vincristine neuropathy nuggets and pearls

Verstappen CCP,Heimans Koeppen S, et al. JJ,  Dose-related vincristine-induced peripheral neuropathy with unexpected off-therapy worseningNeurology March 22, 2005 vol. 64 no. 6 1076-1077

 

Article described microtubule related neuropathy due to vincristine in 114 patients. 

 

1.  High dose group experienced more signs and symptoms than low dose group.

2.  Off therapy worsening signs and symptoms occurred in about 30 percent, mostly in the first month off. Most patients improved off therapy however.

3.  Paresthesias and numbness in both groups developed earlier in hands than feel and were more prominent in hands

4.  Paresthesias, numbness and pain occurred at more than 50 percent in both groups

5.  Resulting physical limitations include trouble buttoning clothes, climbing stairs, writing and walking

6. The dose intensity of VCR has changed considerably over the years. Studies 30 years ago describe dose intensities of 2 to 4 mg/week, frequently leading to a severe mixed sensorimotor peripheral neuropathy.Today, VCR is usually administered in a dose of ≤2 mg once every 1 to 4 weeks.

7.  Off therapy deterioration is also well described in cisplatin and paclitaxol related neuropathy.

 

 

 

 

Sjogren's Pearls

J. Birnbaum. Peripheral nervous system manifestations of Sjogren syndrome: clinical patterns, diagnostic paradigms, etiopathogenesis, and therapeutic strategies. The Neurologist 2010; 16:5:287 -- 297 .

1.Syndromes that can cause sicca symptoms and which should be typically excluded, include hepatitis B or hepatitis C, HIV, sarcoidosis, and a history of radiation to either the header the neck.

2. 30% to 50% of patients have negative auto antibodies and require a lip biopsy for diagnosis.

3.  Sensory ganglionapathy : aka sensory  neuronopathy is dramatic with isolated or disproportionate impairment of kinesthetic awareness, with profound handicap of proprioception, even affecting the larger joints. Sensory deafferentation can cause patients to become wheelchair-bound, or have pseudoathetoid movements which may be misdiagnosed as a movement disorder. The most common presentation is distal dysesthesias.  Differential diagnosis includes paraneoplastic syndromes, Bickerstaff brainstem encephalitis, and effect of drugs for example, cisplatin and pyridoxine. Nerve conduction studies typically absent sensory nerve action potential(snaps) and preserved compound motor action potentials (cmap). T2 hyper intensities in the dorsal spinal cord are described. Response to I VIG is inconsistent.

4.  Small fiber neuropathy: the cardinal feature can be excruciating burning pain. There is disproportionate or selective impairment in pinprick and temperature with preserved vibratory sense and proprioception. The onset is subacute or chronic usually. The differential diagnosis includes diabetes, amyloidosis, chemotherapy and other medications, genetic syndromes (i.e. Fabry's) and complications from HIV treatment.

5.  Patients with findings of small fiber dysfunction disproportionally affecting the proximal extremities, torso or face in unorthodox patterns may have Sjogren's. Patients may also have classic length dependent symptoms.

6.   Sjogrens and vasculitis: patients with mononeuritis multiplex should be evaluated for cryoglobulinemia especially with high titer rheumatoid factor, with disproportionate C-4 hypo-complementemia, or normal C-3. Small vessel vasculitis and low levels of C-4 complement in Sjogren's space placed the patient at 6 to 40.  fold risk for non-Hodgkin's lymphoma. Therefore the development of systemic features such as fever or weight loss merit close scrutiny. Nerve or muscle biopsy showing vasculitis more likely responds to immunosuppressive therapy. Mori described patients with axonal MMN who also had cranial neuropathies. The most common is trigeminal neuropathy  which may be indolent, progressive, or bilateral. The unifying feature may be ganglionapathy.  Facial nerve also may be affected. Acute cranial neuropathy plus rapid multiple mono neuropathies may prompt concern for vasculitis.

7. Demyelinating neuropathies are rare but may be noted subclinically. EMG may know isolated prolonged F. waves.
8. Autonomic features are seen in 50% of Sjogren's patients. Inquire about urinary frequency or hesitancy, erectile dysfunction, increased or decreased sweating, orthostatic or temperature intolerance, constipation or increased bowel movements. Adie's pupil , space orthostatic hypotension, and abnormal sweating occurs in 57, 40, and 70% of patients with sensory neuronopathy respectively.

9. Anti-nicotinic ganglionic receptor antibody role is under investigation in Sjogren's. This antibody differs from the anti-muscarinic receptor antibody seen in myasthenia gravis.

10. Inflammatory myopathies occur only in 1 to 2%. Myalgias  may be caused by autoimmune thyroid disease, vitamin D. deficiency, or fibromyalgia. Always assess vitamin D level. Vitamin D may be low due to malabsorption, bacterial deconjugation of bile acids due to gastric motility seen in autonomic neuropathies, type one renal tubular acidosis or coexisting celiac sprue.

Clinical utility of seropositive voltage gated calcium chanell complex antibody

Jammoul A, Shayya L, Mente K et al.  Neurology Clinical Practice  2016; 6:409-418.

Authors differentiate "classic" group with limbic encephalitis or neuromyotonia (9.6% of total) and note the others had a panoply of diagnoses that were nonclassic.  The classic group was more likely to have high titers of ab, but there was overlap.  91 % of lcassic and 21 % of nonclassic had levels > 0.25 nM.  75 % of patietns in high level ab group had autoimmune disorders, and 75 % of patients with low level titers did not.  26 % of patients had a remote malignancy (active, remote, solid or hematologic) but not ab titer difference was noted among the groups . 

Conclusions:  1.  High VGKC ab levels are found in patients with classic and other autoimmune disorderes,  Low level ab titers are seen in nonspecific and mostly nonautoimmune disorders

2.  The presence of VGKC antibodies rather than the level may serve as a marker of malignancy

Notes this is bad on a chart review of 6,032 patients who underwent evaluation . 

The nonclassic group includes PNS and CNS diorders including neuropathy, dementia, ALS, CJD.  Some patietns had nonspecific symptoms such as stutering speech, nausea and vomting and orthostasis without diagnosis of neurologic disease. 

Cancers were oftendiagnosed due towhole body CT/PET; 2 patietns had previously unknown cancer (Ovarian and lung).  Cancer occurred more commonly in those over age 45.  Many cases of ab finding were remote by over ten years from actual tumor.

Clinical spectrum of voltage gated potassium channel (VGKC) autoimmunity

Tan KM, Lennon et al. Neurology 2008; 70:1883-1890. 

