editorial Greenwood BM. NEJM 2007; 357:2507-08 (editorial) and (same issue)
Mai NTH et al. Dexamethasone in Vietnamese adolescents and adults with bacterial meningitis pp. 2431-2440
and
Scarborough M et al. Corticosteroids for bacterial meningitis in adults in subSaharan Africa pp. 2441-2450.
The prologue is that meta-analysis in industrialized countries showed that dexamethasone given to children with Hemophilus B type b meningitis before antibiotics reduces sequelae, especially hearing loss (McIntyre PB et al. Jama 1997; 278:925-931. Studies in adults in ind. countries also show a benefit (NEJM 2002; Lancet Inf Dis 2004). A trial of 598 children in Malawi, about one third of whom were infected with the HIV virus, showed "convincing evidence of lack of benefit." Most African pediatricians have accepted the result (Lancet 2002). The study above (Scarborough et al.) of adults age greater than 16 with acute bacterial meningitis given dexamethasone 16 mg bid for four days with ceftriaxone showed no benefit of dexamethasone on any endpoint. In contrast, the study by Mai et al. in Vietnam of 435 persons odler than 14 with .4 mg/kg dexamethasone for 4 days of placebo before ceftriaxone, showed benefits in some analyses on death, hearing loss in treated group (if TB patients are excluded). Notable was the strikingly higher mortality in Africa v. Vietnam (54 v. 11%) possibly due to HIV infection, or a different infection (Str pn in Malawi S. suis in Vietnam). A South American study showed no benefit of dexamethasone, but benefit of glycerol (Clin Infect Dis 2007, author Peltola et al.). Editorial concludes the focus should be on vaccines although dexamethasone might be used in the developed world.
Monday, December 17, 2007
Friday, December 07, 2007
Serotonin syndrome and its differential diagnosis and treatment
Boyer EW, Shannon M. Current Concepts. The Serotonin Syndrome. NEJM 2005; 352:1111-20.
General notes
1. The serotonin syndrome (SS) is not an idiopathic drug reaction but a predictable consequence of excess serotonergic drug stimulation of the CNS and peipheral receptors.
2. It has a spectrum of findings ranging from barely perceptible to lethal.
The classical triad is mental status changes, autonomic hyperactivity and neuromuscular abnormalities. Symptoms can include tremor, diarrhea, delirium, rigidity, shivering, mydriasis, tachycardia, hypertension, and hyperthermia. Inadvertent increase in the dose of a causative drug can provoke a dramatic deterioration.
Drugs and drug combinations include MAOI's, TCA's, SSRI's, opiates, OTC cough suppressants, antibiotics, weight reduction drugs, antiemetics, antimigraine drugs, drugs of abuse, herbal products, drugs that inhibit CYP2D6 and CYP3A4 systems, PAST use of fluoxetine (within 6 weeks), or illegal drug ecstasy. Most cases occur within minutes to hours after initiating a new medicine or increasing a dose. It does not resolve if offending drugs are still given.
Clinical notes: lower extremity hyprereflexia and clonus is much worse than the upper extremity. Horizontal ocular clonus and opsolclonus may occur. Mutism is not infrequent. Startle is increased, and repetitive head rotaton may occur. Patients may degenerate into frank shock. Diagnosis: Clonus (inducible, spontaneous or ocular) is the most important finding. The differential includes anticholinergic poisoning, malignant hyperthermia, and NMS which all are differentiated on clinical/historical grounds.
Anticholinergic patients have normal reflexes and "toxidrome" of mydriasis, agitated delirium, dry oral mucosa, hot dry skin, urine retention, absent bowel sounds (always present in SS). Malignant hyperthermia has increasing end tidal CO2 levels, ypertonicity, hyperthermia, and metabolic acidosis, within minutes of exposure to inhalational anesthesia. Skin exam shows mottling, cyanosis juxtaposed to bright red flushing. The skeletal muscles are rigid, and there is areflexia. NMS is an idiopathic reaction to DA agonists with slow onset, bradykinesia, lead pipe rigiditym hyperthermia, fluctuating consciousness and autonomic instability that evolves over hours to days (whereas SS has rapid onset and hyperkinesia).
Management involves removing offending drug, supportive care, control of ANS instability, and occassionally benzodiazepines. Moderately ill patients should aggressively correct CV and respiratory problems and receive 5H2a antagonists. Severely hyperthermic patients (41) should also be sedated, paralyzed and intubated. Benzodiazepines may be life saving. Physical restraints are not advised. The antidote is usually cyproheptadine, giving 12-32 mg over a 24 hour period (initial dose of 12 mg then 2 mg q 2 hours prn, given po, crushed in a Dobhoff). I-m thorazine can be used. Hypertension and tachycardia can be treated with short acting drugs such as esmolol and nitroprusside. Hyperthermia should be treated with nondepolarizing drugs such as vecuronium, NOT succinylcholine. Antipyretics are not indicated since fever is due to muscle activity and the hypothalamic set point is working OK. Propanolol is not indicated as it can cause hypotension and shock, and abolish reflex tachycardia. BCT and dantrolene are not useful (unlike NMS and malignant hyperthermia).
Cyproheptadine can be sedating but that is OK. Chlorpromazine can cause hypotension which is irrelevant.
General notes
1. The serotonin syndrome (SS) is not an idiopathic drug reaction but a predictable consequence of excess serotonergic drug stimulation of the CNS and peipheral receptors.
2. It has a spectrum of findings ranging from barely perceptible to lethal.
The classical triad is mental status changes, autonomic hyperactivity and neuromuscular abnormalities. Symptoms can include tremor, diarrhea, delirium, rigidity, shivering, mydriasis, tachycardia, hypertension, and hyperthermia. Inadvertent increase in the dose of a causative drug can provoke a dramatic deterioration.
