Sunday, November 29, 2009
Saturday, November 28, 2009
The first article-- the best of the four-- describes how much FDA information never reaches clinicians (1). Clinicians and the public rely on the Food and Drug Administration (FDA) for drug and product approvals and denials, and for disseminating accurate information about drugs in their product inserts. I learned that the lengthy, often poorly written and weakly summarized debates about drugs are posted publicly at www.accessdata.fda.gov/scripts/cder/drugsatfda/. The authors cited glaring examples of critical information that somehow was not included in the product labels. Zometa (zoledronic acid, Novartis), used to treat hypercalcemia of malignancy, at the 8 mg dose, caused more renal toxicity and death than the 4 mg dose and was no more effective. Nonetheless, the labelling suggested using the higher dosage "in refractory cases." The product label did not mention increased mortality at the higher dose.
Lunesta (eszopiclone, Sepracor), sold 800 million dollars last year with the help of a direct to consumers marketing campaign. Yet the efficacy data, buried on page 306 of 403, shows patients slept 15 minutes earlier and 37 minutes longer than placebo, with no clinically meaningful improvement in next day alertness or functioning. Similarly, Rozerem (ramelteon), another approved sleep drug, caused younger adults to fall asleep 14 minutes earlier, and older ones 7 minutes earlier, with no improvement on subjective assessments of sleep quality.
The very next article details ways the same government can "further" improve health care. Victor Fuchs (2). advocates incremental rather than radical health care reform. The first of his four proposed reforms is to eliminate employer based health care coverage tax exemptions. The purpose is to raise 200 billion dollars in new revenues, that is taxes, to make the tax system "fairer" since the tax benefit is a regressive tax. He alleges it benefits the wealthy. (Wait a minute-- my practice employs 15 people, who have relatively low incomes and have the same insurance I have. A biller who had breast cancer last year would never have gotten treatment without our comprehensive health insurance). This would allow the creation of insurance exchanges, the second idea, that would, using Fuchs' words, be not as "generous" to "consumers" (actually, sick patients) as the private plans they replace. Supposedly, these exchanges would decrease "broker" costs.
The third, chilling suggestion of Fuchs is the appointment of an "expert" commission to devise changes to the ways Medicare reimburses providers. Fuchs cites "special interests" as blocking the "public good," as a charged way to rally the troops. Again, citing my own practice, with 50 % overhead, a 10 % payment cut equals a 20 % loss of income. Could it be, that by going after providers who have already been sucked dry, Fuchs will drive people out of practice, resulting in fewer providers, thereby raising the cost of care? Fuchs' final idea is an office for technology assessment that would be "quasi-independent." Of whom, I might ask.
The third article-- the last to be reviewed here- describes implementing evidence based medicine in Washington state (3). The state has total authority, except where prohibited by federal statute, to use evidence based methods to assess drugs, devices, surgical procedures, diagnostic tests, imaging procedures, and medical equipment. The author decries the political "pressure" wrought by patients who testify that the benefitted from a technology the state wants to eliminate. Obscenely, the same authors equate pharmaceutical direct to patient marketing with physician "autonomy" and "financial incentive" in ordering tests.
The authors note the "challenges" of this policy, citing the example that thymectomy of myasthenia gravis, used since 1912, has never undergone a rigorous trial. This author will note a few more nonevidence based treatments: penicillin for infection, appendectomy for appendicitis, and burr holes for subdural hematomas of the brain. Are these procedures necessary? Shall the government be in a position to decide? May I be so impudent to suggest satisfaction surveys be returned for all cases of physician assisted suicide?
The assumption of evidence based medicine is that care from one can be generalized to another and is equivalent to another. Evidence is important, and can help us learn how to be better doctors. But, evidence is not the be all and end all. Sometimes doctors have to take the controls from the nurse practitioners and PhD's and make decisions that are in the best interests of the patient. The reasons may not be obvious to the lay public but may be based on sound understanding of pathophysiology. Experience and judgment, absent from these vacuous bureaucratic declarations, still are what most patients seek.
1. Schwartz LM, Woloshin S. Lost in transmission: FDA drug information that never reaches clinicians. N Engl J Med 2009; 361:1717-1720.
2. Fuchs VR. Four health care reforms for 2009. N Engl. J Med 2009; 361: 1720-1722.
3. Franklin GM, Budenholzer BR. Implementing evidence based health policy in Washington State. N Engl J Med 2009; 361:1722-1725.
Friday, November 27, 2009
Several sleep related conditions may mimic and be misdiagnosed as seizures. 80 % of narcoleptics have automatic behavior during sleep. The individual appears awake but is without full awareness. Behavior may be inappropriate and resemble a fugue state.
