Wednesday, May 28, 2014

CJD and non CJD with neuronal markers

Grau-Rivera O, Sanchez-Valle R, Saiz A et al. Determination of neuronal antibodies in suspected and definite Creutzfeld-Jakob disease . JAMA Neurol 2014;71:74-78.

Take home points

1. A small but definite number of 346 patients with suspected CJD had anti neuronal antibody mimics but these six did not fulfil criteria for CJD. Found were NMDAR,LGI1 , CASPR2, aquaphorin 4, Tr(DNER alpha notch 4 epgf and unknown protein.

2. No patients among 46 with definite CJD had these neuronal markers.

These all were studied in CSF

Faciobrachial systolic seizures , correlate with anti VGKC and not CJD

Faciobrachial systolic seizures , correlate with anti VGKC and not CJDYoo J and Hirsch LJ. Limbic encephalitis associated with anti voltage gated potassium channel complex antibodies mimicking CJD. Jama Neurol 2014;71:79-82.

Case with following take home points:
FBDS are highly associated with ant VGKCC and not CJD and are treated with normal AED's

The two disorders otherwise may mimic each other

Anti VGKCC responds robustly to steroids

Both disorders can have elevated 14,3,3 in CSF

Absent restricted diffusion is a "red flag" against CJD

MRI of anti VGKCC is usually high T2 signal in uni or bilateral temporal lobes but they can also show cortical ribbon and basal ganglia changes mimicking CJD

FBDS mimic myoclonus but EEG confirms seizures

Spect scans show abnormal basal ganglia metabolism

Saturday, May 17, 2014

RA meningitis as stroke mimic

Bourgeois P et al.  Rheumatoid arthritis presenting with stroke like episodes. Neurology 2014; 82: 1564-5. 
70 yo male presented with series of TIA like events over ten days consisting of right leg more than arm weakness.  He had poorly controlled RA.  MRI was negative for brain parenchyma but there was enhancement of meninges and pachymeningitis.  Meningeal biopsy was positive and patient was successfully treated by Solumedrol 1 gram per day followed by 1 mg/kg/day prednisone, tapered over months with no recurrence. 
Other reported presentations of RA meningitis include cranial neuropathy and seizures.  CSF is abnormal.  Authors propose that RF in CSF is a useful biomarker if positive as false negatives occur.  Path can show 3 patterns: rheumatoid nodules, meningeal inflammation or vasculitis.
In other series there was high mortality although this patient survived.

Friday, May 16, 2014

Management of hepatic encephalopathy in hospital

Review Article
Leise MD, Poterucha J, Kamath PS et. al.  Management of hepatic encephalopathy in the hospital.  Mayo Clin Proc 2014; 89(2) 241-253.

Working Party for hepatic encephalopathy nomenclature:

Type A HE-- secondary to liver failure
Type B HE enteric hyperammonemia without liver disease
Type C  -- is associated with some liver disease.

Severity Grades
I-IV scale
0 normal
MHE normal exam,  nild changes visuoperceptive or psychometric tests
I Personality change, attention ddeficit, irritability, depressed state, tremor, dyscoordination
2  Changes sleep/wake cycle,letharygy , mood, behavioral/ cognitive changes; asterixus, ataxic gait, slow/slurred speech
3  Somnolence, confusion , disorientation, amnesia; muscle rigidity, nystagmus, clonus, Babinski sign, hyporeflexia
4  stupor and coma; oculocephalic reflexes, unresponsive

other scale SONIC (spectrum of neurocognitive impairment in cirrhoses)
covert HE (CHE) includes minimal HE (MHE) and grade I HE
overt HE encompasses grade II-IV. 

episodic HE
persistent HE impairs day to day executive function


50 percent of cirrhosis patients develop HE, and prognosis for these patients is worse even taking into account Model End Stage Liver Disease (MELD) scores.

Occurrence of OHE is approximately 22,000 per year
80 % are precipitated by an event such as GI bleed or iinfection

Most patients do not get needed maintenance care after hospital discharge

Reason for readmission is lack of education or inappropriate use of lactulose. 

Treatments- Induction therapies for episodic OHE

Nonabsorbale disaccharids-- lactulose (B galactosidofructose) and lactitol (B galactosidosorbitol) reduce ammonia by acifying colon with shift of ammonia to ammonium, shifting colonic flora from urease to nonurease producing bacterial species, and by cathartic effect.  Clinical studies are mixed/poor but its still first line in all but most sever cases.

Neomycin, metronidazole,and other antibiotics. -- neomycin is FDA approved for acute but not chronic HE to decrease gut derived bacterial derived ammonia. The evidence is weak, for OHE, and its use complicated by ototoxicity and nephrotoxicity.Possible slight benefit with metronidazole or vancomycin but each are very toxic.

