Corticosteroids for bacterial meningitis

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.

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.

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.

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).

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.

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.

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.

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

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.

Localizing value of the abdominal aura

and its evolution. A study in focal epilepsies. Henkel et al. Neurology 2002; 58:271-276. Abdominal auras were more common in TLE than in extratemporal epilepsy. (52 % v 12 %). They also were more frequent in mesial TLE and than cortical TLE. Abdominal auras were followed by oral and manual automatisms in 100 % of patients with TLE and only 2/13 patients with extratemporal epilepsy. The evolution of an abdominal aura into an automotor seizure increases the likelihood (probability) of TLE to 98.3 %.

Immune reconstitution s. ass c PML/AIDS

MArtinez JV et al. Neurology 2006; 67:1692-1694. A patient with PML due to HIV received HAART and deteriorated. He developed enhancing lesions. HAART wa stopped for 2 weeks, and he was given dexamethasone 32 mg/day with slow taper, and partially imnproved.

Paraneoplastic syndromes involving the nervous system

Darnell R B and Posner JB. NEJM2003; 349:1543-54. Review article . Mechanisms of disease.

Authors discuss immune mediated diseases, affecting 0.01 percent of patients with cancer. However some are more common. LEMS affects 3 % of patients with small cell lung cancer, and mg affects 15 % of patients with thymoma, and demyelinating neuropathy affects 50 % of patients with sclerotic form of multiple myeloma (rare form).

Neurologic condition usually appears first, and cancer searches may be unrewarding, and whole body PET scan should be considered. CSF pleocytosis may dissipate but elevated IgG may persist. The predominant cell type is T cells.

Clinical conditions include
Limbic encephalitis
brain stem encephalitis
cerebrellar degeneration
opsoclonus-myoclonus
visual syndromes ((cancer associated retinopathy and ON)
Parkinsonism
necrotizing myelopathy
inflammatory myelitis
motor neuron disease
subacute motor neuropathy
stiff person syndrome
sensory neuronopathy
autonomic neuropathy
acute sensorimotor neuropathy
polyradiculpathy (GBS)
brachial neuritis
chronic sensorimotor neuropathy
vasculitic neuropathy
neuromyotonia
LEMS
myasthenia gravis
polymyositis
dermatomyositis
necrotizing myopathy
myotonia.


Antigens that are present do not cause neurologic disease unless they cross the blood brain barrier and react with neurons expressing the onconeural antigen.

Pearls
patients with Hu antigens mayhave small cell lung cancer restricted to a nodule despite that most small cell lung cancers are metastatic at diagnosis. The prognosis of the cancer may also be better, even, eg. among patients with anti Hu antibodies who lack a paraneoplastic syndrome. T cells are critical elements of the response. They may be activated by apoptotic tumor cells. In a few conditions, antibody responses are more important, including LEMS, MG and a rare form of cerebellar degeneration. These forms have antigens that are cell surface receptors. Anti Sox antibodies are thought predictive of SCCL in LEMS

Immune treatments are widely used but not known to be effective. Keine-Guibert protocols IVIG .5 g/kg for five days, iv methylprednisolone at 1 g/d for 3 days and iv cyclophosphamide at 600 mg/m(2) of body surface area for one day on day 4. The treatment can be repeated if it appears effective, at 3 week intervals, or if prednisolone was effective, using one day per month of ivig/steroid/cytoxan together. Also used is tacrolimus, .15 mg/kg/d for 14 days, then .3 mg/kg for 7 days.

SUNCT syndrome and SUNA syndrome & PH

These are grouped as trigeminal autonomic cephalgias, together with cluster headache. (TACs)

SUNCT= short acting unilateral neuralgiform headache with conjunctival injection and tearing. Usually SUNCT headaches are retroorbital with stabs, groups of stabs or sawtooth pain and may occur 3-200 times per day and last 15-240 seconds. They are strictly unilateral and may resemble paroxysmal hemicrania, cluster headache or trigeminal neuralgia. They may resist treatment although in one case in Neurology a patient responded to topiramate, AAN2009 lamictal was reported as drug of choice. Men experience it more in a 2:1 ratio, whereas paroxysmal hemicrania occurs more in women and last 15 minutes v. less than a minute for SUNCT. The location of the pain is supraorbital, orbital, retroorbital, temporal, in the top or side of the head, in a V2 or V3 distribution, or in the teeth, neck or ear. All patients have conjunctival injection and tearing. GBN also has been used. Neurology(2002) patients with pituitary tumors (adenomas) after beginning therapy with bromocriptene. Other cases are triggered by exercise. In the above series, authors speculate that extension of the tumor into the cavernous sinus may be contributory.