Drugs and drug combinations include MAOI's, TCA's, SSRI's, opiates, OTC cough suppressants, antibiotics, weight reduction drugs, antiemetics, antimigraine drugs, drugs of abuse, herbal products, drugs that inhibit CYP2D6 and CYP3A4 systems, PAST use of fluoxetine (within 6 weeks), or illegal drug ecstasy. Most cases occur within minutes to hours after initiating a new medicine or increasing a dose. It does not resolve if offending drugs are still given.
Clinical notes: lower extremity hyprereflexia and clonus is much worse than the upper extremity. Horizontal ocular clonus and opsolclonus may occur. Mutism is not infrequent. Startle is increased, and repetitive head rotaton may occur. Patients may degenerate into frank shock. Diagnosis: Clonus (inducible, spontaneous or ocular) is the most important finding. The differential includes anticholinergic poisoning, malignant hyperthermia, and NMS which all are differentiated on clinical/historical grounds.
Anticholinergic patients have normal reflexes and "toxidrome" of mydriasis, agitated delirium, dry oral mucosa, hot dry skin, urine retention, absent bowel sounds (always present in SS). Malignant hyperthermia has increasing end tidal CO2 levels, ypertonicity, hyperthermia, and metabolic acidosis, within minutes of exposure to inhalational anesthesia. Skin exam shows mottling, cyanosis juxtaposed to bright red flushing. The skeletal muscles are rigid, and there is areflexia. NMS is an idiopathic reaction to DA agonists with slow onset, bradykinesia, lead pipe rigiditym hyperthermia, fluctuating consciousness and autonomic instability that evolves over hours to days (whereas SS has rapid onset and hyperkinesia).
Management involves removing offending drug, supportive care, control of ANS instability, and occassionally benzodiazepines. Moderately ill patients should aggressively correct CV and respiratory problems and receive 5H2a antagonists. Severely hyperthermic patients (41) should also be sedated, paralyzed and intubated. Benzodiazepines may be life saving. Physical restraints are not advised. The antidote is usually cyproheptadine, giving 12-32 mg over a 24 hour period (initial dose of 12 mg then 2 mg q 2 hours prn, given po, crushed in a Dobhoff). I-m thorazine can be used. Hypertension and tachycardia can be treated with short acting drugs such as esmolol and nitroprusside. Hyperthermia should be treated with nondepolarizing drugs such as vecuronium, NOT succinylcholine. Antipyretics are not indicated since fever is due to muscle activity and the hypothalamic set point is working OK. Propanolol is not indicated as it can cause hypotension and shock, and abolish reflex tachycardia. BCT and dantrolene are not useful (unlike NMS and malignant hyperthermia).
Cyproheptadine can be sedating but that is OK. Chlorpromazine can cause hypotension which is irrelevant.
Sunday, December 02, 2007
Therapy for nerve agent poisoning
Newmark, J. Therapy for nerve agent poisoning. Arch Neurol 2004; 61:649-652
Nerve agents include tabun (GA), sarin (GB), soman (GD), cyclosarin (GF) and VX. All evaporate and are gone within 24 hours, except VX which is oily and the only one which is persistent. VX is the most lethal substance known to man. The drugs were weaponized in Nazi Germany, used by Iraq against Iran in the Iraq-Iran war, and used in 2 subway attacks in Japan in 1994-5.
Clinical scenario-- in a shopping mall, you hear a "pop" and see smoke, your vision dims and nose runs severely. People may collapse, breathing heavily or seizing, with constricted pupils.
The mechanism is similar to organophosphate pesticides, although they are much less fat soluble and therefore more toxic. Theyinhibit AchE, acetylcholinesterase, producing a cholinergic crisis. Most exposures occur through the vapor route and act within seconds to minutes. The initial symptoms are miosis and rhinorhhea and salivation. Later, brochorrhea and bronchospasm occur. They are absorbed at the alveoli, and although they are not important clinically, the gold standard of diagnosis is RBC AChE. Circulating toxin first affects the GIT causing cramping, pain, nausea and defecation. It will affect the heart variably with unpredictable effects on BP and HR. They cause massive overstimulation of peripheral neuromuscular synapses witha progression from fasciculation to twitching that may be misinterpreted as a seizure. When ATP is depleted (a late finding) the patient will eventually have flaccid paralysis. Rapid CND cholinergic stimulation will cause LOC, seizures, inhibition of medullary respiratory center with central apnea. Death is due to respiratory failure (combined) due to bronchospasm, bronchorhhea, inadequate function of respiratorymuscles, and central apnea.
Liquid exposure has a longer slower onset and offset than vapor. Skin decontamination may not suffice if not done immediately, as nerve agent may be trapped subcutaneously and continue to penetrate.
Patients recovered frommild poisoning have a neurobehavioral syndrome including HA, personalitychange, depression, and higher order problemswith memory and reading. It may resemblePTSD or postanoxic encephalopathy. Chronic effects are few, with one report of a PN and a few of vestibular problems.
THERAPY:
Ventilatory support can be lifesaving even for someone in full arrest, if an antidote is given. Treatment has not changed since 1945 and includes an anticholinergic drug to counteract crisis, an oxime to reactivate inhibited AChE, and an AED to prevent seizures. In the field,atropine is used with i-m autoinjectorswith an initial therapy of 2,4,or 6 mg with retreatment every 5-10 minutes as needed. 0.5 or 1.0 mg ampules are available for children. In the hospital it may be given intravenously. Atropine binds to muscarinicreceptorsbut not nicotinic receptors, so twitching and dyscoordination will continue. The respiratory problems are life threatening and atropine saves lives,per the Iranian experience.
The fielded oxime is 2-pralidoximm chloride (2 PAM). The i-m dose is 600 mg per autoinjector. The upper limit is 2000 mg/hr due to the risk of sudden elevation of blood pressure. Oximes reactivate catalytic cholinesterase and simultaenously split nerve agent or organophosphate insectisides into harmless, rapidly metabolized fragments. After nerve agent binds AChE , the resultant complex spontaneously loses a side chain ("aging") rendering the remaining enzyme-inhibitor complex unable to be reactivated by oxime. Most nerve agents age slowly and the reaction can be ignores (sarin over hours, VX over days to weeks) but soman over two minutes. Once the complex has aged, the oximes are useless although not harmful to the patient.