Idiopathic recurring stupor was described in 1990. The stupors may occur a few times weekly to a few times annually, and last from hours to days. All cases show a widely distributed nonreactive 13-18 hz activity. Flumazeni, a benzodiazepine antagonist, quickly but temporariy reverses the stupor and eeg findings. The culprit is thought to be endogenous benzodiazepines called "enzopines" that act on the GABA A receptor for benzodiazepines. These ligands may alsobe important in learning, memory, hepatic encephalopathy, and panic attacks. CSF enxopine-4 levels are more than 100x higher than in control subjects.
Thursday, November 26, 2009
Meyer TK. The Neurologist 2009; 15:313-318. Also points from Rosenfield DB,and Viswanath NS. Neurolaryngology.in Evans R. Diagnostic Testing in Neurology Philadelpia, Saunders, 1999, pp. 223-229.
Larynx functions: phonation, deglutition, airway protection, control of respiration. Laryngeal closure also allows increased abdominal pressure for defection, parturition and stabilization of thorax for heavy lifting.Humans have a lower larynx than grazing animals,helping phonation but more precarious for airway control.
Parkinson's disease-- vocal folds are atrophied and bowed with incomplete closure. Patients perceive their own hypophonic speech as of adequate loudness. Voice is also due to bradykinetic efforts from inadequate bellows mechanism (diaphragm and chest wall). Treatment includes bilateral bulking injections to vocal cords to facilitate glottal closure which can be temporary or permanent. Lee Silverman voice technique also helps.
Vocal Cord paralysis. Patient has weak breathy wet voice. It usually occurs due to tumor or surgery. If one vocal cord does not close, can do implant medialization, which will improve voicing and cough in all, and speech in 70 %.
Spasmodic dysphonia-- is a focal dystonia of 2 types. Adductor s.d. is characerized by harsh strangled quality with voice breaks. Abductor s.d is characterized by sustained breathiness with breathy voice breaks. The dystonia is task specific, eg. with breathing, sparing other functions such as swallowing. SD is female predominant with 73 % ADSD, 17% ABSD. Its associated with essential tremor in 30 % and other dystonias in 14 %. Botox is best treatmentfor both types, although the procedure is different for each.
Historical points in dysphonia. Getting stuck,shaking, or improving with alcoholsuggests ET. Trauma can cause dislocated arytenoid cartilage. Pain indicates focal pathology or GERD. Abrupt onset maybe psychogenic. Fluctuations may represent myasthenia.
2 Hysterical dysphonia. The vocal cords are normal during larygoscopy, cough is normal, articulation in whisper is normal.
3. Monrad Krohn's cough test for hysterical monoparesis. Stands behind patient, grab both lattismus dorsi,ask patient to cough, lats contract prove integrity of brachial plexus.
4. Double crossed arm pull test for hysterical monoparesis. Grab patient's wrists which are crossed across his chest and tell him, "when I say now, pull back as hard as you can." He may pull both sides.
5. "Make a fist " test for psychogenic wrist drop. Wrist elevates with a fist (functional position) or with holding a pencil in posiition.
6. Reversed hands test for functional monoparesis. Interlock hands, ask patient to move finger pointed to.
7. Backward displacement test for psychogenic foot drop. Push patient backwards and see anterior tib dorsiflexors spring into action.
8. Hoover test.One hand under each heel. Ask patient to raise the good leg, and the other one will inadvertently push down in functional patient. If ask patient to push down with both legs, if organically paralyzed he won't if hysterical he might.
9.Raimiste's leg abduction/adduction test for hysterical weakness. Similar to Hoover test for abduction and adduction of legs.
10. Psychogenic visual field deficit with tubular vision, same deficit for near and far Similar, spiral visual field defect may occur with smalllr field with each trial.
2. Pallanesthesia refers to vibratory testing.
3. The directional scratch test on the dorsum of the palm and leg may be superior to other tests of vibratory or position sense (Hankey and Edis, JNNP, 1989). Scratch a line across 2 cm and ask patient if scratch was up or down. If unable to perform accurately (ie, 100 %), repeat with distance systematically increased to make the test quantitative.
4. Two point discrimation with a paper clip can be done touching the patient with one or both ends of the paper clip and asking if patient got one or more than touch. Thresholds for normal two point discrimination in patients more than 7 years old, 2-4 mm on fingertips, 4-6 mm on dorsum of fingers, 8-12 mm on palms, 20-30 mm on dorsum of hands,
Wednesday, November 25, 2009
1. Keeping time can be regulated at a genetic molecular level with clock genes. This affects both ASPD and DSPD.
2. SCN sends a signal to pineal, which feedbacks to SCN altering circadian rhythms. The main influences on are light, melatonin, and physical activity.