In Cohen AS et al, Brain 2006 (129:2746-2760) a series of 43 patients were reported with SUNCT and 9 with the less known SUNA syndrome. 2 SUNA patients had tearing, 4 had conjunctival injection but none had both. Other cranial autonomic features seen include nasal blockage, rhinorrhea, eyelid edema, facial sweating, flushing or ear flushing. Most patients did not have a refractory period between attacks and were agitated with the attacks. Pain severity is greater in SUNCT than SUNA. In general analgesic overuse ought to be avoided.


SUNA stands for "Short-lasting Unilateral Neuralgiform headache Attacks with cranial autonomic symptoms." Occassionally it can present with Horner's syndrome.

Other pearls for diagnosis: ipsilateral photophobia and phonophobia differentiates TACS from migraines. Interictal pain occurs in one third, often those with personal/family history of migraine. In patients with cluster headache, more than half have OSA so do a sleep study. TAC like pain occurs at a very high rate with pituitary tumors, so MRI with pituitary thin cuts is indicated.

Paroxysmal hemicrania (PH) has a unilateral brief headache attack that occurs several times daily. It most often but not exclusively affects first division of trigeminal nerve. It lasts 2-30 minutes (longer than SUNCT/SUNA) with 1-40 attacks per day, and may be episodic in 20 percent (attacks for up to a week with a month or more remission between) or chronic in 8- percent with no remission of remission of less than a month. Distinctively, it responds to indomethacin.

(I try to AVOID basic science but) common to all 3 is activation of posterior hypothalamus on all syndromes.

Symptomatic (or secondary) TACs occur rarely, and clinical features alerting to possibility include atypical phenotype, abnormal exam, and refractory to treatment. Summarized by Cittadini et al (Neurologist 2009; 15: 305-312) include historical points such as unusual triggers such as postprandial, or sitting or standing; altered consciousness, impotence, galactorrhea, acromegaly, fever, and purulent nasal discharge. Physical signs included opthalmoplegia, optic atrophy, temporal hemianopia, Adie syndrome, swelling of the eye, persistent partial or complete Horner's syndrome, absent nasal tickle reflex, signs of acromegaly, testicular atrophy, and absent radial pulse. In PH atypical features included onset with carotid massage (gangliocytoma extending to carotid artery from pituitary lesion).

Since one in ten patients may have incidental pituitary microadenoma and one in 500 an incidental macroadenoma, the role of imaging may be less certain, with decided risk of unknown importance of discovering and treating an incidental finding.

AAN 2010 suggested SUNCT/SUNA responsive to occipital stimulator

Applause sign is specific clinical test for PSP

Dubois B et al. "Applause sign" helps to discriminate PSP from FTRD and PD. Neurology 2005;64: 2132-2133. When asked to clap three and only three times as quickly as possible, after demonstration by examiner, an inability to stop clapping indicates PSP. Clapping from 4->10 times is abnormal. An applause sign was seen in 71 % of patients with PSP but none with FTD or PD.


a separate article described superior cerebellar atrophy in PSP

Drop attacks due to superior canal dehiscence

Brantberg K, Ishiyama A, Baloh RW. Drop attacks secondary to superior canal dehiscence syndrome. Authors describe 2 patients. They note drop attacks occur in late Meniere's syndrome but can be early as well with vestibular dysfunction and normal hearing. They are in these cases associated with a sensation of being pushed or environmental tilts.

