Simvastatin for SPMS is recruiting

The MS-STAT trial: a phase II trial of high-dose simvastatin for secondary progressive multiple sclerosis: baseline trial profile; Chataway J, Anderson V, Chan D, Frost C, Hunter K, Kallis C, Greenwood J, Schuerer N, Alsanousi A, Nicholas R; Journal of Neurology, Neurosurgery, & Psychiatry (JNNP Online) 81 (11), e55 (Nov 2010)

Background Therapeutic options for secondary progressive MS (SPMS) are very limited. Simvastatin is an attractive drug with potentially anti-inflammatory (e.g., reducing leukocyte migration) and neuro-protective effects (e.g., up-regulation of the major cell survival protein bcl-2), in addition to being well tolerated. In trials of early stage MS it is undergoing trials as a single agent or in combination therapy with standard disease modifying treatments. This is the first trial in SPMS. Trial Overview Double-blinded/placebo-controlled (1:1) with 80 mg of simvastatin. Two-year follow-up. Entry EDSS 4.0-6.5. Brain atrophy rate as determined from T1-weighted volumetric MRI using the brain boundary shift integral is the primary outcome measure. Secondary outcomes include disability scores, neuropsychological assessments and immunological profiling. Results 408 patients were referred, 203 screen failures, 140/140 patients were randomised. Age 52 years (range 35-65), 68% female, MS duration 21 years (8) with a secondary progressive phase of 13 years (7). Median EDSS 6.0 (IQR 0.5). MSFC 10 m walk/s 23.6 (25.6); Nine-hole peg test/s 34.6 (13.2); PASAT/60 35.3 (14.2). MSIS-29ver 2.0 scores: physical 49/80 (11), psychological 20/36 (8), total 69/116 (14). All data as mean (SD) unless stated. Conclusion This trial is fully recruited and will report in late 2011. ClinicalTrials.gov, number NCT00647348.

Testing for Vitamin D Pearls

Kennel KA et al. Vitamin D deficiency in adults : when to test and how to treat.  may Clin Proc 2010: 85; 753-758

1.  Terminology:  D2 = ergocalciferol is obtained from vegetables and oral supplements.  D3= cholecalciferol is obtained from UVB sunlight, oily fish and some fortified foods such as milk and bread.  25 (OH) D= calidiol, contains D2 and D3.  1,25 (OH)2D= calcitriol and is converted in kidney and other tissues by the one alpha hydroxylase gene. 

2.   Deficiency is caused by lack of exposure to sunlight, dietary deficiency or malabsorption.  Measuring calcidiol is best measurement of body stores of 25 (OH) D total vitamin D and is best test for deficiency, whereas 25 (OH)  D  D2 and D3 is useful for monitoring to detect noncompliance, or malabsorption. In general the D content of food is low, and D levels come from sunlight and supplements.

3.  1,25 (OH)D can be falsely normal in vitamin D deficient patients due to hyperparathyroidism and thus should not be measured.

4.  Reference ranges may vary based on geographic location, season, ethnic background, age. 

5.  Vitamin D toxicity has never been reported with a level less than 80, and usually requires over 140.   Fear of toxicity is overblown.  This is because calcitriol, the renal 1,25 OH D, feedbacks directly limiting its production via 24 hydroxylase gene.  Calcitriol also feeds back on the PTH gene.  The alternative result is inert metabolites of Vit D, including 24,25 calcidiol and 1,24,25 calcitriol.

6.  Used but not clinically validated for severe Vitamin D Deficiency:  loading dose of 50,000 weekly for 2-3 months, or tiw for one month.  A minimum total dose of 600,000 iu predicts increasing the level to normal (>30).  A lower dose is used for moderate deficiency.  Maintenance of 800-2000 iu is needed to prevent slideback. 

7.  Powder D3 does NOT clog feeding tubes unlike D2. 

Motor cortex stimulation for pain in multiple sclerosis

Motor cortex stimulation for intractable neuropathic facial pain related to multiple sclerosis; Tanei T, Kajita Y, Wakabayashi T; Neurologia Medico-Chirurgica (Tokyo) 50 (7), 604-7 (2010)

A 33-year-old man presented with ongoing severe right facial pain and sensory disturbances caused by multiple sclerosis (MS). Neuroimaging demonstrated demyelinating lesions in the right dorsal pons and medulla oblongata. The pain was refractory to carbamazepine at 800 mg/day, gabapentin at 1800 mg/day, morphine at 30 mg/day, amitriptyline at 60 mg/day, and diazepam at 4 mg/day, along with twice-monthly ketamine (60 mg) drip infusions. The patient underwent motor cortex stimulation (MCS), resulting in>60% pain relief, reduction in the required doses of pain medications, and discontinuation of ketamine administration. MCS is effective for MS-related neuropathic facial pain.