3. Advanced or delayed circadian rhythm disorders occur. Assess with: 7 day eveningness/morningness questionnnaire, sleep diary, actigraphy, core body temperature, melatonin level (24 hour or sleep onset DLMO, clinically available, from saliva) or PSG- ambulatory .
4. Advanced and delayed sleep phase disorder. Rectal body temp usually nadirs 4-6 am, so someone who nadirs at 11 am (college kid?) has a delayed circ disorder. Same patient, melatonin spikes at 1 am whereas for most of us it happens at 9 pm. DSPS has higher rate of BPAD
jet lag pier.acponline.org googlejetlag calculator
east ward trouble falling asleep
west ward trouble staying asleep.
if lags going to Europe, avoid bright light in AM. Speeds up realignment.Needs a week to realign otherwise. Going back west, use melatonin at bedtime at destination.
Other quick hits
REM sleep centers include pons -- perilocus cereleus for atonia, and vestibular nuclei for generation of REM and basal forebrain also plays a role as do other areas.
Wednesday, November 18, 2009
Costello DJ et al. The Neurologist 2009;15:319-328
ALD kids get spastic paraparesis with detrusor instability. Defect is VLFA's ABCD1 mutation. MRI lesion is leukodystrophy starting posteriorly, may enhance partially and be confused with inflammatory disease. Adults may present with neuropsychiatric disease, followed by spasticity, ataxia, seizures, and death. Two thirds of female carriers also develop some sort of progressive myelopathic picture. They may have more pain and be misdiagnosed as having MS or fibromyalgia. Adult cerebral (AC-ALD) is more fulminant than X-ALD.
MLD is aut rec. Presentations in younger patients include disturbed gait, ataxia, quadriplegia, optic atrophy, and peripheral neuropathy, to decerebrate rigidity. In adults, presentation is often neuropsychiatric with misdiagnosis of schizophrenia, or even normal, with neuropscyh testing especially showing problems with visuospatial construction. There are dramatic elevated sulfatides due to arylsulfatase deficiency.
In Krabbe disease, beta galactocerberosidase occurs, is characterized by , in adult form, various motor presentations with progressive cognitive decline, seizures, cortical blindness with 20 % having uniform slowing of nerve conduction studies. Substrate (galactosylceramide) levels are increased but only mildly, but within oligodendrocyte, there are 100 fold increases in psychosine which is cytotoxic and selectively damages oligodendrocytes. Its been described up to age 84. Get posterior predominant involvement, no enhancement.
In Vanishing White matter disease, adult onset, there is cognitive involvement, pseudobulbar palsy, spastic paraparesis, with an important association with ovarian failure, "ovarioleukodystrophy." Its caused by mutations in e1f2b, affects ribosomes and proteins, causes cystic degeneration and rarefaction of the white matter. Clinical features not completely understood, probably is more common than thought.
Alexander disease-- due to mutation in GFAP, causes Rosenthal fibers. Get bulbar and pseudobulbar palsy with white matter abnormalities starting in front.
Canavan disease-- increased NAA in urine, Spectroscopy is good to diagnose this.
Hereditary diffuse leukoencephalopathy with spheroids is almost exclusively diagnosed in adults. Present with deteriorated behavior and personality and seizures. Diagnosis is by tissue.
Pelizaeus Merzbacher is X linked but like ALD carrier females have a forme of disease. Tremor, ataxia, dementia, and progressive spastic paraplegia occur. Mutation on PLP 1 on X q 22 occur. Classic hypomyelinated CNS disorder.
Recessive hypomyelinating leukoencephalopathy (RHL) =PM like disease is a hypomyelinating disease.
others see text, also for Rx
infection due to enhanced vector competence. Spread by mosquitoes to humans, togavirus. Abrupt onset fever, joint swelling, myalgia, headache, back pain, and rash. Diagnosis is by CDC IgM and IgG. Rare neurologic cases include encephalitic infections of newborns and elderly.
Other presentations include encephalomyelitis, myeloradiculitis, acute flaccid paralysis (GBS like), encephalopathy and seizures. A mutation in viral envelope dramatically changed infectivity. Endemic travellers to new areas cause infections
Nipah and Hendra viruses.
classification is henipavirus of paramyxovirus. In Australia it first was identified as a highly infectious disease of horses and close human contacts/handlers. Aseptic meningitis and encephalitis occurred in Hendra, a location in Australia.