The MARK 1 set (Meridian Medical Technologies, Columbia, MS) has a 2 mg atropine and 600 mg 2-PAM autoinjectors and is already approved by the FDA for the general use.
Standard AED's (antiepileptic drugs) are not useful for seizures due to nerve agents. Only benzodiazepines are effective. The military uses diazepam 10mg autoinjectors. Midazolam is the most effective, given i-v, in terms of speed of actions, low dose required, and broad spectrum. Epilepsy does not develop and chonic AED's are not advised.
The fourth drug available is pyridostigmine bromide, which may be useful if soldiers are concerned about a rapidly aging poison (soman) . Pyridostigmine will sequester a percentage of the patients excess AChE and render it unavailable to be irreversibly inhibited by a a nerve agent. Therefore a lethal dose becomes survivable with antidotes.
Care must be provided inthe field, not in the hospital (too late). Additional information is available at the chemical casualty division website at http://ccc.apgea.army.mil or the Army Medical Research Institute of Chemical Defense at (410) 436-3276.
Nerve agents include tabun (GA), sarin (GB), soman (GD), cyclosarin (GF) and VX. All evaporate and are gone within 24 hours, except VX which is oily and the only one which is persistent. VX is the most lethal substance known to man. The drugs were weaponized in Nazi Germany, used by Iraq against Iran in the Iraq-Iran war, and used in 2 subway attacks in Japan in 1994-5.
Clinical scenario-- in a shopping mall, you hear a "pop" and see smoke, your vision dims and nose runs severely. People may collapse, breathing heavily or seizing, with constricted pupils.
The mechanism is similar to organophosphate pesticides, although they are much less fat soluble and therefore more toxic. Theyinhibit AchE, acetylcholinesterase, producing a cholinergic crisis. Most exposures occur through the vapor route and act within seconds to minutes. The initial symptoms are miosis and rhinorhhea and salivation. Later, brochorrhea and bronchospasm occur. They are absorbed at the alveoli, and although they are not important clinically, the gold standard of diagnosis is RBC AChE. Circulating toxin first affects the GIT causing cramping, pain, nausea and defecation. It will affect the heart variably with unpredictable effects on BP and HR. They cause massive overstimulation of peripheral neuromuscular synapses witha progression from fasciculation to twitching that may be misinterpreted as a seizure. When ATP is depleted (a late finding) the patient will eventually have flaccid paralysis. Rapid CND cholinergic stimulation will cause LOC, seizures, inhibition of medullary respiratory center with central apnea. Death is due to respiratory failure (combined) due to bronchospasm, bronchorhhea, inadequate function of respiratorymuscles, and central apnea.
Liquid exposure has a longer slower onset and offset than vapor. Skin decontamination may not suffice if not done immediately, as nerve agent may be trapped subcutaneously and continue to penetrate.
Patients recovered frommild poisoning have a neurobehavioral syndrome including HA, personalitychange, depression, and higher order problemswith memory and reading. It may resemblePTSD or postanoxic encephalopathy. Chronic effects are few, with one report of a PN and a few of vestibular problems.
THERAPY:
Ventilatory support can be lifesaving even for someone in full arrest, if an antidote is given. Treatment has not changed since 1945 and includes an anticholinergic drug to counteract crisis, an oxime to reactivate inhibited AChE, and an AED to prevent seizures. In the field,atropine is used with i-m autoinjectorswith an initial therapy of 2,4,or 6 mg with retreatment every 5-10 minutes as needed. 0.5 or 1.0 mg ampules are available for children. In the hospital it may be given intravenously. Atropine binds to muscarinicreceptorsbut not nicotinic receptors, so twitching and dyscoordination will continue. The respiratory problems are life threatening and atropine saves lives,per the Iranian experience.
The fielded oxime is 2-pralidoximm chloride (2 PAM). The i-m dose is 600 mg per autoinjector. The upper limit is 2000 mg/hr due to the risk of sudden elevation of blood pressure. Oximes reactivate catalytic cholinesterase and simultaenously split nerve agent or organophosphate insectisides into harmless, rapidly metabolized fragments. After nerve agent binds AChE , the resultant complex spontaneously loses a side chain ("aging") rendering the remaining enzyme-inhibitor complex unable to be reactivated by oxime. Most nerve agents age slowly and the reaction can be ignores (sarin over hours, VX over days to weeks) but soman over two minutes. Once the complex has aged, the oximes are useless although not harmful to the patient.
The MARK 1 set (Meridian Medical Technologies, Columbia, MS) has a 2 mg atropine and 600 mg 2-PAM autoinjectors and is already approved by the FDA for the general use.
Standard AED's (antiepileptic drugs) are not useful for seizures due to nerve agents. Only benzodiazepines are effective. The military uses diazepam 10mg autoinjectors. Midazolam is the most effective, given i-v, in terms of speed of actions, low dose required, and broad spectrum. Epilepsy does not develop and chonic AED's are not advised.
The fourth drug available is pyridostigmine bromide, which may be useful if soldiers are concerned about a rapidly aging poison (soman) . Pyridostigmine will sequester a percentage of the patients excess AChE and render it unavailable to be irreversibly inhibited by a a nerve agent. Therefore a lethal dose becomes survivable with antidotes.
Care must be provided inthe field, not in the hospital (too late). Additional information is available at the chemical casualty division website at http://ccc.apgea.army.mil or the Army Medical Research Institute of Chemical Defense at (410) 436-3276.
Multiple auras: clinical significanceand pathophysiology
Widdiss-Walsh P, Kotagel P et al. Multiple auras: clinical significance and pathophysiology. Neurology 2007; 69:755-761.