80 patients were found, 71 with clinical information available.  Mean age 65.

Neurologic symptoms were subacute or chronic including

1.  cognitive impairment 71 %-- see below

2.  seizures 58 %-- several types

3.  dysautonomia 33 %

4.  myoclonus  29 %

5.  dyssomnia 26 %

6.  peripheral nerve dysfunction 25 %

7.  EPS 21 %

8.  brainstem/cranial nerve dysfunction 19 %-- vision loss/blurred vision, diplopia, dysarthria, hemifacial spasm, facial numbness, anosmia.

9.  hypothalamic involvement-- 38 %-- hyponatremia (36 %) , hyperphagia, (8%) 

Common misdiagnosis was CJD (14 %)..  Other misdiagnoses:  viral encephalitis, recurrent TGA, generalized anxiety disorder, conversion disorder.

Associated tumors (paraneoplastic) 33 % confirmed histologically

carcinoma 18, adenoma 5, thymoma1, hematologic 3.

Associations

hyponatremia  36 %

other organ specific autoantibodies 49 %

coexisting autoimmune disorder 33 % (thyroiditis, DM)

34/38 responded to immunotherapy, half "vigorously" so.

Classic reports of association:

1.  Morvan's syndrome

2,  acquired neuromyotonia

3.  epilepsy

4.  limbic encephalitis

5.  dysatuonomia

6.  lung carcinoma
7. FACIAL BRACHIAL DYSTONIC SEIZURE

Cognitive presentation:

1.  frontosubcortical (personaltiy change, disinhibition,  executive dysfunction) 13 %

2.  Visual hallucination (10 %)

3.  Depression or agitation (13 %)

Treatment of orthostatic hypotension in Parkinson's disease

Source: Neurology 2009 supplement cited above, p.S83

 

1. Consider a role for medication, including selegeline, levodopa, DA agonists and MAO inhibitors.

2.  Increase sodium intake, especially in daytime.

3.  Avoid lying flat which leads to release of renin. Elevate HOB and legs.

4.  Postprandial hypotension can be avoided with small meals, with low carbohydrate intake and avoiding alcohol

5.  Caffeine with breakfast can be helpful

6.  Heat related vasodilatation, vasovagal activities (straining at stool, playing wind instruments, singing all can be considered/limited if applicable.

7.  Isometric exercise especially swimming

8.  Avoid knee high TEDS, consider waist high Jobst stockings or abdominal binders.

 

Medication:

1. Florinef up to 0.5 (start with 0.1 mg).

2. DDAVP 5-40 ug intranasally at bedtime can be tried.  Monitor Na+ in first 4-5 days of treatment and monthly thereafter.  It can cause a severe and life threatening hyponatremia.

3.  Midodrine, start at 2.5 mg per day, do not go above 10 tid, and do not give at bedtime.

4. Erythropoietin 4,000 units biw especially if anemic also.

5.  End of dose sweating can be an "off" phenomenon and can eb treated with more dopamine.

Treating constipation in Parkinson's disease, and urinary problems

Regimen suggested in Neurology 72:21:2009 S4 pp S80-81.

Bowel:

Management consists of dietary changes, exercises and pharmacotherapy.

1.  Dietary changes-- Increase bulk, and soften stool.  Drink 6-8 glasses of water per day.  Increase fiber, decrease baked goods.  @ meals should have high fiber raw vegetables.  Oat bran can be used.  Exercise, including walking, is encouraged. 

 

If stools remain hard, docusate, or lactulose 10-20 grams per day can be used.  Miraelx (otc) can be used.  Patients should be educated about possibble delayed onset and reminded to do the things in paragraph one above. 

 

Third line is milk of magnesia and other laxatives or enemas.  Apomorphine rescue therapy can be used. 

 

Urinary:

Nocturia is earliest problem, then urgency, frequency and hesitancy.  Consider detrusor hyperreflexia v. incomplete/delayed relaxation of the pelvic floor.  Supine hypertension can also cause pressure natriuresis.  Incomplete emptying can be an "off" symptom. UTI should be considered if any change occurs in symptoms. 

 

Avoid nighttime water drinking.  Try Detrol or Ditropan.  Midodrine can worsen symptoms due to increasing sphincter tone.  Diazepan, baclofen or dantrolene can be used to relax sphincter tone occassionally. 

 

neurodoc

Diagnosis of parkinsonism

Classic criteria indicate the triad of resting tremor, akinesia/bradykinesia, and cogwheel rigidity, with two of three being associated with the diagnosis of Parkinson's disease.  At the London Brain bank, the diagnosis was not confirmed in 24 of 100 patients with these premorbid clinical symptoms (Hughes et al., JNNP 1992).  The alternative triad of parkinsonism, assymetry, and response to levodopa correctly identified 98 % in 73 patients reported in a subsequent trial (Hughes et al., Brain 2002) and was therefore considered better. 

 

neurodoc

Optic atrophy helpful hints

 

from AAN 2010 course

differentiate pallor from atrophy

 

segmental patterns

signs of prior disc-- swelling high water marks and gliosis, fuzzy edges,

collateral venous vessels-- retinal choroid collaterals, AION or post pappilledeme

macular exudates pretty "fireworks" around macula

attenuated arterioles-- "ghost vessels" with  gliosis

 

neurodoc

mimics of optic atrophy

from aan course 2010

 

physiologic temporal pallor

aphakia/pseudoaphakia-- after take out lenses after cataract surgery

anemia

myopic discs

optic nerve hypoplasia

myelinated optic nerve fiber layers

 

neurodoc

neuropthy downloads UTAH

http://library.med.utah.edu/NOVEL/

 

neurodoc

MGUS Pearls

from Ramchandren S, Lewis RA.  Monoclonal gammopathy and neuropathy.  Curr Opin Neurol 2009; 22:480-485.

Note-  search this blog for "MGUS" and various information posted elsewhere will not be repeated

Pearl -  Differentiate into subtypes based on type of proteins found, and clinical syndromes

eg.  osteosclerotic myeloma has an 85-100 % incidence of neuropathy, depending on whether they have partial syndrome or full POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M spike and skin changes).  In myeloma one third of patients have subclinical PN, and half of these may be small fiber neuropathy, in others, NCS and EMG is required to detect.  In contrast, PN is much less frequent in Waldenstrom's macroglobulinemia (5-10 %) and amyloidosis (17 %). 