SCD is a peripheral audivestibular disorder manifested by sound and pressure induced vertigo due to absent bone coverage at the apex of the semicircular canal. The diagnosis is by inducing vertical or torsional eye movements in the plane of the superior canal when exposed to sounds or pressure changes. High resolution CT shows bony dehiscence in canal. Audiological tests show increased threshold in the low frequency range for air but not bone conduction.

The 2 patients described with unprovoked drop attacks not provoked by coughing, straining or loud noises (Tullio phenomenon).

Malignant transformation in MGUS

Eurelings M et al. Maligannt transformation in polyneuropathy associated with monoclonal gammopathy. Neurology 2005; 64:2079-2084.
Of 193 patients with MGUS and polyneuropathy, 17 had a hematologic diagnosis at onset. The rate of transformation in the remaining patients was 2.7 % per year. Independent predicting factors associated with transformation were progressive neuropathy, weight loss, fevers, night sweats and Mm-protein level.
Notes: diagnotic criteria for MGUS include M proteinlevel< 30 g/dl, bm plasma cell infiltrate of less than 10 %, absent lytic lesions in bone, anemia, hypercalcemia, renal insufficiency, and stable M protein level, as well as absent fatigue, weight loss, bone pain or susceptibility to infections. There was no effect of IgG v IgA or kappa v lambda

Intermittent third nerve palsy ddx

Cluster HA
cryptococcus n. infection meningitis
aneurysm
cavernous sinus lesion
pituitary lesion
trauma
diabetes

Laryngospasm in Kennedy Syndrome

Sperfeld AD et al. Laryngospasm. An underdiagnosed symptom of x-linked spinobulbar muscular atrophy. Neurology 2005;64: 753-4. L is defined as the sudden onset of the sensation of the inability to move air in and out, lasting a few seconds and followed by stridor. It occurred in 23/49 patients surveyed with KS. Itsalso associated with GERD.

Paparounas K. Kennedy disease: insights and conclusions. Arch neurol (correspondence) 2004;61: 603. Distinctive features that are virtually pathognomic of the disease include (in the originally cited article) endocrine features such as gynecomastia. The author states that perioral fasciculations and facial fasciclations are present in 95 % of patients and are "highly characteristic if not pathognomonic." Its not found in any other disease. KD patients also have decreased vibratory sense, especially in the feet, even among patients without sensory dysfunction. The original author responded that perioral fasciculations are a late finding.

The diagnosis of Kennedy syndrome or SBMA (spinal bulbar muscular atrophy) by a simple blood test (Athena) is important because SBMA has a much more benign course with a 10 year survival of 82 % with no PEG use and only rare CPAP use. (Chahin et al. Neurology 2008:70:1967-1971.

Segawa disease DYT 5

AD guanosine triphosphate cyclohydrolase I (GTP-1_ deficiency. Thsi is a hereditary doap response generalized dystonia, typically with onset in childhood, that responds to low dose levodopa. It is due to partial deficiency of tetrahydrobiopterin.

Clinical pearls include the presentation with equinovarus by age 6, and four extremity dystonia by teens, difficulty with hand pronation/supination, marked diurnal fluctuation, and rarer findings such as writer's cramp or guitarist's cramp. Adult onset may have bradykinesia,, tremor mimicking PD, or focal hand dystonia.

Rheumatoid pachymeningitis

Starosta MA et al. Clinical manifestations and treatment of r.p. Neurology 2007;68:1079-1080.

Disorder can occur early or after many years of RA, RF and ESR are usually elevated but the esr may be only middling. The usual presentation is headache or cn palsy esp cn 8. On biopsy, unlike autopsy, nodules are infrequently found, in dura, and path showsx inflammatory cells, fibrosis. In autopsy series, the finding is nodules with central necrosis with histiocytes and mononuclear esp. plasma cells. Treatment with prednisone and other drugs (MTX, cytoxan) are effective.

Rash to yellow dye in levodopa-carbidopa

Chou KL , Stacy MA. Skin rash associated with simemet does not equal levodopa allergy. Neurology 2007; 68: 1078-9. Patients experiencing a rash on sinemet requiring stopping and rechallenging were actually allergic to a yellow dye (D&C Yellow 10 and FD&C Yellow 6) and were able to tolerate forms of levodopa not containing the dye. The safe forms included C/L 25/250 or 10/100 , CR forms of Sinemet, Stalevo and Parcopa, or Madopar (benserazide/levodopa).