Ninety percent of those with two aura types and 100 % of those with three aura types have right hemisphere localization of their seizures. Some examples were rising epigastric sensation with a simultaneous unpleasant odor or visual field distortion. Multiple auras previously are considered commoner in in patients "alien tissue" (v. mesial temporal sclerosis).
Ninety percent of those with two aura types and 100 % of those with three aura types have right hemisphere localization of their seizures. Some examples were rising epigastric sensation with a simultaneous unpleasant odor or visual field distortion. Multiple auras previously are considered commoner in in patients "alien tissue" (v. mesial temporal sclerosis).
Thursday, November 15, 2007
Miscellaneous drug facts most people do not know
Antiepileptic drug random facts
1. Phenytoin (more misc. on than we already new)- a. increases HDL levels.
b. Formula to adjust PTN dose. In zero order kinetics, a fixed AMOUNT not percentage of phenytoin is metabolized. Vd= .7 L/kg Loading dose = (Vd) x (desired change in concentration) so eg. raise the level from 5 to 18 in a 100 kg man would mean Vd=70L, loading dose = 70 x 13= 910 mg. Phenytoin is saturably absorbed in duodenum and affected by food and by antacids
2. Cerebyx has the same Tmax as Dilantin due to time required to cleave the "fos" of fos phenytoin. Cerebyx also has some cardiac toxicity despite the absent phenylene glycol adjuvant. Infusion can be faster than Dilantin but not more than 150 mg/min. It prevents the purple glove but not time to treat SE.
3. PTN, CBZ and PB block efficacy of some chemotherapeutic agents (see post)http://neurologyminutiae.blogspot.com/2007/11/drug-interactionsenzyme-inducers-and.html
4. Depakote
a. may be useful in brain tumor treatment irrespective of AED effect (see post) http://neurologyminutiae.blogspot.com/2007/07/valproic-acid-and-brain-tumors.html
b. Depakote is highly bound but not to albumen; and free levels are difficult to measure. Its level rises in cirrhosis. Its path is 80 % direct glucuronidation, 17 % is in same oxidative path as free fatty acids and enters the carnitine shuffle, leading to 4, en VPA. Many ICU patients are carnitine deficient which shunts VPA to toxic metabolism so give these patients carnitine 25 mg/kg png over six hours leads to less NH4+.
5. Vimpat can cause angioedema
DRUGS FOR DEMENTIA
1. Rivastigmine patches can be left on for more than 24 hours as they have a 24 hour half life (in effect, patients are throwing away active drug). Wearing multiple patches, duly labelled, is one way to dispense a higher dose, usually with limited adverse effects
2. Memantine has histamine blocking properties and its use may limit GI adverse events of individuals taking rivastigmine or other drugs.
3. Cholinesterase inhibitors inhibit metabolism of suxamethonium, prolonging neuromuscular blockade
OTHER
1. Prazosin is highly effective for post-traumatic stress disorder
2. Levodopa-carbidopa and gabapentin are two rare drugs that are gastric absorbed and in fact compete with each other. Better to stop the gabapentin in Parkinson patients.3. Protease inhibitors potentiate toxicity of GHB, so HIV patients attending circuit parties are at extra high risk of coma and death.
4. Drug rash to Sinemet is due to yellow dye not levodopa carbidopa (see post) http://neurologyminutiae.blogspot.com/2007/04/rash-to-yellow-dye-in-levodopa.html
5. Natalizumab also blocks trafficking of B cells into CNS
6. . Atorvastatin, even brief exposure, causes a marked decrease in blood Co Q 10 concentration (shares the synthetic pathway of cholesterol). Primary CoQ10 deficiency causes mitochondrial encephalomyopathy with recurrent myoglobinuria; this may pertain to AE's of atorvastatin. Also, CoQ10 is an excellent free radical scavenger and the effects on degenerative disease are not known. Rundek et al,. Arch Neurol 2004; 61: 889-892.
1. Phenytoin (more misc. on than we already new)- a. increases HDL levels.
b. Formula to adjust PTN dose. In zero order kinetics, a fixed AMOUNT not percentage of phenytoin is metabolized. Vd= .7 L/kg Loading dose = (Vd) x (desired change in concentration) so eg. raise the level from 5 to 18 in a 100 kg man would mean Vd=70L, loading dose = 70 x 13= 910 mg. Phenytoin is saturably absorbed in duodenum and affected by food and by antacids
2. Cerebyx has the same Tmax as Dilantin due to time required to cleave the "fos" of fos phenytoin. Cerebyx also has some cardiac toxicity despite the absent phenylene glycol adjuvant. Infusion can be faster than Dilantin but not more than 150 mg/min. It prevents the purple glove but not time to treat SE.
3. PTN, CBZ and PB block efficacy of some chemotherapeutic agents (see post)http://neurologyminutiae.blogspot.com/2007/11/drug-interactionsenzyme-inducers-and.html
4. Depakote
a. may be useful in brain tumor treatment irrespective of AED effect (see post) http://neurologyminutiae.blogspot.com/2007/07/valproic-acid-and-brain-tumors.html
b. Depakote is highly bound but not to albumen; and free levels are difficult to measure. Its level rises in cirrhosis. Its path is 80 % direct glucuronidation, 17 % is in same oxidative path as free fatty acids and enters the carnitine shuffle, leading to 4, en VPA. Many ICU patients are carnitine deficient which shunts VPA to toxic metabolism so give these patients carnitine 25 mg/kg png over six hours leads to less NH4+.
5. Vimpat can cause angioedema
DRUGS FOR DEMENTIA
1. Rivastigmine patches can be left on for more than 24 hours as they have a 24 hour half life (in effect, patients are throwing away active drug). Wearing multiple patches, duly labelled, is one way to dispense a higher dose, usually with limited adverse effects
2. Memantine has histamine blocking properties and its use may limit GI adverse events of individuals taking rivastigmine or other drugs.
