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.

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.

CDC toolkit for concussion

http://www.cdc.gov/ncipc/tbi/physicians_tool_kit.htm

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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.

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.

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.

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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.   

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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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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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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.

Delirium due to consuming toner cartridge cleaner

Tancredi DN , Shannon MW. Case 30-2003: A 21 year old man with sudden alteration of mental status. The patient was a 21 year old who b had been drinking, then acted strangely, smelled of urine, awake and noncommunicative. Pupils were reactive. Iv droperidol resulted in coma, then hyperagitation. He had consumed laser printer toner cartridge cleaner to augment the effects of alcohol, that is metabolized to GABA. He awoke and insisted on leaving.
Discussion comments on gamma hydroxybutyrate that was used in the 1980s by bodybuilders, enhanced ethanol,date rape drug, but is still manufactured illegally, quite easily, at home. Criminalization led to the use of congeners. Gamma butyrolactone has since been restricted. Gamma valerolactone is a solvent in industrial applications. This patient took 1,4 butanediol which is used in compact disc and printer cleaners, but is legal. It metabolizes to gamma hydroxybutyrate which acts at specific receptors and at the GABA b receptor. Intoxication shows about one third have hypothermia, bradycardia, or both, are inebriated with an agitated delirium. Severe effects are coma and apnea, which uniquely, resolves extremely rapidly with a return to awareness. Amnesia occurs. Ethanol inhibits alcohol dehydrogenase, halting the metabolism of 1,4 butanediol. There may be a biphasic period of risk of coma due to interactions and patients should have prolonged observation. Treatment is supportive. Studies are underway using 4-methylpyrazole (fomepazole) an alcohol dehydrogenase inhibitor also being studied in methanol and ethylene glycol intoxication. More clinical information can be found here: http://neurologistnotes.blogspot.com/2007/12/ghb.html

See discussion of SSADH here: http://neurologyminutiae.blogspot.com/2008/02/succinic-semialdehyde-dehydrogenase.html

Cavernous carotid aneurysms

One third are asymptomatic at diagnosis, one third have headaches, and one third have cranial neuropathy (3,4,5,6). HA may resolve with gabapentin. Associations of include htn, multiple aneurysms, connective tisue diseases such as Ehler-Danlos s. type 4 and xanthoma elasticum.

Differential of trigeminal headaches &blink reflex

SUNCT (see separate entry)
Cluster
cervical (c2) myelitis with occipital headache
cavernous sinus syndrome-- aneurysms
pituitary tumor
cavernous sinus malignancy
MG

Evaluation of:
Blink reflexes were abnormal in 15 % of patients with atypical facial pain . 35 % of patients showed decreased habituation of the blink reflex. Thermal QST was abnormal in 55 % with abnormal facial pain and in all with trigeminal neuropathy. Blinks could help sort out brainstem and peripheral lesions, the trigeminal neuropathy patients. Source Forssell H et al. Neurology 2007; 69:1451-9. (authors are Finnish, and so am I)

Smallpox and bioterrorism and the neurologist

Variola infection requires only a few drops inhaled from oral, nasal or pharyngeal mucosa. Infected patients may shed virions one or two days before symptoms until all scabs and crusts are shed. They are most infectious in first ten days. It produces an asymptomatic viremia, followed by a toxic viremia when it spreads to the spleen and other organs.

Neurologic symptoms include splitting headaches with pain over whole or just lumbar spine, hallucinations, delirium, depressive psychosis, manic depressive states that all may last into convalescence. Ocular disease (variola residua) may be bilateral with loss of sight from leukoma adherens or complications causing enucleation .

Intravenous cidofavir which is nephrotoxic may be useful. Smallpox vaccine (vaccinia virus) within seven days after exposure (incubation period) can prevent or attenuate the disease. Contraindications to preexposure vaccination are immunosuppression, HIV infection, pregnancy, or household sexual contacts with contraindications. Such patients should get vaccinia immune globulin with smallpox vaccine, but it may be unavailable.

Postvaccinial encephalitis is seen almost exclusively in those getting primary vaccination. In kids younger than 2 it can occur in 6-10 days,with most patients dying. In those older than 2, it has 35 % mortality, or those who recover do so within two weeks. Strain used may be important. Authors favor preexposure vaccination and stockpiling of vaccinia immune globulin. Eczema vaccinatum results from vaccinating an atopic patient or contacts of someone with eczema.

Pitfalls-- confusing generalized vaccinia, vaccinia necrosum or eczema vaccinatum with true smallpox, therefore rapid development of a pcr test is needed. Another pitfall is vaccinating an immunocompromised individual, that may have a 33 % mortality.

Neurologic symptoms of anthrax

The major one is fulminant and rapidly fatal hemorrhagic meningoencephalitis. Fever with neurologic deterioration and dark necrotic pustules on the extremities, gram postive rods in CSF and multifocal cerebral bleeding, anthrax should be considered. Inhalational form is muchmore likely to cause the above than cutaneous forms. Death usually occurs within one week. Conversely, headache and confusion are common presenting signs.

Posterior thalamic hemorrhage and pusher syndrome

Karnath HO et al Posterior thalamic hemorrhage induces "pusher syndrome." Neurology 2005; 64: 1014-1019.
The syndrome occurs when stroke patients use an unaffected limb to "push" away from nonparalyzed side. Authors have found subjects with posterior thalamic stroke experience their body as upright when it is actually are tilted 20 degrees towards the lesional side. The result of the contraversive pushing is loss of postural balance and falling. The study involved about 46 thalamic stroke patients.

Forearm exercise screening test for mitochondria myopathy

Jensen TD et al. A forearm exercise screening test for mitochondrial myopathy. Neurology 2002; 58:1533-1538. Authors comapred 12 patients with MM to 10 with mucular dystrophy and 12 normal controls. All subjects performed intermittent handgrip exercise (squeeze one second, rest one second) for 3 minutes. Blood samples were collected from median cubital vein before during and after exercise to measure oxygen saturation and lactate levels. MM patients did not have the normal oxygen desaturation seen in other subjects. The lactate test did not show a significant change. The authors propose this as a sensitive and specific screening test for MM, almoot as good as muscle biopsy.

Localization of orgasmic seizures (aura)

Janszky J et al. Orgasmic aura originates from the right hemisphere Neurology 2002; 58:302-304. The authors reviewed 2 new cases and 22 already published. Among 15 with unilateral eeg foci, 13 (87%) had right and 2 (13%) had left hemisphere focus. The lesions included right temporal AVM, 3 had right postcentral parasaggittal focus. Authors comment on the rarity of auras have lateralizing value and this being an exception among epilepsies. Reviewing the chart, several patients had left hand or leg jerking, ictal speech, sitting, automatism, a sensation of fear. Authors believe amygdala is important, but that parasaggittal cases are due to stimulation of the cortical areas important for genital sensation.