ALS pearls-- ALS mimics

spondylitic myelopathy -- limb fibs should go away within six months of fixing spine

inclusion body myositis pearl check finger flexors esp FPL FDP, forearm atrophy and check for absent fascics and symmetry

spinal cord AVM

heavy metal intoxication -- lead-- check for basophilic stippling and consider treatment with dmpa

lymphoproliferative disorder

multifocal motor neuropathy with conduction block (anti GM1 seen in about half) rsponds to IVIG

vasculitis

motor polyradiculopathy

infectious (polio, WNV)-- EMG shows poor recruitment, then fibs in 4-6 weeks

Bulbospinal mononeuropathy (Kennedy's syndrome) X linked, presents in men with symmetrical weakness, atrophy and fasciculations of bulbar and proximal limb muscles, testicular atrophy and gynecomastia.Occurs early, diagnosed by a CAG repeat, and is associated with a normal lifespan. Consider in males with slow course. Fascics are more pronounced in this disorder, but its all LMN.

Spinal muscular atrophy (Werdnig Hoffman, Kugelberg Welander)-- kids, young and old adults

Progressive lateral sclerosis (UMN variety) is associated with a normal lifespan

Benign fasciculations

cramp fasciculation syndrome-- easily treated with membrane stabilizers

Monomelic atrophy-- focal variant

frontotemporal dementia- identical path finding seen by Neumann ALS spectrun disorder?

Machado Jospeh disease= spinocerebellar atrophy tpe 3. See prominent anterior horn disorder plus ataxia and myelopathy

polyglucosan body disease-- rare UMN and LMN findings plus sensory changes and shite matter changes on MRI, with rare glucosan bodies seen on sural nerve biopsy.

Acid maltase deficiency may mimic PM abnormal respiratory muscles.

Syrinx

true neurologic TOS thoracic outlet syndrome -- shows decreased median CMAP, normal median SNAP, decreased ulnar SNAP, decreased medial antebrachial SNAP; needle shows median > ulnar hand involvement; lower trunk median/radial innervated forearm muscles (FPL, EIP)

myofibrillar myopathy-- = Desmond's myopathy-- mimics IBM. Get quad atrophy, medial gastroc, dysphagia, atrophy of VM/VL but rectus femoris is spared and is normal

Sensory Guillian-Barre Syndrome

Oh SJ, LaGanke C, Claussen GC. Sensory Guillian Barre. Neurology 2001; 56:82-82. Describes eight patients collected with a sensory equivalent of classical GBS. These patients had acute onset of a sensory ascending neuropathy that peaked within 4 weeks, generally had an antecedent viral illness, areflexia, CSF albumen-cytologic dissociation, demyelination in at least two nerves, (esp MOTOR nerves), favorable outcome. 3 patients were treated with immunomodulatory treatments.

Neck pain and calcium deposition

Nodera et al. Neurology 2007; 68:383 (Neuroimages). Japanese. A 43 year old man had neck pain, sore throat, dysphagia, and low grade fever upon awakening. He had limited ROM of the neck. CT showed calcification ANTERIOR to C1-2 with thickened prevertebral tissues due to effusion. Retropharyngeal calcific tendinitis is uncommon and confused with abscess but the characteristic calcium deposit is diagnostic. It is self limiting.