3. Cholinesterase inhibitors inhibit metabolism of suxamethonium, prolonging neuromuscular blockade
OTHER
1. Prazosin is highly effective for post-traumatic stress disorder
2. Levodopa-carbidopa and gabapentin are two rare drugs that are gastric absorbed and in fact compete with each other. Better to stop the gabapentin in Parkinson patients.3. Protease inhibitors potentiate toxicity of GHB, so HIV patients attending circuit parties are at extra high risk of coma and death.
4. Drug rash to Sinemet is due to yellow dye not levodopa carbidopa (see post) http://neurologyminutiae.blogspot.com/2007/04/rash-to-yellow-dye-in-levodopa.html
5. Natalizumab also blocks trafficking of B cells into CNS
6. . Atorvastatin, even brief exposure, causes a marked decrease in blood Co Q 10 concentration (shares the synthetic pathway of cholesterol). Primary CoQ10 deficiency causes mitochondrial encephalomyopathy with recurrent myoglobinuria; this may pertain to AE's of atorvastatin. Also, CoQ10 is an excellent free radical scavenger and the effects on degenerative disease are not known. Rundek et al,. Arch Neurol 2004; 61: 889-892.
A 16 year old girl with progressive weakness of the let leg
Hahn AF, Mauermann ML, Dyck PJB, Keegan BM/ CPC. Neurology2007;69:84-90. Insidious onset of left LE weakness started at age 13, progressing to complete footdrop. She had normal sensation and reflexes. She had gobs of negative tests. Motor exam showed mild weakness in posterior tibialis and hamstring, severe weakness in the tibialis anterior, to extensors and peroneii, and normal gastrocnemius and toe flexors. She had mild pes cavus. EMG showed normal left tibial nerve conductions, left peroneal motor and surals were absent or severely abnormal. Needle testing showed marked denervation distal to the short head of the biceps. QST's were normal. MRI showed mild increase int he size and signal intensity of the left peroneal nerve in the peroneal division only. Anatomic localization implicated the common peroneal nerve or divisional sciatic nerve. Discussant notes that the tibial and peroneal divisions of the sciatic nerve are segregated as the sciatic nerve passes from the sciatic notch, so a sciatic lesion can mimic a peroneal neuropathy. In such cases needle EMG of the short head of the biceps is crucial. MRI neuronography showed enlarged peroneal nerve ipsilaterally. The diagnosis on biopsy of the nerve was intraneural perineuroma (aka localized hypertrophic mononeuropathy). It presents as a painless motor mononeuropathy in younger patients in a variety of nerves (posterior interosseous, radial ulnar). MRI differentiates from fibrolipomatous hamartoma, but not intraneural ganglion cysts. Intraoperatively, internal neurolysis can suggest the diagnosis also. Unlike true onion bulbs, which are S100 positive, these are S100 negative and EMA positive.
Friday, November 09, 2007
SSPE
Cole AJ, Henson JW, Roehrl MHA et al. Case 24-1007: A 20 year old pregnant woman with altered mental status. NEJM 2007; 357: 589-600.
Case showed a young pregnant woman with clinical presentation of aseptic meningitis: confusion, lymphocytic pleocytosis in CSF, FIRDA on EEG, ,MRI showing dysfunction in a non hSVE pattern affecting internal capsule and cerebellar outflow tract, gads of negative tests. MRI affected left temporal lobe and pons. The patient had chorea which brought up Strep infection and Syndenham's chorea but ASO was only minimally positive and ACL's were negative. There was marked increase in CSF IgG levels, IgG index and oligoclonal bands. According to Dr. Cole, that narrowed it to syphilis, chronic rubella encephalitis, and SSPE.
Measles causes 3 different CNS diseases: postinfectious encephalomyelitis, subacute measles encephalitis, and SSPE. SSPE occurs 7-10 years after infection with behavioral changes, headache, adventitious movements, and sometimes seizures. Myoclonic jerks and PLEDs on EEG may occur. It may occur from childhood until fifth decade of life. It persists in places where measles vaccination remains uncommon. It is more common if measles occurred at age < 2 years, and may be more common in pregnancy. The diagnostic test is measles specific CSF IgG antibody index compared to serum. Iit maybe compared to a control infection such as mumps. This patients was treated with interferon and pranobex for eight weeks, delivered a healthy baby and then expired. SSPE is considered almost always a progressive disease. This patient may have shown signs in a prior pregnancy of a movement disorder.
Case showed a young pregnant woman with clinical presentation of aseptic meningitis: confusion, lymphocytic pleocytosis in CSF, FIRDA on EEG, ,MRI showing dysfunction in a non hSVE pattern affecting internal capsule and cerebellar outflow tract, gads of negative tests. MRI affected left temporal lobe and pons. The patient had chorea which brought up Strep infection and Syndenham's chorea but ASO was only minimally positive and ACL's were negative. There was marked increase in CSF IgG levels, IgG index and oligoclonal bands. According to Dr. Cole, that narrowed it to syphilis, chronic rubella encephalitis, and SSPE.
Measles causes 3 different CNS diseases: postinfectious encephalomyelitis, subacute measles encephalitis, and SSPE. SSPE occurs 7-10 years after infection with behavioral changes, headache, adventitious movements, and sometimes seizures. Myoclonic jerks and PLEDs on EEG may occur. It may occur from childhood until fifth decade of life. It persists in places where measles vaccination remains uncommon. It is more common if measles occurred at age < 2 years, and may be more common in pregnancy. The diagnostic test is measles specific CSF IgG antibody index compared to serum. Iit maybe compared to a control infection such as mumps. This patients was treated with interferon and pranobex for eight weeks, delivered a healthy baby and then expired. SSPE is considered almost always a progressive disease. This patient may have shown signs in a prior pregnancy of a movement disorder.
Saturday, November 03, 2007
Drug interactions,enzyme inducers and anticancer
PTN, CBZ and PB induce cytochome P450 and reduces bioavailability of many chemotherapeutic drugs and warfarin. The former include camptothecins (topotecan and irinotecan) and taxanes (paclitaxol).