Nipah virus, closely related, occurred in pig farms in Singapore and Malaysia in 1998. Encephalitis and pneumonitis were common, with a 40 % mortality. The incubation perido was two weeks, with a 3-4 day prodrome. Mortality was 73 %. MRI usually showed multiple small subcortical lesions on T2 and FLAIR images without edema. PEARL- relapsing and delayed onset disease can occur. in 3 % or so average 8 months after first event, with an acute onset the second time. There was an associated systemic vasculitis with thrombosis and parenchymal necrosis in the CNS. Syncytial multinucleated endothelial cells are pathognomomic and occurred in 25 %. A subsequent outbreak in Bangladesh was not associated with pig farms and was shown to be associated with flying foxes and fruit bats with spread through urine of latter. Human to human transmission occurred, including between patients and health care workers.
Tyler KL. Emerging viral infections of the CNS. Part II. Arch Neurol 2009; 66: 1065-74.
Due to exotic pet (mammal ) trade from Africa including Gambian pouched rats, dormouse, and rope squirrels, spread to prairie dogs in the US to humans.
Most common symptoms, 50 percent or more have rash, fever, chills, adenopathy, myalgias, sweats and cough. Rash follows several days later and typically is maculopapular, proceeding through stages with papules, vesicles, and pustules. The rash is centifugal and involves the hands or feet in 80 %, legs or feet in 65 %, head in 6 %, and resembles chicken pox. Unlike chicken pox (and like syphilis and ricketsial infection) there is lymphadenopathy and involvement of the palms of the hands and soles of the feet. Diagnosis is with skin biopsy, PCR, and ELISA.
One six year old developed encephalitis. Diagnosis was made by serum IgM and IgG and CSF IgM, with negative PCR.
Sunday, November 15, 2009
Rituximab for myasthenia gravis developing after bone marrow transplant
Lebrun C, Bourg V, Tieulie N, et al. Successful treatment of refractory generalized myasthenia gravis with Rituximab. Eur J Neurol 2009: 16: 246-250. 6 patients with refractory disease after thymectomy , got 375 mg/m2 weekly for four weeks then monthly for for two months, then subsequently based on clinical status. A few patients needed infusions for 1-2 years. All patients ultimately tapered mestinon and prednisone and other drugs.
Diaz-Manera J, Martinez Hernandez E, Querol L. et al. Long lasting treatment effect of rituximab in MuSK myasthenia. Neurology 2012; 78: 189-193 . 17 patients with resistant MG 9defined as failing 3 second line agents. Rituxan was given 375 mg/m2 for four weeks then monthly for two months, then if intereference with ADL's. All patients with uSK reached minimal manifestation status by 3 months after treatment, and maintained MMS or remitted by 35 months. Note-- drug seems best suited for MuSK patients.
Anderson et al.Rituxan in refractory myasthenia gravis: a prospective open-label study with long term followup.. Ann Clin Trans Neurol 2016; 3: 552-555. Refractory MG given Rituxan by abvove protocol or 750 mg/m2 every 2 weeks x 1 month. 3 people got additional cycles. At 22 months all patients improved, and pred, IVIG and PE needs decreased.
One case exists of PML in a MuSK myasthenic patient (Kanth KM, Solórzano GE, Goldman MD. PML in a patient with myasthenia gravis treated with multiple immunosuppressing agents. Neurol Clin Prac. 2016; 6: e17-e19).
Durability of responseRobeson KR, Kumar A, Keung B et al. Durability of the rituximab response in acetylcholine receptor autoantibodfy positive myasthenia gravis. JAMA Neurol 2016 : 4190.
After the first cycle, 63 % had sustained remission, 19 % had pharmacological remission and 19 % MMS not requiring treatment.
Of those who discontinued all other forms of therapy, did so at a mean of 8 months (range 1-13) after the last cycle. 9/16 (56 %) relapsed at aa mean of 36 months, but all improved with further immunosuppressive therapy. All patietns tolerated it well.
+ four more.
Zebardast N, Patwa HS, Novella SP, Goldstein JM. Rituximab in the management of refractory myasthenia gravis Muscle Nerve. 2009 Oct 22. (Yale). Studied six refractory patients. Began rituxan 375 mg/m2 weekly for 6 weeks, then 2 treatments every 20-30 days and decreased prednisone. 8 months later received a second course of 5 infusions weekly. A third course of 4 weekly infusions were given 6 months after that. All patients received 4-6 doses of weekly infusion, with subsequent infusions at 6 months if needed.
Nelson RP Jr, Pascuzzi RM, Kessler K, Walsh LE, Faught PP, Ramanuja S, Pescovitz MD, Loehrer PJ Sr. Rituximab for the treatment of thymoma-associated and de novo myasthenia gravis: 3 cases and review. J Clin Neuromuscul Dis. 2009 Jun;10(4):170-7. Review.