IgM paraprotein patients have half of patients with paraprotein and neuropathy, and 15 % of those with paraprotein and no neuropathy. IgG patients only have 35 % of patients with paraprotein and neuropathy, but 75 % of patients with paraprotein and no neuropathy.  IgA patients have 15 % of those with paraprotein and neuropathy, 10 % of those with paraprotein and no neuropathy.   Thus IgM is NOT the most common paraprotein, but is the most common to cause neuropathy.  Most have MGUS, a few haveWaldenstrom's and  other lymphoproliferative disorders.  IgM binds myelin sheath and neural antigens in patients with IgM and neuropathy, not in those with IgM and no neuropathy.  Of those with IgM paraprotein and neuropathy, half have anti MAG antibodies.  Electron microscopy shows deposition on myelin and separation of myelin by MAG via complement.  Reducing anti MAG IgM also improves the neuropathy. 

IgG paraprotein patients are as above, less likely to develop PN by far, and those that do have all types of neuropathies (distal , length dependent axonal and CIDP).  CIDP patients with IgG paraprotein are otherwise identical to those CIDP patients without IgG paraprotein.  Unless in a patient with myeloma, amyloid or POEMS, IgG paraprotein is likely to be incidental.  A few patients with IgG or IgA paraprotein also have deposition on myelin like IgM patients so previous statement is not absolute.

IgM paraprotein patients with PN usually have kappa light chains and half have anti MAG antibodies.  They are older males (60s) with "DADS" which stands for "distal acquired demyelinating sensory neuropathy."  Large fibers affecting VS and proprioception cause problems with balance that are progressive.  DADS M (DADS with an IgM paraprotein) is probably distinct from DADS no M.  A few patients have an aggressive course.  EMG in DADS M has accentuated distal slowing and long latency motor nerves and attenuated or absent sensory nerves. 

IgG/IgA MGUS have no homogenous presentation, but usually have less balance problems. 

2. Myeloma patients have peripheral neuropathy due to perineural or perivascular IgG kappa deposition, or treatment related neuropathy.  IgM paraprotein is seen rarely in myeloma, and have sensory > motor symptoms.  If amyloid is present, its more likely to be painful.  EP is more likely to show axonal damage, but may show demyelinating sometimes.No intervention changes PN but therapy of MM exacerbates PN. 

3.  POEMS-- Paraprotein is usually IgA or IgG lambda.  Synonyms for condition are Crow-Fukase syndrome or Takatsuki syndrome.  Patients are younger (40s) with severe sensory and motor features.  Presentation is progressive distal weakness, paresthesias, and numbness more often than CIDP like.  Weakness if usually in ankles most severely.  Patients are wheelchair bound within a year.  There is 40 % mortality at five years.  EMG shows demyelination with secondary axonal loss. Conduction block is rare. Nerve biopsy can show endoneurial deposits.  Treatment is for underlying, and PN is reversible for localized process such as plasmacytoma.  High dose chemotherapy with autologous blood stem cell rescue is being explored.  Misdiagnosed early as CIDP.  Diagnosis of: demyelinating PN, monoclonal gammopathy and one of the three:  osteosclerotic myeloma, Castleman's disease or increased VEGF.  Also must have one or more of following:  organomegaly, endocrine dysfunction, edema , skin changes (hypertrichosis or hyperpigmentation), papilledema, thrombocytosis, polycythemia). 

4.  Waldenstrom's is rarely associated with PN but when it is, its usually IgM kappa with or withour anti MAG antibodies.  Its clinically indistinguishable from MGUS related PN with anti MAG or DADS M.  Responds to plasma exchange since IgM paraprotein is intravascular, may also use steroids and alkylating agents and Rituxan.

5.  Amyloidosis PN is usually present for a long time first.  A. is a multisystem disorder with IgG or IgA lambda paraproteins and deposition of light chains in target organs.  Either vascular insufficiency or toxicity of amyloid causes the PN.  Painful progressive distal sensory and motor PN  often with autonomic findings is seen.  NCS show axonal sensory > motor neuropathy.  Mean prognosis is 25 months. 

6.  Patients with DADS and IgG or IgA MGUS respond to treatment regimens used for CIDP patients without MGUS.  DADS M polyneuropathy may be misdiagnosed as CIDP but respond more poorly to treatment regimens used for CIDP.

7.  CANOMAD is a rare disorder (chronic ataxic neuropathy with opthalmoplegia, M protein, cold agglutinins, and anti disialosyl antibodies against gangliosides, including GD1b, GD3, GQ1b, and GT1b.  There is a chronic PN with sensory ataxia and areflexia, with sparing of strength.  Its similar to Miller Fisher syndrome that has antibodies to GQ1b, but is chronic and progressive rather than monophasic and acute. 

Normal pressure hydrocephalus assessments

Questionnaire/assessment: (from the Neurologist)
http://neuropsychminutiae.blogspot.com/2010/07/nph-questionnaires-for-initial.html

Guidelines for the Initial Management of NPH (published in Neurosurgery)  2005; 57:3.

Links, support groups, information, etc.
http://www.ninds.nih.gov/disorders/normal_pressure_hydrocephalus/normal_pressure_hydrocephalus.htm


Well done powerpoint presentation
http://www.usafp.org/USAFP-Lectures/2007-Lectures/16%20March%20-%20Friday/Ryan%20-%20NPHredo.ppt

MRI criteria:

1. Maximal frontal horn width divided by diameter of inner table, usually >.33, but often > .4
2. Lack cortical/hippocampal atrophy/extensive white matter lesions
3. Callosal angle > 40 degrees
4. Altered brain water content
5. Aqueductal and fourth ventricular flow void on MRI

Gait criteria:  At least two of the following

1. Gait/Balance- at least two of following present
2. Decreased step height
3. Decreased step length
4. Decreased cadence/speed
5. Decreased trunk sway
6. Widened stance
7. Toes turned outward while walking
8. En bloc turning- turns take three or more steps
9. Impaired balance- two or more corrective steps for eight steps on tandem gait testing

Cognition (at least two of following)

1. Cognition- two of following present
2. Psychomotor slowing
3. Decreased fine motor speed
4. Decreased fine motor accuracy
5. Difficulty dividing or maintaining attention
6. Impaired recall especially for recent events
7. Impairment of executive functions- multi-step procedures, working memory, formulation of abstractions, insight
8. Behavioral or personality changes

Urinary symptoms: one of following

 

1. Episodic urinary incontinence not attributable to other causes
2. Persistent urinary incontinence
3. Fecal and urinary incontinence

OR  One of following

1. Urinary urgency
2. Urinary frequency- 6 or more voids in 12 hour period
3. Nocturia- more than two voids in night

 Clinical diagnosis

Probable iNPH:  Gait or balance impairment, plus cognitive or bladder control disturbance, or both.  MRI shows an Evans ratio of greater than .3 with no evidence of obstruction.  Diagnosis based on probable NPH predictes 48-64 % of time a good response to surgery.