Mayo Clin Prcds combination of risperidol and gingko caused priaprism
Mayo Clin Prcds combination of risperidol and gingko caused priaprism
Friday, July 06, 2007
Valproic acid and brain tumors
Besides its antiepileptic effects, valproic acid promotes differentiation of neurons into mature cell liens and inhibits proliferation of neuroectodermal lines. This has led to the use of valproic acid in pediatric patients who are s/p chemotherapy and radiation therapy for malignant glioma (Driever etal. al Klin Ped 1999; 21:323-8). Valproic acide also inhibits histone deacetylases, as do topamax and one of the metabolites of levitiracetam (PBA).
MGMT gene silencing and temozolamide in GBM
Hegi et al. NEJM 2005; 352:997-1003
Epigenetic gene silencing of the MGMT (06 methylguanine DNA methyltransferase) DNA repair gene by promoter methylation compromises DNA repair and is associated with longer survival in GBM patients receiving chemotherapy. This was also found to be true in radiotherapy; patietns with a methylated MGMT promoter had a survival benefit.
Epigenetic gene silencing of the MGMT (06 methylguanine DNA methyltransferase) DNA repair gene by promoter methylation compromises DNA repair and is associated with longer survival in GBM patients receiving chemotherapy. This was also found to be true in radiotherapy; patietns with a methylated MGMT promoter had a survival benefit.
Oligodendroglioma: towards definition and treatment
Reifenberger G, Louis DN. Oligodendroglioma: towards molecular definitions in diagnostic neurooncology. Journal of Neuropathology and Experimental Neurology. 2003; 62:111-126.
Since 1988 the treatment options have differed for different types of gliomas. Recurrent anaplastic astrocytomas sometimes respond dramatically to PCV (procarbazine, lomustine and vincristine). Since 1990 the same is true for newly diagnosed analplastic oligodendrogliomas. The response may be durable and may also occur with temozolomide, an oral agent.
Diagnostic markers such as Olig1 and Olig2 are not reliable. Microtubule associated protein (MAP2) is not specific although it is sensitive. In 1998 Cairncross reported response to chemo is strongly related to allelic losses on 1p or 19q in resected tumor tissue. The correspond to WHO grade II tumors. Testing is performed at a few specialized labs and is not considered routine. At MGH LOH 1p and 19q testing costs $800. In another study, Kim and Kim (Acta Neuropath 2005) found two light microscopy histological features, tumor cellularity and perinuclear halo were associated with the two markers above.
Since 1988 the treatment options have differed for different types of gliomas. Recurrent anaplastic astrocytomas sometimes respond dramatically to PCV (procarbazine, lomustine and vincristine). Since 1990 the same is true for newly diagnosed analplastic oligodendrogliomas. The response may be durable and may also occur with temozolomide, an oral agent.
Diagnostic markers such as Olig1 and Olig2 are not reliable. Microtubule associated protein (MAP2) is not specific although it is sensitive. In 1998 Cairncross reported response to chemo is strongly related to allelic losses on 1p or 19q in resected tumor tissue. The correspond to WHO grade II tumors. Testing is performed at a few specialized labs and is not considered routine. At MGH LOH 1p and 19q testing costs $800. In another study, Kim and Kim (Acta Neuropath 2005) found two light microscopy histological features, tumor cellularity and perinuclear halo were associated with the two markers above.
Sunday, June 17, 2007
Saturday, May 19, 2007
Listeria encephalitis
case discussion in Reviews in Neurological Diseases. The typical presentation is rhombencephalitis with a fever. It affects often pons and medulla in middle aged adults who are not immunocompromised. The prodrome is low grade fever, headache, encephalitis, vomiting and malaise lasting up to two weeks, followed by abrupt onset of cranial nerve palsies and encephalopathy. The cranial nerve palsies are often strikingly assymetric. The most common findings are dysphagia, dysphonia, dysarthria, facial weakness, diplopia and nystagmus. INO is described in those with a pontine abscess. Urinary retention is described due to involvement of Barrington's nucleus. CSF gram stain is often negative and diagnosis may require serologic tests. There is 75 % chance of survival if treatment is initiated promptly.
Saturday, May 05, 2007
Brain MRI findings in mitochondrial cytopathies
Barragan-Campos H et al. Arch Neurol 2005; 62:737-742. 21 patients were described, including 7 with CPEO, 7 with Kearns-Sayre, 6 with mitochondrial neurogastrointestinal encephalopathy, and 1 with myoclonic epilepsy with ragged red fiber myopathy. MRi showed widespread white matter hyperintensity in 90 %, supracortical atrophy in 18, cerebellar atrophy in 13 ABSENT BASAL GANGLIA HYPERINTENSITY CORRELATED WITH KEARNS SAYRE AND SUPRATENTORIAL ATROPHY WITH mitochondrial neurogastrointestinal encephalopathy.
Clinical criteria: CPEO-- ext opthalmopledia, proximal myopathy and RRF. KS-- ext opthalmoplegia, heart block, pigmentary retinopathy, cerebellar ataxia, eolevated CSF protein (the latter two were "optional"). MNGIE-- leukoencephalopathy, CPEO, PN, chronic intestinal pseudoobstruction MERRF- myoclonic epilepsy, myoclonic ataxia, dementia, and RRF.
Clinical criteria: CPEO-- ext opthalmopledia, proximal myopathy and RRF. KS-- ext opthalmoplegia, heart block, pigmentary retinopathy, cerebellar ataxia, eolevated CSF protein (the latter two were "optional"). MNGIE-- leukoencephalopathy, CPEO, PN, chronic intestinal pseudoobstruction MERRF- myoclonic epilepsy, myoclonic ataxia, dementia, and RRF.
Wednesday, May 02, 2007
Cryptococcus/fungals/meningoencephalitis pearls (Dr Perfect AAN 2007 lecture)
1. Cryptococcus neoformans serotype A and D (grubii and neofomans) and serotype B and C (Cr. gattii) are major serotypes. Gattii affects more normal hosts and has more torulomas.
