood level of valproate, possibly due to increased renal excretion.  Beware of other p450 metabolized medications.  Valproate is a broad spectrum antiepileptic drug, with action against all seizure types including postanoxic myoclonus, and does not sedate or cause hypotension.  Therefore it may be DOC in patients with a DNR order.  Dose is 25 mg.kg

8.  Initial dose of thiopental in ICU setting is 2-4 mg/kg bolus, then 3-5 mg/kg/hour. Pentobarb has slower onset and offset than thiopental and should be dosed initially at 5 mg/kg with repeated boluses of same until seizures stop, with initial maintenance at 25-50 mg/minute, titrated to burst suppression.  Half life is over 34 hours.  Midazolam initial dose is .2 mg/kg, repeated every five minutes up to 2 mg/kg until seizures stop, with a continuous dose range of 0.05 - 2.9 mg/kg/hour. 

9. Propofol has rapid onset and rapid clearing.  Dose is bolus of 1-2 mg/kg,  then a continuous infusion of 1-15 mg/kg/hr with a maximum dose of 5 mg/kg/hr if maintained for days. Beware of "propofol infusion syndrome" of metabolic acidosis, cardiac failure, rhabdomyolysis, hypotension, and death.Risk factors are prolonged doses (> 48 hours), high doses (>5 mg/kg/hr), head injury, lean body mass, and concurrent use of catechols or steroids.  Concurrent clonazepam may also help prevent PIS (Rosetti et al, Epilepsia 2004).

10.  Intravenous levitiracetam is useful in benzo refractory partial seizures, usually stopping it  without causing severe AE's (Knake et al. JNNP 2008).

11.  Ellis looked at patients with grade 3 or 4 hepatic encephalopathy, and found of 42 total patients split between prophylactic AED and controls, subclinical status was common among the control group (45 %) but not in the treated group with    (15 %).  At autopsy the control group had more brain edema (Ellis et al, Hepatology 2000).  This constitutes an argument for continuous EEG monitoring.

12.  In renal patients, AED's are divided into the dialyzable and the nondialyzable.  Highly bound drugs (PTN, VPA, CBZ) are not dialyzed significantly.  Moderate protein binding eg LTG (lamotrigine) may need pre and post dialysis levels.  AED's THAT REQUIRE REPLACEMENT AFTER DIALYSIS ARE GBN, PREGABALIN, ETHOSUXIMIDE, LEVITIRACETAM, PHENOBARBITAL AND TOPIRIMATE. The serum concentrations of these can decrease 50 % after dialysis

13.  Among posttransplant patients, many seizures occur, and many are nonconvulsive. In liver transplant, the incidence may be as high as one third, slightly less in pancreatic, much less with other organs.  Day 4-6 post transplant is highest occurrence.  Most patients do not have prior seizures.  Short term AED's are indicated.

Medications that reduce seizure threshold

from Neurologic Clinics 2008

Antidepressants esp. buproprion and maprotilene
antipsychotics especially phenothiazines and clozapine
Lithium
baclofen
AED withdrawal
super high phenytoin levels
theophylline
Analgesics esp. meperidine-demerol, fentanyl and tramadol
opiod withdrawal
benzodiazepine withdrawal
barbiturate withdrawal
antibiotics-- beta lactams (cefezolin), carbapenems (imipenem), quinolones, isoniazid (treat with B6), metronidazole
antiarythmics-- lidocaine, digoxin, mexelitine
radiographic contrast dyes
immunomodulators-- cyclosporine, tacrolimus, interferons
chemotherapeutic drugs-- alkylating agents such as chlorambucil and busulfan
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