Paraneoplastic cerebellar degeneration antibodies

Anti Yo (PCA-1) ovarian and breast cancer; anti Tr antibodies -- Hodgkin's lymphoma; also for Hodgkin's lymphoma: Anti-mGluR1 and Anti Zic4 antibodies. Above are PREDOMINANTLY associated with PCD. SOMETIMES associated with PCD are anti VGCC (LEMS, small cell lung cancer); anti Hu (ANNA-1)(encephalomyelitis, PCD, sensory neuronopathy) (small cell lung and other CA); anti Ri (ANNA 2) (PCD, brainstem encephalitis; paraneoplastic opsoclonus/myoclonus)(breast, gyne and small cell CA);anti CV2/CRMP (encephalomyelitis, PCD, chorea, PN, uveitis)(small cell lung, thymoma, others); anti MA protein (limbic, hypothalamic, brainstem encephalitis, infrequently PCD)( testicular, lung and other cancers); antiamphiphysin (stiff person s, encephalomyelitis, PCD) (breast and small cell) CHART is FROM NEJM 2007; 356:612-620. MORE Tumors with anti Yo antibodies express Yo antigen which is a cytoplasmic protein called CDR2 that interacts with c-Myc. It is expressed in the Purkinje cells of the cerebellum and the large neurons of the brainstem. It sequesters c Myc and downregulates; disruption with antibodies may increase c Myc activity leading to apoptosis (although the T cell immune response may also be important).

rapidly progressive ataxia ddx

in immunocompentent patients:

stroke,
multiple sclerosis
sarcoidosis,
primary or metastatic diseases,
paraneoplastic disorders,
toxins/drugs (lead, anticonvulsants, salicyclates, aminoglycosides, sedatives, fluorouuacil, cytarabine),
Miller Fisher syndrome,
infection (HIV, viral/postviral cerebellitis, Creutzfeld Jacob disease, progressive multifocal leukoencephalopathy),
alcoholic cerebellar degeneration, thiamine deficiency,
autoimmune ( SLE, Sjogrens, Hashimoto's disease, cerebellar ataxia with anti GAD or antigliadin antibodies).

Lack of utility/overuse of muscle biopsy

Filosto M et al. The role of muscle biopsy in investigating isolated muscle pain. Neurology 2007; 68:181-186.
editorial Kissel JT. Muscle biopsy in patients with myalgia. Neurology2007; 68:170-171.

Filosto et al. reviewed clinicals and neuropath on 240 patients presenting with muscle pain isolated or cramping. 80 % had biopsy abnormalities but only 20 %got a specific diagnosis and only 6 % a specific myopathy. Patients with obvious causes eg. statin use were excluded before analysis. CK levels and EMG did not predict pathology. Patients need to go under rigorous selection prior to biopsy.

cryoglobulinemic vasculitis PN

Gemignani F et al. Clinical spectrum of cryoglobulinemic neuropathy. JNNP 2005; 76:1410-1414.

Most common presentation is middle aged female patients who develop small fiber sensory neuropathy (73%). Less often, then sensorimotor neuropathy (18 %) then least often, mononeuritis multiplex (8%) occurs. Symptoms were tingling paresthesias (55%), sensory ataxia (38%), thermal dysesthesias (42%) pain (42%) and RLS (45 %). 29 % were asymmetrical. Patients did not have autonomic dysfunction.


Study occurred of 71 patients referred to academic center. Cryoglobulnemic syndrome was defined as intense recurring purpura and cryocrit>5 %, and "mild" syndrome with minimal purpura and cryocrit <5%. 46 % presented with PN. Hepatitis C caused the cryoglobulinemia in more than 90 %.

Comment--most cases were noo biopsied.

Mimics of GBS Part II

Chemical toxins
vacor (rodenticide)ingested due to homicidal or suicidal intent. Impairs fast axon transport. Clinical findings are initially abdominal pain, nausea, vomiting, necrosis of pancreas beta cells causes hyperglycemia, rapid distal motor/sensory/Autonomic neuropathy with weakness, areflexia, dysesthesias, OH, urine retention, and cranial neuropathy, then later stupor, EEG changes, DKA, EKG changes. Long term residua often include DM and ANS dysfunction. Acute tx is gastric lavage and induced emesis.

Organophosphates -- found in malathion, parathion, dursban. 10-20 days after exposure they produce a distal axonopathy, calf cramps, extremity paresthesias and distal weaknesss. A SEPARATE syndrome is NMJ disorder with cholinergic toxicity and respiratory insufficiency.

n-Hexane solvent associated with glue sniffing and industrial exposure. Clinical includes distal sensory loss and severe weakness that progresses for months after exposure ends.