 

Possible iNPHL  Urinary or cognitive impairment without gait impairment

 

Pearls:

1. Rely on family assessment as much as what patient says about gait assessment
2. Levodopa trial occassionally needed to sort out festination
3. TInetti Assessment Scale (TAT) for gait assessment screening has a B level of evidence from AAN reviews  and is found here:  http://agrc.ucsf.edu/files/Tinetti%20AssessmentTool%20(gait%20and%20balance%20test)%20(Week%202%20-Mobility).pdf
4. TAT misses a velocity component for gait assessment so also use TUG (timed get up and go) and is found here http://www.dhmc.org/dhmc-internet-upload/file_collection/tug_0109.pdf that also has a Level B evidence from AAN
5. Other instruments that can be used are the ten minute walk, Berg balance test  http://www.fallpreventiontaskforce.org/pdf/BergBalanceScale.pdf  and the Short Physical Performance Battery   http://www.grc.nia.nih.gov/branches/ledb/sppb/index.htm
6. Urinary incontinence may be described as urinating just before reaching the toilet
7. Cognitive differentiation from Alzheimer's disease can be accomplished by testing that includes factors that innclude components that should not be affected by NPH, such as Boston Naming Test (in addition to findings that would be affected such as letter fluency and memory and executive function)
8. Atypical presentations in young may include headache, and poor job performance rather than memory loss.
9. Obstruction of aqueduct or fourth ventricle due to "late onset aqueductal stenosis" may improve with endoscopic third ventriculostomy (ETV).  These patients should NOT undergo LP due to risk of herniation
10. Thinned /  distended callosum may predict shunt responsiveness, may be seen as "bowing" on sagittal views
11. Presence of "B" waves and increased pulse amplitudes correlate with symptomatic iNPH and responsiveness to shunting.  Authors use 48 hours of monitoring followed by 72 hours of drainage.
12. Behaviorally and by fMRI, increased Stroop testing and finger tapping correlates with SMA functional activity
13. Response to serial LP's correlates with 88 % response to surgery.  Can measure with Tinetti and TUG tests (links above) .  With high volume tap, expect improvement in velocity, turning, stride length, number of steps to turn, and tendency to fall, among others.  Test immediately before and after shunt, and again q 2-4 hours.  Consecutive day LP's x 3 days increased sensitivity to 88 %. 
14. ELD (extended lumbar drainage x 3 days) if no response, very few patients will benefit from surgery.
15. With ELF and physiologic measurements, authors claim 75-90 % improvement in first year after shunting, and 80 % sustained improvement after two years, with substantial overall Medicare expenditure savings. 
16. If a programmable shunt is used, the billing code is 62252
17. Obviously need a good neurologist to make the diagnosis and exclude various neurodegenerative diseases

Coin rotation test validation

 

Hill BD et al. The Neurologist. 2010; 16: 249-253

 

Authors validate a longstanding easy test for fine motor processing used for decades at LSU in 86 normals.  Task consists of counting number of 180 degree rotations of a quarter in ten seconds by the dominant and nondominant hands.  A correction for drops is used, but not that important.  Task is to rotate a quarter using thumb and fingers one and two in ten seconds with an examiner using a timer and counting.  If the coin is dropped, the subject gets another ten seconds.  The adjusted score is the number of rotations in ten seconds minus (0.1 x rotations x drops).  Traditionally, LSU has used a cut score of ten to indicate impairment.  Authors believe a cut score (for both hands) of 13 is better, with increased sensitivity and some loss of specificity.

 

Risk of falling in Parkinson's disease patients

from Kerr et al. Neurology 2010; 75: 116=124

Authors looked at 101 independently living patients without walking aids and put various factors through a computer to predict risk of falling.  The factors that increased the risk include

• dyskinesias
• symptomatic orthostasis
• sleep disturbance
• Tinetti, Berg, and TUG (timed up and go) measurements
• poor peripheral sensation and knee extension strength and greater a-p sway when standing on firm surface
• UPDRS total score and FOG (freezing) questionnaire
• For previous nonfallers, key measurement was A-P sway on firm surface as risk for future conversion to falling
• UPDRS factors that were most important were rising from chair, rapid alternating movements and leg agility

Billing pearls (Random)

1.  Never write "benign" positional vertigo, its "paroxysmal" positional vertigo unless you want to be downcoded.

2.  Discharge day codes 99238 for less than 30 minutes, 99239 for more than 30 minutes, document time including spent at nursing station doing prescriptions, need not be continuous.

3.  Critical care codes  99291, 99292 for first hour (minutes 31-74) and each additional 30 minutes, respectively.  Must MANAGE some critical aspect of care and not just consult.  Use different ICD9 code than the attending if you are not primary on case.  Time need not be continuous, and time spent off unit eg. looking at X rays with radiologist counts, unlike floor patients.  Aggregate time with partners if applicable.  This is appropriate for er tpa administration.

4.  Prolonged care codes 99356, 99357 for INPATIENTS for first hour (minutes 31-74 and each additional half hour respectively.  Document reason for prolonged service, submit note to carrier, list start and end clock time required.  Time spent off unit eg radiology does not count, but time spent on unit coordinating care counts.

5.  Prolonged care codes 99354, 99355 are analagous to (4) above except they are for outpatients and Face to face time (start and end clock time) must be documented along with reason. 

6.  Modifier 25 for procedure same day as an E/M service usually EEG and EMG are exempt.

7.  Documentation for high level visit: Indicate chronic illness with severe exacerbation and/or side effects such as MS exacerbation, seizure, Dilantin toxicity (if you are still using Dilantin), risk of Morbidity and mortality (INR high in stroke patient), Abrupt neuro change (TIA, seizure, AMS). 

Must include in note  1) 1 new problem needing additional assessment  or 2) 2 old problems inadequately controlled .  Document at least a three way differential (Alzheimer's v. frontotemporal v. LBD?; or MS v. CIS v. ON due to sarcoid).  Document at least 3 management options (Copaxone, Rebif, Betaseron; steroids; gabapentin: Detrol   or    Aggrenox v. Plavix v Asa, lipitor v. simvastatin; SQ heparin to prevent DVT's).   or iv (parenteral) controlled substances.