Stieglbauer K, Topakian R, Schäffer V, Aichner FT. Rituximab for myasthenia gravis: three case reports and review of the literature.J Neurol Sci. 2009 May 15;280(1-2):120-2. Epub 2009 Mar 9. Review.
Lebrun C, Bourg V, Tieulie N, Thomas P. Successful treatment of refractory generalized myasthenia gravis with rituximab.Eur J Neurol. 2009 Feb;16(2):246-50. Authors followed 6 patients with poor response to immunosuppressive meds. All but one were ACH receptor negative and 3 were anti Musk positive. IVIG did not help. Doses: 375 mg/m2 weekly for 4 weeks After one month steroids were discontinued and anticholinesterase meds decreased. Rituxan cont. every 2 months for six months. Benefit persisted for 2 years of f/u (patient one). Steroids were tapered after the first infusion.
Stübgen JP. B cell-targeted therapy with rituximab and autoimmune neuromuscular disorders. J Neuroimmunol. 2008 Nov 15;204(1-2):1-12. Review.
Illa I, Diaz-Manera J, Rojas-Garcia R, Pradas J, Rey A, Blesa R, Juarez C, Gallardo E.Sustained response to Rituximab in anti-AChR and anti-MuSK positive Myasthenia Gravis patients.J Neuroimmunol. 2008 Sep 15;201-202:90-4. Epub 2008 Jul 23.
Dalakas MC.Invited article: inhibition of B cell functions: implications for neurology.Neurology. 2008 Jun 3;70(23):2252-60. Review.
Saturday, November 14, 2009
1. Antiretroviral distal sensory neuropathy (ARV-DSP) occurs with didanosin (ddI), zalcitarabine (ddC), stavudine (d4T) plus more recently, adanavir, saquinavir, and ritonavir. It occurs chiefly in first year of treatment or in patients with preexisting neuropathy. Symptoms occur with drug onset and resolve with discontinuation of the drug.
2. DSP due to HIV was formerly associated with high viral load, and low CD4 count and occurs in nearly 100 % at autopsy, and 30-50 percent in clinical practice. Other risk factors are older age, low nadir CD4 count, poor nutrition, coexisting diabetes, and use of neurotoxic drugs (such as antiretrovirals) or alcohol.
3. Of newer drugs, duloxetine is FDA approved for DPNP (diabetic peripheral neuropathy pain) and is under study in HIV DSP. Lamotrigine has been shown to be effective. Elavil and NSIAAD's have not been shown to work.
4. Polyradiculitis is usually pure motor and can be due to CMV, TB, cryptoccosis, and meningeal lymphocytosis. Treponema also has been described. Presentation was usually progressive weakness starting weeks before onset. One case had cervical disease, the rest were lumbar.
Tuesday, November 10, 2009
rapid acceleration and deceleration of brain can be estimated as follows
a=(v2-v0)/2sg, easily calculates deceleration based on initial speed v0, final speed v2, and distance travelled s. The result obtained is in terms of g, which is equivalent to 10.73 yards per second (Varney and Roberts 1999). Since the final speed is zero after player stops, formula becomes a= -v0squared/2sg. Then, calculate force applies by F=mg. The number 200g force has been proposed as the amount to cause permanent damage but is not really known.
Mendez MF. The neuropsychiatric aspects of boxing. Int J Neuropsychiatry Med 25: 249-262, 1995.
Stewart WF, Gordon B, Selnes O. et al. Prospective study of central nervous system function in amateur boxers in the United States. Am. J Epidem 139;573-588, 1994. Bouts fought before 1984 when safety measures were instituted were correlated with neuropsychological impairments.
Abnormalities in sustained attention and visuomotor speed with absent normal practice effects. Preseason baseline assessment by SLAM model is becoming gold standard for concussion assessment and management.
Sideline assessment use SAC,a 5-10 minite measure (McCrea et al, 1996).
JT Barth et al, 1989, 2002 4 yr prospective study of MTBI in college athletics in Sports Laboratory Assessment model (SLAM) with 2300 football players at 10 universities with pre and post neuropsychological assessments. It used a matched control group plus patients as their own control group. After very mild injuries athletes showed a 5-10 day recovery curve for mild cognitive deficits.
Consensus Conference: Rehabilitation of persons with traumatic brain injury . NIH Consensus Development Panel on Rehabilitation of Persons with TBI. JAMA 282:974-983, 1999. Neuropsychological deficits include problems with memory, attention, concentration, executive skills.