Rifaximin :-- not FDA approved for episodic HE, only for secondary prevention of OHE Trials did not show substantial difference from lactitol but seemed to work faster.  RCT of rifaximin v. placebo showed benefit on composite outcome at doses of 1200-2400 mg per day for grades !-3.  May be better tolerated than lactitol.    A study of grades 3-4 with lactulose + placebo v. lactulose+ rifaximin  had more complete reversal in dual treated group (76 v. 51 %), shorter hospital stays and less ten day mortality (49 v. 24 %).

Zinc :Zinc deficiency occurs in 96 % of patients with MELD score of 12.  inc is necessary for two smmonia reduction pathways: ornithyl transcarbamylase in liver (ammonia converted to urea) and glutamine sythetase in skeletal muscle (glutamate to glutamine). One of 4 RCT's showed benefit.  Caution: zinc should be taken 2 hours before ciprofloxacin, and long term use causes copper deficiency,

L  ornithine-L aspartate : aka LOLA stimulates ammonia reduction pathways, like zinc.  Best use is in chronic HE. Has been shown to be effective, but is not available in USA

Branched chain amino acids : in cirrhosis, patients have decreased BCAA's and increased aromatic amino acids.  BCAA's are a source of glutamate which helps metabolize ammonia in skeletal muscles.  Benefits of BCAA's include better albumin synthesis, decreased insulin resistance, less hepatocellular carcinoma, and better immune function.  Studies poor quality with mixed results.  European Society for Cliical Nutrition and Metabolism recommends 1.2 g/kg / day of protein for compensated cirrhosis, and 1.5 g/kg/day for decompensated cirrhosis.  They also have grade A recommendation for standard protein supplementation for HE grade 2 or less, and BCAA for HE grades 3 and 4.

Percutaneous embolization of large portosystemic shunts :In European study , n= 37, for medically refractory patients given this, 59 % were free of HE in 100 days, 48 % in 2 years.  90 % of patients with cirrhosis improved.

Molecular adsorbent recirculating system : aka MARS based on albumin dialysis principle.  It removes protein and albumin bound toxins such as bilirubin, bile acids, nitrous oxide and enodogenous benzodiazepines, and non protein bound ammonia.  Effect on survival is in question, but HE is improved.  It is safe and tolerated and FDA approved for HE related to decompensated liver disease.  May reduce availability of certain antibbiotics and has medical contraindications.

Secondary prophylactic maintenance strategies in HE

Lactulose  : there is solid evidence for lactulose alone, or in combination with rifaximin.  Lactulose or lactulose plus probiotics had less recurrent OHE (37 5, 45 %, and 64 % respectively). 

Rifaximin :  in rifaximin v. placebo, treated group had less recurrence and rehospitalization than placebo.  It is FDA approved for secondary prevention of HE

General approach to induction and maintenance of  first episode of HE  :

1.  Screen for precipitants of OHE including GI bleed, infection, new medications such as opiods and benzodiazepines, constipation, diarrhea, dehydration, alkalosis, hypokalemia, or hypoxemia (seen in 80 % at least one).  Then manage precipitant and use lactulose also.

2.  For nonresponders, look for other precipitants, reeval the diagnosis, make sure the patient is having 3-4 stools per day.  Could then add neomycin (FDA approved but many side effects, or rifaximin which is off label. 

3. For patients who benefit use lactulose maintenance therapy especially for Child-Turcotte-Pugh class B/C

General approach to induction and maintenance of  recurrence of HE  :

1.  Same as (1) above; check number of stools with and compliance with lactulose.  Review meds

2.  If bloating or excessive diarrhea occur with any dose of lactulose, use rifaximin instead. In breakthrough HE on lactulose, add rifaximin (preferred) or neomycin (less preferred). 

3.   If breaks through on 2 drugs above, perform contrast enhanced CT to look for large intra-abdominal portosystemic shunt, or use MRA if patient is contrast risk.  Consider a shunt embolization in CTP class A cirrhosis or low MELD score (< 12-15).  60-90 percent may remit. 

4.  If embolization is not indicated consider additional treatments such as zinc, LOLA (if available), BCAA

Treatment of Severe HE grades 3-4 :

1. ABC, look for precipitants, lactulose 15-30 cc png q 1-2 hours until 3 stools achieved.  Alternative is 300 cc lactulose in 700 cc sterile water in an enema.  , may repeat prn.  Add rifaximin .  If unresponsive, perform head CT/ EEG to check diagnosis.  If diagnosis is correct, look for shunt to embolize.; if none use BCAA, zinc and LOA

MHE: Counsel patient about risks of driving

Wednesday, May 14, 2014

Fwd: MRI findings in idiopathic intracranial hypertension

Sent: 5/13/2014 2:29:27 P.M. Eastern Daylight Time
Subj: MRI findings in idiopathic intracranial hypertension

1.  empty sella
2.  flattening of posterior globes
3.  distension of perioptic subarachnoid spaces
4. narrowing of transverse venous sinuses
more from Images in Neurology JAMA Neurology 2013; 70:7937-8.