New consults need CC, 4 facts for HPI, 1 fact each for PSF (past, family, social history), 10 point ROS (see below), 23 point Neuro SSE (see below). 

8.  Office followup high level requires  CC, 4 facts HPI, med list, social fact, 10 point ROS (may sign and date patient form containing some of these), PLANS (labs, meds, to address problem).   midlevel office visit requires CC, 4 point HPI, mention some PMH or current meds, 2 system ROS, palns to address problem (1-2 chronic problems of moderate degree, or uncertainty re risk or prognosis).  Level 3, low level requires a self limited stable problem eg chronic pain needing E/M, CC, pertinent positives and negatives, and PLANS to address problem.  Most documentation falls out on 3 way differential and plans. 

9.  ROS items to be covered in your office intake sheet come from the list:  constitutional, eyes, ENZT, CV, Respiratory, GI, GU, musculoskeletal, skin and or breast, neurologic, endocrine, hematologic/lymphartic, allergic/immunologic, psychiatric.  May be on a separate sheet patient fills out and checks off if MD signs and dates AND refers to it in office note.  Comprehensive ROS has 10 (TEN) items out of 14.

10.  Neuro single system exam requires 25 bulleted items, need to include 23.  These include one of three CV elements (more may be needed for care but not for documentation). The other 22 that must be included are regular parts of neuro exam.  Mandatory-- any 3 vitals (BP, HR, RR, temp, height, weight, orthostatics), general appearance, Fundoscopic exam, one of 3 cardiovascular elements (carotids, heart auscultation, peripheral vascular system), Memory (orientation, attention, recent and remote memory, language, and fund of information), CN's 2;  3,4,6; 5, 7, 8, 9, 11, 12).  CN's one and ten are not required.  Motor exam includes strength (4 ext), tone (4 ext with note of atrophy or abnormal movements), DTR's 4 ext's including pathologic reflexes, Coordination, Gait and station.  Sensory exam-- need one element of sensation recorded. 

Notes-- must document WHY you can't walk a comatose patient eg. .  Constitutional signs and vital signs can be recorded by staff.  Office needs to have an approved abbreviation list.  Note must be legible.  Templates OK, macros OK, pocket cards with elements available from AAN.

Example of a comprehensive Neuro SSE: Well developed.  120/80, HR 72, RR 16.  fundi OK no bruit.  MS: awake, alert, oriented x 3, dig 6 F, 3/3  objects at 5 minutes, nl naming and vocabulary.  CN. VFF, EOMI, facial sensation and power normal, hears well, palate.tongue midline, SCM normal.  Sens: normal PP.  Motor-- nl tone/bulk/power 4 ext. FNF, gait nl, DTR's 2+ and symmetric throughout, normal.

11,  Couselling and coordination of care may be used instead of documentation.  Counselling involves face to face discussion with patient and/or family re tests, treatments, alternatives, prognosis, education.  Coordination of care may involve interactions with other MD's or providers.  Time is key.  Documentation should state number of minutes spent face to face, that more than half time was spent on counselling and coordination of care, with some general idea of what was done.  No history or exam is needed for documentation.

12.  Be sure to document physician referring name for consults.  Be sure to document MDM in detail. 

sCJD mimics NCSE in ICU patients

Lapergue B et al.  Neurology 2010; 74:1995-1999.

10 patients with sCJD were admitted to neuro ICU with initial misdiagnosis of NCSE.  Mean age 64 +/- 13, with gait ataxis (7),cognitive impairment (5), myoclonus (1), visual (5) or auditory (1) hallucinations and sudden stroke like hemiparesis (2).  Disease duration was 106 days (+/- 30 days).  with EEG's strongly suggesting NCSE ( see article for examples).  EEG's responded to therapy with antiepileptic drugs,  On reexamination, EEG's did not show rhytmic activity, but rather periodic or semiperiodic sharp wave complexes with period of .5-1.0 seconds.  These were attenuated by auditory or painful stimuli.  They also fluctuated with drowsiness.  Importantly, there was no clinical improvement with EEG improvement.  MRI showed characteristic changes in 9/10 and 14,3,3 was seen in all patients. 

List: Most common 7 organisms in bacterial meningitis

Streptococcus pneumoniae
Neisseria meningitided
Listeria monocytogenes
Staphylococcus aureus
Haemophilus influenza
Escheria coli
Streptococcus agalactiae

source Lin AL, Safdieh JE.  The Evaluation and Management of bacterial meningitis: current practice and emerging developments.  The Neurologist 2010: 16:143-151.

The Heidenhain variant of Creutzfeldt-Jakob disease

From Neurology resident/fellow page
The Heidenhain variant of Creutzfeldt-Jakob disease


The Heidenhain variant of Creutzfeldt-Jakob disease presents with isolated visual

symptoms for 2-4 weeks, and these may include disturbed perception of colors or shapes,

visual hallucinations, or cortical blindness with anosognosia (Anton syndrome). The

clinical course of this variant is rapidly progressive. Diagnosis is difficult in the early

stage since the neurological examination is otherwise normal and typical EEG findings

are absent. Visual symptoms may be erroneously attributed to ophthalmologic disease,

which in some cases lead to needless ocular procedures. This is particularly important

since prion particles can be transmitted by ocular tissue. Brain MRI may show the

characteristic cortical ribbon sign with diffusion restriction in the parieto-occipital cortex.

CAPS : A treatable neurologic disorder

Kitley JL, et al. Neurology 2010; 74: 1267-1270
Cryopyrin associated periodic disorder (CAPS) is a  rare disorder that, untreated, will progress to amyloidosis, renal failure and death.  It responds dramatically to anti interleukin 1 therapy with cankinumab.  Authors summarize 13 published cases of CAPS neurologic features, including one case of their own and twelve of the literature. 

Highlights
-- includes 3 previously thought to be unrelated conditions, which are the Muckle Wells syndrome, familial cold autoinflammatory syndrome (FCAS), and chronic infantile neurologic, cutaneous and articular syndrome (CINCA). 

Presentation of  adult patients with CAPS included
-- Headache in 12/13; migraine like in 10
-- myalgia in 9
-- hearing impairment in 7
-- papilledema in 6
--optic pallor in 2

MRIs were normal
CSF in 1 patient showed high OP and pleocytosis
FCAS presents with fever, rash, and conjunctivitis provoked by cold; is mildest
MWS is more severe with progressive SN deafness, one third developing amyloidosis, nephrotic syndrome and renal failure
CINCA presents in infancy and is most severe
Some have history of aseptic meningitis

All show episodic fever, urticarial like rash, conjunctivitis, flu like symptoms, acute phase response with anemia, high ESR and CRP, and elevated serum amyloid A.