Drugs
CV-- amiodorone, streptokinase
Hem-- cytarabine, suramin.

amiodoarone chronic progressive predominantly distal s-m neuropathy. NCS show distal latency prolongation and slowing to 11 m/s. Dose is 200-400 mg per day.

streptokinase-- 10-20 cases, 10-20 days after exposure, paresthesias of hands and feet, cndxn blocks, elevated CSF protein, coincident to peak SKN titers, dramatic response to IVIG.

cytarabine-- 0.6 % of cases with doses more than 200 mg/m2/d. progressive distal sensorimotor neuropathy, hours to days after last treatment.

Suramin -- PN in 40 % of patients with levels> 350 ug/ml Rarely GBS like presentation.

Vasculitis
Churg-Strauss s-- may resemble GBS. Eosinophilia is seen. Tx with pred/MTX. Asthma, vasculitic lung involvment, eosinophilia and mononeuropathy are common but not universal.

Other cryoglobulinemia, PAN.

AIP-- Motor PN.
Refsums
Diptheria ("extinct" in US, present in developing countries)
Poliomyelitis--
West Nile Virus
Botulism
WNV
CMV polyradiculopathy
critical illness myopathy
critical illness neuropathy
Myelopathy

AIDP atypical forms and mimics PT I

Levin KH. Variants and mimics ocf Guillian Barre Syndrome.The Neurologist 2004;10:61-74

typical case AIDP: febrile antecedent esp. campylobacter jej, CMV, EBV, infl, mycoplasma, coxsackie, hepatitis virus. Other noninfectious causes include Hodgkins dis, and events such as surgery, childbirth, and immunization. Within 2 weeks, get symmetric leg paresthesiae, tingling, crawling sensations, pain esp in back (50%), ascending weakness. 50 % develop weakness diaphragmand cranial nn. > 50 % have autonomic findings. CSF dissociation acellularity, increased protein, and typical NCS (not detailed here).
Variants: asymmetric; pure motor; prominent sensory loss; preserved DTR's; regional presentations (pharyngeal/brachial/cervical); paraparetic; facial diplegia with paresthesias; pure sensory neuropathy; pure autonomic neuropathy; Miller Fisher variant; axon loss variants (AMAN, AMSAN).
Miller Fisher syndrome-- triad opthalmoplegia, areflexia, ataxia (follows sensory loss). NCS show loss of SNAP amplitude. Course is often benign,maynot require IVIG/Plasmapx. may include facial weakness, dysarthria, dysphagia, abnormal pupils, limb weakness. 95 % have ANTI GQ1B antibodies.
AMAN-- Chinese disease-- NCS show motor amplitude loss without demyelination. High correlation with campylobacter. Antibodies to GD1a and GM1 at node of Ranvier. Involves complement activation and macrophage infiltration.
AMSAN-- cannot differentiate from AMAN until enough time has elapsed to show NCS findings. Typically this does not respond to IVIG/plasmapx.

Mimics:
tick paralysis-- notoriously overlooked in children, esp preadolescent girls. Ticks may infest scalp. Symptoms develop 2-4 days later including paresthesias, gait ataxia, diplopia, dysarthria, rapid weakness. Tick is dermocenter andersonii. Paralysis reverses within 24 hours of tick removal. Australian ticks cause paralysis that lasts longer. NCS show reduced CMAP amplitudes.

marine toxins-- ciguatoxin (diflagellates eaten by algae), tetrodotoxin (pufferfish) and saxitoxin
(dinoflagellates eaten by shellfish)cause paresthesias and weakness within hours. NCS show slow motor/sensory responses (mimics GBS) and dispersed CMAP.

buckthorn berry-- in SW USA and Mexico. Affects children and cattle causing rapid weakness within a few weeks. Limited amt published.