2. Consider IRIS (immune reconstition syndrome) in HIV patients starting HAART or with any CHANGE in immunosuppressive regiment. If patient seems to be getting worse in spite of treatment, this may be one of the few times to pay attention to the Crypto antigen titer. If it is dropping the patient may have IRIS and may not be failing therapy.
3. Don't put a shunt in until the patient is already on treatment-- you'll just have to replace it later. Increased ICP can occur on presentation chronic and indolent, acutely during early therapy, or classic hydrocephalus with therapy. Consider increased ICP if frequent and severe headaches, pappilledema, hearing loss, or pathologic reflexes present. Consider repeat LP's as a treatment modality. Shunts don't work often in comatose patients.
4. Indications for surgery include diagnostic biopsy, toruloma greater than 3 mm, zygomycetes and infarcted tissue, phaeohyphomycosis, shunt placement.
5. Diagnosis of other fungi clues: neutrophilic meningitis (aspergillus, scedosporium, blastomyces, zygomycetes), large volume CSF cultures (Blasto/histo/coccidio). Histoplasmosis antigen, sporotrix CSF antibodies, cocciiodes CFA, aspergillus galactomannan.
6. Wangiella (Exophiala) dermatitidis meningitis occurs due to injectable steroids that are contaminated, with a 1-11 month incubation period. Therapy with voriconazole.
7. Hyalohyphomycosis-- occurs in near fresh water drownings, due to steroids, and diabetes, usually from sinus disease, causes abscesses, surgery is critical for diagnosis and debulking.
8. Drug resistance is rare but it occurs.
See what's free at AOL.com.
Leprosy Pearls-- lecture by Dr Swift at AAN 1007
1. Most people (95 %) have immunity to leprosy and cannot get it.
2. Leprosy is only infection that invades the peripheral nerve. Palpation of nerves is important.
3. Invasion can take form of nodular or diffuse infiltration.
4. Erythema nodosum leprosum is an immune reaction that occurs with treatment than can result in severe damage of skin, anterior eye, testes, and nerves and cause infarction/ulcers especially of skin.
5. The three types are tuberculous ( immune reaction present), lepromatous (immune reaction absent) and intermediate or borderline. Borderline is unstable and tends towards lepromatous or tuberculous (reversal reaction).
6. Signs include affected cool areas with involvement of upper lip (cooler than lower lip), tip of nose, ears, extensor surfaces of extremities, scrotum and testes, anterior third of eye. May have sparing between toes (warmer). Failure to close eyes results in corneal drying and lower lid hangs away (lagopthalmos). Buccinator wrinkles since buccinator is deep. Ulnar clawing, acute angle glaucoma, or corneal abrasions due to eyelids turning in. Knee and ankle jerks are normal. Scalp is only affected in bald patients.
7. Treatment of paucibacillary (tuberculoid) leprosy is with a combination of rifamycin, ofloxacin, and minocycline (check standards which always change). In paucibacillary intermediate disease use rifamycine 600 mg monthly and dapsone 100 mg daily for 6 months. In multibacillary (lepromatous) use triple therapy with dapsone 100 mg/day, rifamycine 600 mg/mo, and clofazimine 50 mg per day for 12-14 months. Also treat reactions with prednisone 60 mg/day or equivalent. Rehab procedures of affected skin are helpful. Patients are at high risk of osteomyelitis due to neuropathy. Casting has been tried.
See what's free at AOL.com.
Cerebral Abscess-- Quick Hits from AAN (Bartt lecture) 2007
1. Mortality has declined in recent years. In a recent review of 94 patients admitted to intensive care, 26 % died and 36 % had long term morbidity. Recent rates of death are 13-14 % in both children and adults. Factors that predicted mortality (independently) were sepsis and GCS < 9 , not location, deficits, organism or need for surgery. (Tattevin et al., 2003, AM J MED).
2. Resolution of ring enhancing MRI is longer than the six weeks needed to treat the abscess with intravenous antibiotics.
3. The purpose of surgery is to treat mass effect.
4. Do not treat mycotic aneurysms (or worry excessively about them) until 4-6 weeks of treatment has already occurred.
5. Steroids can reduce antibiotic penetration through the blood brain barrier and are not proven in abscess.
6. Risk factors for abscess 1.7 % for acute or chronic sinusitis (esp ethmoid or sphenoid), 1-2 % for HIV, 4 % for stem cell or bone marrow transplant, 2.1 % of cyanotic heart disease, and 3.1-37.5 for pulmonary AVM's (worse with multiple AVMS's).
7. Otitis is more common in young males as a cause.
8. The most common cause is headache in 70-80 % and less than half have HA, fever and focal deficit. Less than half have pappilledema. Nausea, vomiting, pappilledema are more common in otogenic with symptoms in posterior fossa and of increased intracranial pressure.
9. Sed rate and blood cultures may be positive in less than 20 % and especially if bacterial endocarditis is present.
10. Factors on imaging favoring abscess over tumor (metastasis) include a more regular rim, homogenous enhancement, a thinner wall towards the ventricular surface, daughter satellite lesions and RESTRICTED DIFFUSION ON DIFFUSION WEIGHTED SEQUENCES all favor abscess.
11. Do a TEE to look for paradoxical abscess and PFO in patients with a cryptogenic abscess.
12. Therapy suggestions:
Immunocompromised with lobar pneumonia, TMP-SMX; antifungals if bug not identified.
Listeria--PCN
Frontal (sinus, odontogenic)-- aer/anaer-- PCN + Flagyl or 3rd gen ceph + Flagyl
Temporal (Otogenic) - Str, Entero, Bacter.-- PCN + Flagyl + 3rd gen ceph.