Nosocomial bacterial meningitis pearls

Van de Beek et al.  NEJM 2010; 362: 146-154.  Current Concepts.  Review article.


1.  Post craniotomy, one third of cases occur in first week, one third in second week, and one third after second week, up to "years" after craniotomy.  The incidence is 0.8-1.5 %.


2.  Internal ventricular catheter infection causes infection 4-17 % of time.  Colonization at time of surgery is the most important cause, and most cases occur within one month.


3.  External ventricular catheter shunts has an 8 % incidence of infection with a sharp rise after five days.  Article suggests no reason to remove a catheter just because 5 days has elapsed.


4.  CHT usually has a basilar skull fracture if infections occur.  This is most common cause of recurrent meningitis.


5.  Gram staining and culture are hallmarks of diagnosis and measurement of cells and diff may be falsely negative in many cases. especially ventricular catheters.


6.  Post neurosurgery, a CSF lactate level of > 4 mmol/L has a sensitivity of 88 %, specificity of 98 %, PPV of 96 %, and a NPV of 94 % for bacterial meningitis.  However, one review suggested many cases would be missed with this cutoff.


7.  Antibiotics postop or post head injury should be vancomycin plus ceftazidine, cefepime, or meropenem.  Goal should be serum trough of 15-20 for vancomycin.  In intraventricular therapy, close the drain for an hour after the first dose.  The trough should equal ten times the MIC of the antibiotic to sterilize the CSF. 

8.  External lumbar catheter infection rates have been reported between .8 and 5 percent.  After LP infection rate is one in 50,000 with 80 cases per year in US. 

9.  Acinteobacter is more common in nosocomial infections that may be resistant.  Initially may use iv meropenem, with or without intrathecal or intraventricular aminoglycoside, if resistant use colistin or polymyxin B.  Colistin in one study sterilized 13/14 patients and cured those.  In another study, all patients treated with colistin survived.

Pharmacology minutiae of antiepileptic drugs

from E Ramsey at AAN

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

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

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

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

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

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

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

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

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

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

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

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

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

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

enterovirus
1.  more sensitive than viral culture

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

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

TB meningitis diagnostic test pearls

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

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

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

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

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

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

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

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

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

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

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

Ventriculitis pearls and a few more meningitis pearls

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

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

3.  Hemorrhagic CSF is considered a risk factor

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

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

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

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

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

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

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

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

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

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

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

Infratentorial abscess after bacterial meningitis

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

Neurocritical infection/ meningitis pearls

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

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

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

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

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

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

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

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

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

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

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

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

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


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

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

Blast TBI and other TBI pearls

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

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

3.  Secondary injury factors are the focus of treatment. 

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

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

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

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

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

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

10. Pseudoaneurysms and vasospasm are very common.

status epilepticus pearls

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

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

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

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

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

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

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

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

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

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

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

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

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

Medications that reduce seizure threshold

from Neurologic Clinics 2008

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

Concussion pearls

1.  See prior posts on sideline assessment and Vienna return to work
2.  Younger athletes (high school) take longer to recover from concussions than college or NFL players on neuropsychologic testing and should be kept out longer accordingly.
3.  the role of multiple concussions in a single season or time between concussions is unclear but under investigation
4.  Clinical head injury in football is strongly related to translational forces.  Rotational forces follow translational forces.  These forces are highest with helmet to helmet hits and backward falls onto ground
5.  Head down strike increases the mass of the striking player 67 % due to alignment of the torso, and thereby increases the severity of concussion accordingly.
6.  Thicker larger and lighter helmets improve the function of prevention and decrease concussion severity
7.  Clinically differentiate early (temporal) injury involving dizziness and later (>40 msec) injuyr involving fornix and midbrain that is more likely associated with memory loss.
8.  The notion of grading concussion the day of the injury may be in error as late cognitive changes are far more important in predicting delayed recovery

Concussion: University of Pittsburgh sideline mental status examination card

Orientation questions
        What stadium is this?
         What city is this?
         Who is opposing team ?
          What month is it?
           What day is it?

Post-traumatic amnesia
            Remember three words:  girl , dog and green (ask player to repeat them)

Retrograde amnesia
           Ask "What happened in prior half"
           "What happened before you were hit"
          "What was the score before the hit"
          "Do you remember the hit"

Concentration
          ask the player to say the days of the week backwards, starting from today
          ask the player to say the following numbers backwards:  63, 419

Memory
          ask the player to recall the three words given earlier


Vienna conference return to play recommendations1.   Remove from game if any signs of concussion- any items missed on sideline exam
2.   No return to play in current game
3.   Medical evaluation after injury   a. rule out serious focal injury     b. neuropsychologic evaluation
4.   Stepwise return to play    a.  rest till asymptomatic      b.   light aerobic      c.  sport specific training     d.  noncontact practice      e. full contact practice     f. return to play

Concussion- player complaint and observer notation

from Mark Lovell  University of Pittsburgh signs and symptoms of concussion

Signs observed by staff                          player complaint

Appears dazed or stunned                     headache

Is confused about assignment                 nausea

Forgets plays                                         balance problem or dizziness

Unsure of game/score opponent             double or fuzzy/blurry vision

Moves clumsily                                      sensitive to light or noise

answers questions slowly                       sluggish/slowed down

loses consciousness                                "foggy" or "groggy"

behavior/personality change                    concentration or memory problem

retrograde amnesia                                  later sleep problem

anterograde amnesia                                fatigue

orbital pseudotumor due to thyroid opthalmopathy v, myositis

Differential points:  left image, from internet, shows medial rectus hypertrophy which (along with inferior rectus) is characteristic of thyroidopthalmopathy.  This condition is also tendon sparing.  Right image is orbital pseudotumor which in this case affects lateral rectus and tendon.  The condition on right can be secondary to a number of different conditions including RA, orbital tumor, Crohn's disease, and others. 

AAN quick hits 2010 novel uses of medication

pseudoatrophy MRI in MS helped with lamotrigine


cerebellar ataxia benefitted with varenicycline


frataxin level in FA helped with single dose erythropoetin




cell death in SCA type 3 (Machado-Joseph disease) helped by Lithium


improved ataxia and tremulousness with levodopa treatment for Angelman's disease

improved hypoxic damage with SSRI's in medically refractory partial epilepsy

CIS conversion to CDMS reduced by atorvastatin 80 mg

SUNCT/SUNA response to occipital nerve stimulator

CLIPPERS syndrome

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids.  Clippers.  (Mayo Clinic) AAN 2010 P02:182.  Eight patients had a distinctive clinical and radiological CNS disease with treatment.  Presentation was episodic diplopia or facial paresthesias with subsequent progressive ataxia, diplopia, dysarthria and paresis responsive to high dose steroids.  MRi showed gado enhanced peppering of pons extending into the medulla.  Weaning steroids always led to worsening.  Neuropath showed perivascular T lymphocytic infiltration without evidence of granulomas, lymphoma or vasculitis. 