5.  distended perioptic nerve sheath
6. protrusion of the papilla 
7. "strangled optic nerve appearance
8. optic disc edema and retinal layer edema

Fwd: presentations of chronic traumatic encephalopathy


Sent: 5/13/2014 2:29:28 P.M. Eastern Daylight Time
Subj: presentations of chronic traumatic encephalopathy
Stern et al.  Neurology; 2013: 81:1122-1129
Clinical review of 36 patients, all male athletes.  They were based on autopsy studies at Boston University Center for CTAE.
11 patients had episodic memory impairment  and executive dysfunction (cognition group) initially, only later behavioral and mood disturbances.  Nine patients initially had depression and thirteen had initial behavior (explosivity, impulsivity, violence).  The behavior-mood group totalled 22.  Three patients were asymptomatic.
Age of onset of behavior / mood group was mean 51,  of cognition group, mean was 69.
Among football players, the most susceptible positions were runningback (21 %), linemen (48 %) and linebacker (10 %). 
Ten subjects were diagnosed as dementia: 10 with AD, 4 with "dementia pugilistica" or "football related" and 2 unspecified.  All 10 had stage 4 CTAE.  Seven were from the cognitive group, 2 from mood group, and 1 from behavior group. From diagnosis to death was mean 8 years. 
Mean age of onset was 57.7 years, mean age of dememntia diagnosis was 72.6 years .  4 had a history of falls, 1 of tremor.  All 10 had memory/executive dysfunction, 7 had language deficits, 2 had visuospatial deficits, 6 were described as having a "short fuse."  Mood group had 2 with predominant sadness and 2 with anxiety, 
ApoE$  homozygotes occurred more frequently than in population. 

Fwd: Secondary causes of pseudotumor cerebri syndrome

Sent: 5/13/2014 2:29:28 P.M. Eastern Daylight Time
Subj: Secondary causes of pseudotumore cerebri syndrome

(from Neurology, 2013; 81:1159-1165
cerebrovenous abnormalities:
cerebral venous thrombosis (CVT)
bilateral jugular thrombosis or surgical ligation
middle ear or mastoid infection
increased right heart pressure
superior vena cava syndrome
AV fistulas
hypercoagulable states
Medications and exposures:
Antibiotics: tetracycline, minocycline, doxycycline, nalidixic acid, sulfa drugs
Vitamin A and retinoids
hypervitaminosis A, isotretinoin, all trans retinoic acid for PML, excessive liver ingestion
Hormones:  HGH, thyroxine (in children), leuprorelin acetate, levonorgestrel (Norplant), anabolic steroids
Withdrawal from chronic corticosteroids
Medical conditions
Endocrine:  Addisons, hypoparathyroidism
hypercapnia-- sleep apnea, Pickwickian syndrome
Renal failure
Turner syndrome
Down syndrome

Fwd: Diagnostic criteria for pseudotumore cerebri


Sent: 5/13/2014 2:29:29 P.M. Eastern Daylight Time
Subj: Diagnostic criteria for pseudotumore cerebri
Neurology 2013; 81:1161
A.  Required
       1.  Papilledema
       2.  normal neuro exam except cranial neuropathy eg abducens palsy
       3.  Neuroimaging-- normal MRI with and without contrast
       4.  Normal CSF composition
       5.  Elevated CSF opening pressure:  , > 250 in adults > 280 in clhildren
Diagnosis of pseudotumor cerebri syndrome without papilledema
       1.  If 2-5 above are satisfied and in addition unilateral or bilateral  VI n palsy
        2.  Absent papilledema/ VI n palsy, diagnosis is suggested but not made with 3/4 imaging criteria met:  empty sella, flattened posterior globe, distended perioptic subarachnoid space with or without tortuous optic nerve, and transverse sinus stenosis.
Under research:  findings of narrowed Meckel's cave and cavernous sinuses on MRI and widened foramen ovale on CT
Uncommon manifestations:  facial paresis, hemifacial spasm, radicular pain, rhinorrhea, otorrhea, III n , IV n and general oculoparesis.
Less specific symptoms of:  headache, transient visual obscurations, pulse synchronous tinnitus, binocular diplopia, neck shoulder and back pain