heavy metals (esp arsenic, gold, thallium).
Arsenic-- 7-14 days after ingestion. presents with N/V/D paresthesias, burning, then stocking glove loss small and large fibers. Weakness is distal to proximal and lead to footdrop. Predominant axon loss, Occassional ans dysfunction.
Gold-- usually secondary to RA treatment. PN, with pain, may be sudden or slow, with or without dermatitis and stomatitis.
Thallium-- usually deliberate ingestion (may be accidental in kids) or due to mal intent. Causes dermatitis, alopecia (usually a LATE finding), GI (N/V/D), CNS (ON, confusion, movement disorders, psych), acute and chronic PN. Starts with painful paresthesias and painful joints, ascending weakness, possibly normal DTR's, autonomic dysfunction

CNS complications of HPCT

Denier et al. Spectrum and prognosis of neurologic complications after hematopoeitc transplantation. Neurology 2006;67: 1990-1997.

Modern study. Ablation of bone marrow with allogeneic grafts are treated with prophylaxis against previously common events such as veno-occlusive disease and pulmonary complications. Now neurologic disease is a major cause of M/M. They occurred in about 16 % of patients receiving HPCT, usually opportunistic infections. Toxoplasmosis was the most common cause (33%) with others getting viral encephalitis, HSVE, and less commonly, metabolic encephalopathy, stroke, peripheral nervous system dysfunction.

Spinal epidural abscess

Darouiche RO. Current Concept: Spinal epidural abscess NEJM 35;19 2012 Nov 9 2006

Article concentrates on bacterial causes. Most patients have predisposing risk factors: DM, ETOH, HIV, drug abuse intravenous, DJD, surgery with instrumentation, placement of stimulators, or potential local source of infection (skin, soft tissue, indwelling catheter, UTI, sepsis). Entry is contiguous spread (1/3) or hematogenous (1/3). Two thirds are staph aureus, 40 % of those Methicillin resistant (MRSA). These are especially common a few weeks after implantation of devices.

Other causes: St epidermidis, e coli, Ps aer., rarely actinomyces, nocardia, mycobacteria, fungi, (candida, aspergillus) parasites (echonococcus and dracunculus). A letter writer added brucellosis as a cause in Spain, Italy and the Near East.

Spinal cord injury can occur either by mechanical compression of vascular occlusion due to septic thrombophlebitis.

Clinical staging system: stage 1, back pain at level; stage 2, nerve root pain of affected level; stage 3, motor weakness, sensory loss, or B/B dysfunction at affected level; stage 4, paralysis. 3/4 have back pain, fever present in half, neurologic dysfunction in one third. Stage 2 is "enigmatic" in thoracic cases. Duration/rate of progression is highly variable but can be extremely rapid.

Abscesses favor large epidural spaces with infection prone fat, and therefore are more common in posterior than anterior and thoracolumbar than cervical. Lumbar even more common due to epidural injections. Generally they extend over 3-4 levels or more.

Diagnosis is by drainage. Sed rate is always high. Differential diagnostic conditions ( osteomyelitism discitis, sepsis, endocarditis) also have S aureus bacteremia. CSF cultures are negative in 75%. Blood cultures are usually positive. Risks of LP includes causing meningitis by introducing infection through the meninges or causing deterioration if tapped below a block.

MRI with contrast is preferred procedure although myelography has > 90 % sensitivity. Spine CT can be done in conjunction with and may suggest changes of osteopmyelitis.

Frequent misdiagnoses include: osteomyelitism discitis, meningitis, UTI, sepsis, endocarditis, disc prolapse, DJD, spinal tumor, transverse myelitis, spinal hematoma. These are made because patient is neurologically intact.

Treatment: medical v. surgical. No trials done. Medical treatment indicated if patient has high risk of surgery, has panspinal infection, or paralysis for more than 24 hours, or if agent is identified and his condition is monitored closely. Surgery can be a limited laminectomy if patient has a panspinal infection. Empiric coverage should include coverage against MRSA, against gram negative bacilli (with a third or fourth generation cephalosporin such as ceftazidime). Letter writer added that medical management was safe as long as the patient didnot deteriorate.

Statistics: 4-22% get irreversible paralysis. 11-75 % are initially misdaignosed.

The most important predictor of outcome is patient's status just before surgery. Patients who undergo surgery in stage 1 or 2 are expected to remnain neurologically intact.