2 type disproportionate anterocollis in Parkinson syndromes

Neurology 2020 AAN PO1.274  Clinical subtypes of disproportionate anterocollis in parkinsonian syndromes Revuelta G, Factor S. 


Myopathic subtype-- neck extensor weakness and limited range of motion, neck extensor myopathy on EMG,


dystonic subtype-- no weakness, full range of motion, laterocollis/torticollis and hypertrophy. 

Other Mitochondria disease: MNGIE

MNGIE-  aut rec, presents with abdominal pain, malabsorption and weight loss.  Peripheral neuropathy and leukodystrophy occur.Serum lactate is almost invariably high.  Elevated thymidine is seen, and WBC shows decreased thymidine phosphorylase (buffy coat??).

Clinical presentations of mitochondrial cytopathies MELAS , MERRF and LHON

Melas- hypoacusis, ataxia, dementia, opthalmoplegia, encephalopathy, stroke like syndromes, exercise intolerance, proximal myopathy, type 2 diabetes.  Due to point mutation, can occur at most ages and mimic multiplle sclerosis with progressive or remitting and relapsing presentations

MERRF  isolated myoclonic epilepsy with or without ataxia, myopathy, peripheral neuropathy, and multiple lipomas in head region.  Neuropsychiatric manifestations including OCD, depression, psychosis and type two diabetes are common.  Any age of presentation to mid 40s.  Progressive decline

LHON-  painless, rapidly progressive vision loss with centrocecal scotoma in teenagers or young adults with male predominance (65-35).  Can mimic MS.

Mitchondrial cytopathies

visit http://www.mitomap.org/ for detailed information on cytopathies

Leigh disease (Complex 1>complex 2,3) aut rec
Succinate dehydrogenase gene (SDHB c and D) paraganglioma and pheochromocytoma, aut dom
polymerase gamma (POLG) mutations-- Alpers syndrome (hepatoencephalomyopathy), CPEO, spinocerebellar ataxia, sensory ataxia neuropathy with dysarthria and opthalmoplegia (SANDO),
ECGF1 (thymidine phosphorylase)- MNGIE

GI differential
liver involvement- Alpers syndrome
irritable bowel, intestinal pseudoobstruction--MELAS
severe GI dysfunction--MNGIE

Neuropathy-- MNGIE, SANDO

Historical points to ask about: deafness, short stature, early cardiac death in family, muscle discomfort or exercise intolerance, early onset DM.
Barth syndrome-- deafness and dystonia

Diagnostic tests
elevated lactate-- 60 percent sensitive, not completely specific
lactate/pyruvate ratio in CSF- may differentiate pyruvate dehydrogenase deficiency from primary mit. cytopathy
plasma amino acids-  elevated alanine may be seen
elevated CPK- may be seen in myopathy, not specific
alpha feto protein- may be seen in Alpers' syndrome early along with increased GGTPand others
thymidine levels-- high in MNGIE
urine organic acids-- high levels of ethylmalonic acid prompts ETHE1 gene for encephalopathy
     high 3 methyl glutaconic acid prompts look for tafazzin mutation for Barth syndrome
folate, B12, vitamin E- may be low in percentage coincidentally or secondarily

MRI- high T2 signal in putamen leading to striatal necrosis characterizes Leigh disease
occipital stroke-- consider MELAS

Cerebral palsy for adult neurologists: pearls

1.  Gross Motor Functional Classification System is most widely used

Level I  Ambulatory in all settings
Level II Walks without aids but has limitations in community settings
Level III Walks with aids
Level IV  Requires wheelchair or adult assistance
Level V  Fully dependent for mobility

Of all CP patients, 40 % are level I, and 66 % are levels 1-3 (ie. ambulatory)

2.  O CP patients, approximately one third will have spastic quadriplegia, one third spastic hemiplegia, one fifth spastic diplegia, and the rest either dyskinetic or ataxic-hypotonic CP.  It is rare for CP patients with spastic hemiplegia or spastic diplegia to be nonambulatory, but 75% of spastic quadriplegia patients are not ambulatory.  Those same patients are much more likely to suffer comorbidities such as epilepsy. 

3.  Genetic defects such as DCX and LISI can be sought, and coagulation pathway abnormalities (Leiden mutation eg.) among those suffering from placental thrombosis.

Care of hydrocephalus in adults pearls

1. Hydrocephalus may be decreasing.  Reasons may include higher threshold for surgery (artefact of practice) increased folate in pregnancy causing less myelomeningocoele.

2.  Unchanged CT scan does not exclude obstruction

3.  ETV or endoscopic third ventriculostomy is a more recent alternative to shunting in a highly select group of patients.  The procedure is more prone to immediate catastrophe, but less to long term infection, although obstruction can occur years later (as it can with any shunting procedure).  ETV may be best for older children with obstructive hydrocephalus or aqueductal stenosis.

4.  A top down approach to assessing meningocoele would sequentially assess hydrocephalus, Chiari malformation, syringobulbia.syringomyelia, tethered cord.

Diagnostic criteria for FXTAS (fragile x associated tremor ataxia syndrome)

Molecular-- CGG repeat 55-200
Clinical
   Major intention tremor, cerebellar ataxia
   Minor  Parkinsonism, moderate to severe short term memory loss, executive function deficit
Radiologic
   Major white matter lesions in middle cerebellar peduncles (MCP sign)
   Minor  lesions in cerebral white matter, moderate to severe brain atrophy

Diagnostic categories

Definite-- one major clinical, and one major radiologic, or present inclusions at autopsy
Probable-- two major clinical, or one minor clinical and one major radiologic
Possible-- one major clinical and one minor radiologic

Dystrophinopathies in adults: pearls

See also http://emgnotes.blogspot.com/2010/01/dystrophinopathy-clinical-diagnostic.html and here are ten more pearls

1.  Many DMD patients now live into 30s and 40s as do carriers or those with BMD.  DMD frequency is about 1:3500 whereas BMD is 1:15,000 to 1:35,000.