Metastatic/ hematogenous-- nafcillin, Flagyl, cefotaxime
Penetrating trauma/ postop--Steph, enterob, pse.-- vancomycin + ceftazadime
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Monday, April 30, 2007
Swallowing rehab measures in dysphagia due to inflammatory myopathy
Diet -- oral, nonoral (PEG) or both
Feeding instructions-- chew food well, swallow twice, small bites, alternate solids and liquids, sit upright during the meal.
Compensation-- Chin tuck, head turn (right and left) , effootful swallow, Mendelsohn maneuver, supraglottic swallow
Exercises-- tongue base retraction, effortful swallow, Mendelsohn maneuver, falsetto, supraglottice swallow.
Interventions done-- cricopharyngeal myotomies most helpful and were most frequently done in IBM Other procedures done were cricopharyngeal or esophageal dilatation, and PEG.
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Malignant transformation of monoclonal gammopathy
Rosinol L. et al. Mayo Clin Proc 2007;82:428-434.
The authors cite a NEJM article (2006) showing a prevalence of 3.2 % and 5.7 % in patients greater than 50 and 70, respectively. The patients can transform after years of stability. To determine the rate of transformation, the authors took into account both the presenting clinical finding and the evolutionary pattern of the M protein. They excluded patients diagnosed in the first 3 years, or with smoldering myeloma. 537 were diagnosed with MGUS, 178 were lost to followup or were followed les than three years, 359 were followed more than 3 years. Patients received a SPEP, UPEP and bonemarrow aspirate. On followup they got an M protein measurement on pep yearly. Evolving type was defined as patients with an increase in the M protein size on electropheresis in each annual visit over three years. 330 patients were nonevolving and 29 were evolving. 32 developed malignancies. Risk factors were the evolving typeand M protein concentration. Of the 32 malignancies, 20 had multiple myeloma and 2 had Waldenstrom's macroglobulinemia after a median followup of 93 months (7 and a half years, just under ten percent). However, 14/29 with evolving MGUS (48 %) developed symptomatic disease, and 18 (5%) on nonevolving progressed. The rate of transformation in the evolving and nonevolving groups after ten and twenty years, respectively, were, 55 and 10, and 80 and 13, respectively.
Initial factors associated with transformation were M protein size greaterthn 15 g/L, proportion of BMPCs (bonemarrow plasma cells) greater than 5 %; higher incidence of IgA v. IgG, and evolving MGUS. No nonevolving patients transformed after twelve years.
The actuarial rate of progression is 1.5 % per year, 17 % at 10 years, 34 % at 20 years, 39 % at 25 years (Kyle et al., different paper). Baldini et al. (Blood, 1996) emphasizes BMPC's as an important risk factor with followup of patients with BMPC ranging from 10-30 percent (normal was around 4) having a 5-6 year followup, having a rate of malignant transformation of 37 v. 7 percent. Cesana et al. (J Clin Oncol 2002) found bm plasmacytosis greater than 5 percent, presence of light chains proteinuria, polyclonal serum immunoglobulin reduction and high ESR as independent factors affecting transformation. Kyle et al. found thatM protein size and non IgG type were the most important predictors of progression. (Kappa v. lambda had relative risk of 4.1). Rajkumar et al.(Blood 2005)found non IgG MGUS, M protein > 15 g/L, abnormal k/l light chain ratio had an actuarial probability of transforming of 58 % at 20 years, whereas patients who lacked all of the above risk factors had a rate of transformation at 20 years of only 6 percent.
Kyle and Greipp(NEJM 1980) described SMM (smouldering multiple myeloma), defined as M protein > 30 and BMPC> 10 % without end organ impairment. Patients with the evolving SMM type show a progressive increase in M protein until myeloma develops, whereas nonevolving types have stable M protein until the onset of disease with a longer time till disease develops. 59 % of SMM patients who were evolving previously had an evolving MGUS, whereas only 4 % of nonevolving SMM had a previously noted MGUS . This is due to genomic hybridization, with high chromosomal losses and iq gains in the evolving patients.
The authors hypothesize that there are two types oo MGUS evolving and nonevolving, and all patients with the evolving type will eventially get disease.
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Sunday, April 22, 2007
Internuclear opthalmoplegia: Unusual causes in 114/410
Keane JR. Arch Neurol. 2005; 62:714-717. Uunusual causes not stroke or MS occur in 28 % overall, 42 % of unilateral cases the author has seen over three plus decades in practice. Of 410 cases, 38 % (157)were due to stroke (5.157 due to cardiac emboli), 139 (34 %) due to MS, and 114 (28%) due to "unusual" causes. These included 16 patients with blunt head injury, one gunshot wound, and one with blood loss after a stabbing. Two motor vehicular collisions led to vertebral artery injury after cervical spine fracture. Tentorial herniation after CNS infection occurred in 2; one had a subdural empyema , bilateral SDH, TB meningitis There were two cases of brainstem toxoplasmosis, 1 lymphoma and 3 brainstem encephalitis, all inHIV patients. 4 patients with cysticercosis had lesions in caudal aqueduct or fourth ventricle. Two patients had neurosyphilis. 12 patients had iatrogenic injury including angiography, tumor emobolization, CEA, cardiac catheterization, 1 hydrocephalus, 1 Wernicke's encephalopathy, 1 brainstem atrophy, one carbamazepine overdose, one cerebellar hemorrhagic infarct with pontine compression, one spinocerebellar atrophy with pigmentary changes.
Pseudo INO was seen in 27/182 patients with myasthenia gravis, 2 patients with GBS, 1/38 with Fisher s, 1 with abetalipoporoteninemia, andcalorics showed an INO pattern in several comatose patients. PSP shows preferential weakness of the medial rectus with improvement with caloric stimulation.
Pseudo INO was seen in 27/182 patients with myasthenia gravis, 2 patients with GBS, 1/38 with Fisher s, 1 with abetalipoporoteninemia, andcalorics showed an INO pattern in several comatose patients. PSP shows preferential weakness of the medial rectus with improvement with caloric stimulation.
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