2.  Dystrophinopathy should be suspected in a child or adult with the following clinical signs/symptoms:  progressive skeletal muscle weakness, increased CPK, intellectual impairment, myalgias, or cardiomyopathy.

3. BMD patients by convention ambulate after 16.  In 40 + year olds, isolated quad weakness can be confused with IBM.  EKG findings are similar to DMD  (arrythmias or decreased EF requiring Ace inhibitors).  Chronic respiratory insufficiency can be associated with right heart failure.

4.  Minimally symptomatic BMD with exertional intolerance, myalgia, myoglobinuria, or elevated CK diagnostic yield increases with subtle signs such as clumsy as child, toe walking, positive family history, calf or tongue hypertrophy, or myopathic units on EMG. 

5.  All patients regardless of symptoms should have periodic pulmonary function testing, EKG, and echocardiography.

6.  Vaccinations including pneumococcal and influenza are recommended with low threshold for treating potential infections with antibiotics.

7.  Anesthetic risks mandate patients wear a med alert bracelet. These risks are minimized with nondepolarizing muscle relaxants. 

8.  Bowel program plus suction continuous via gj tube reduces abdominal pain.  Restricted jaw opening can mandate placement of a tube. 

9. Consider seated position or other creative safety measures during surgery if possible and if indicated.

10.  PT with range of motion and stretching exercises are hallmark.

Autosomal dominant ataxias with known causation

Most common types are SCA I,II, III, VI which comprise > 50 % cases in USA.  * indicates caused by polyglutamine CAG repeat expansion

SCA I--*-- begins as gait disorder, progresses to four extremity ataxia with dysarthria leaving patient wheelchair bound within 15-20 years.There is phenotypic variability and anticipation (genetically).  Clinically there is involvement of cerebellum with neuronal dropout of Purkinje cell layer and clinical involvement of the brainstem.  No supratentotial involvement.  Not as common as type II but well worked out molecularly,

SCA II--*--characterized by ataxia, dysarthria, slow saccades and neuropathy.  Originally Cuban description.  Very common worldwide, especially in India.  Slow saccades are not pathognomonic, they also are seen in SCA I and III.   Dementia, areflexia, myokymia also are seen. Gene expansion includes cytoplasmic protein ataxin, function of which is unknown.  Anticipation is marked, and disease may present in one generation in old age, in the next much earlier.  Number of repeats are 35-77 , with 32-34 "zone of reduced penetrance."

SCA III--*--Very common, is aka Machado-Joseph disease.  Presents with ataxia, eye movement abnormalities (bulging eyes, opthalmoparesis, staring eyes), speech and swallowing abnormalities.  Pathologic abnormalities include cerebellar afferent and efferents, pontine and dentate nuclei, substantia nigra, subthalamic, GP, cranial motor nuclei and anterior horn cells.  Ataxin 3 gene is at fault.  Repeats: normal 12-42, high is 52-84.  Early onset rigidity and dystonia (largest expansions), middle onset adult ataxia, late onset neuropathy (smallest expansions).  A few patients have Parkinson's that is dopamine responsive and even fewer have RLS.  Peripheral involvement is especially variable.  MRI shows range from fourth ventricle enlargement to severe olive sparing spino pontine cerebellar atrophy.

SCA-- V-- "Lincoln family ataxia"--slowly progressive dominant ataxia found in grandparents of Lincoln.  SPTBN2 gene ecoding B III spectrin is at fault. 

SCA VI  --*--  milder disease, pure cerebellar associated with normal lifespan.  Presentation is gaze evoked nystagmus, dysarthria, onset at age 50 or so, impaired vibratory and position sense.Its fairly common in Japan and in Germany.  Caused by expansion/repeat in voltage dependent calcium channel,same gene  that causes episodic ataxia type 2 and familial hemiplegic migraine.  However, mutations in these conditions in the same gene are different mutations.

SCA 7--*-- cerebellar brainstem disease associated with retinal degeneration and blindness.  It has striking instability of transmission especially with paternal transmission, with cases in utero and in childhood.

SCA 8--*-- classical presentation of disease with gait and limb ataxia, swallowing speech and eye movement abnormalities.  Most have progressive ataxia.

SCA 10 --*-- Mexicans with cerebellar symptoms and seizures.  Extremely large expansion is found in SCA 10 gene. Ashizawa.

SCA 11--*--  2 British families reported with benign gait and limb ataxia.  TTBK2 gene.

SCA 12 --*--PP2R2 gene with dominant ataxia presenting with upper extremity tremor, progressing to head tremor, bradykinesia, abnormal eye movements.  Onset 8-55 years.

SCA 13 --*-- dominant ataxia, may present in childhood with MR, dysarthria, nystagmus, +/- hyperreflexia.  Due to KCNC3 gene mutation in voltage gated K channel subunit.

SCA 14 --not repeat--slowly progressive ataxia with dysarthria in early adulthood.  May be pure cerebellar or accompanied by myokymia, hyperreflexia, axial myoclonus, dystonia and vibratory sense loss. 

SCA 15-16-- allelic (ie same allele) disorder occurring in Austrailian and Japanese families, slowly progressive pure cerebellar disorder.  Dysarthria, horizontal gaze evoked nystagmus, sometimes head tremor.  Disease is due to deletions in IPTR gene

SCA 17 --*--Widespread cerebral/cerebellar dysfunction, rare in US, more common in Japan.  Presents with gait and limb ataxia, psychiatric dysfunction, EPS, seizures, may resemble Huntington;s disease.  MRI shows widespread cerebral and cerebellar dysfunction.  Onset in mid to young adulthood.

SCA 26 -- Norwegian pure cerebellar ataxia that maps closely to gene affecting Cayman ataxia and SCA 6 with Purkinje cell degeneration. 

SCA 27-- Dutch disease manifests with hand tremor in childhood.

DRPLA-- *--  progressive ataxia, choreoathetosis, dementia, seizures, myoclonus, and dystonia. Before age 20 there are almost always seizures and a progressive myoclonic seizure like presentation.  Older patients get ataxia with choreoathetosis and dementia.  More common in Japan, but Haw River phenotype is an African American family in the Carolinas with seizures and cerebral calcifications.

episodic ataxias--EA1 and EA2 are due to mutations in K and Ca channel genes.  EA1-- patients ahve minutes of ataxia due to stress, exercise or change in posture. Patients also may have myokymia.   KCNA1 gene. EA2 has ataxia that lasts days , precipitated by stress, exercise or fatigue and is due to mutation of same gene as SCA 6 (CACNA1A4 gene). Acetozolamide may help.  Other EA's with prominent vertigo also are described.