 

Successful Management of Natalizumab-Associated Progressive Multifocal Leukoence

Schröder A, Lee DH, Hellwig K, Lukas C, Linker RA, Gold R; Archives of Neurology (Jul 2010)OBJECTIVE: To describe a case of successful clinical management of natalizumab-associated progressive multifocal leukoencephalopathy (PML) and immune reconstitution syndrome (IRIS) in a patient with multiple sclerosis. DESIGN: Case report. SETTING: University hospital. Patient A 41-year-old woman with relapsing-remitting multiple sclerosis developed PML after 29 natalizumab infusions. INTERVENTIONS: Immediate plasma exchange was combined for removal of natalizumab with application of mefloquine and mirtazapine to limit viral replication and oligodendrocyte infection. A subsequent IRIS was treated with glucocorticosteroids. RESULTS: After 3 months of treatment, cerebrospinal fluid tested negative for JC virus. There was a favorable outcome, and the Expanded Disability Status Scale score remained stable at 3.5 compared with before PML. CONCLUSIONS: In the setting of early diagnosis and consequent treatment, natalizumab-associated PML can be well managed in some cases. This situation differs from the course of PML in other conditions, eg, after the application of depleting monoclonal antibodies, in which irreversible cellular effects are associated with very high mortality.

MACFIMS- cognitive assessment for multiple sclerosis

Benedict R.  Minimal neuropsychological assessment of MS patients.  The Clinical Neuropsychologist 2002; 16:381-397.

Contains tests with alternate forms and test-retest capability. 

Processing speed/Working memory

PASAT
Symbol Digit Modality Test (SDMT)  equally good as PASAT as standalone

Learning and Memory

CVLT-II
Brief Visuospatia Memory Test- Revised

Executive Functions

D- Kefs Sorting Test- sorting cards, Trails, Tower, Design Fluency, Stroop

Visual perception/Spatial Processing

Judgment of Line Orientation

"Language"

Verbal Fluency (COWAT)

Non Macfims-- office assessment
Attention:
1 trial PASAT
Trails (public domain)
Mental control (days forward, backwards, serial 7's)
Cancellation test (public domain)

Memory:
list learning, 10 common, easy, unrelated words, 3 trials, 20 minute delay with recognition trials (yes/no)

Language:

5-10 pictures use for each patient
COWAT equivalents (CFL, PRW, FAS)
semantic category fluency

Motor coordination/processing speed:
9 hole peg
Trails A
SDMT written and oral (public domain)

Subjective:

Multiple sclerosis neuropsychological questionnaire (Benedikt et al., 2004)
15 items, MSNQ

Benign MS and cognition

Portaccio E, Stromillo ML, Goretti B, et al (last author Stefano) .  Neuropsychological and MRI measures predict short term evolution in benign multiple sclerosis.

Consensus for definition of b-MS is those who are fully functional after ten years.  Different systems are used to classify patients.  Authors defined as EDSS < 3 after 15 years of disease duration. 

Authors used Rao BRB and added Stroop test, using a cutoff as 2 SD's below Italian normals.  Patients with 3 or more test failures were classified as cognitively impaired.  Tests included SRT, SPART (spatial recall, 10/36 cutoff), PASAT, SDMT, WLG, Stroop. 

Authors followed patients at a mean of five years, using "still benign" measure.  Disability was EDSS>4, or increase of 1.5 if starting EDSS was zero, or increase of >1 point if starting EDSS was > 1 confirmed at six months.  31.8 percent of patients with "b-MS" were impaired at baseline cognitively.  Additional 16 % failed one test and 19 % failed 2 cognitive tests at baseline.  At followup, 43 % had EDSS progression of one or more points, confirmed.  18 % became "no longer benign," or "NLB."  NLB subjects had more relapses during followup period, but not in year before, and related to male gender and number of tests failed. Also baseline T1 lesion volume was predictive. 

editorial
Benedict RHB, Fazekas F.  Beningn or not benign MS: a role for routine neuropsychological assessment?  Neurology 2009; 73: 494-495.  Authors mention BRB and MacFims, each having alternate forms that permit repeat testing every 2-3 years. 

Cortical lesions and atrophy associated with cognitive impairment in RRMS

Calabrese M, Agosta F, Rinaldi F, et al. (last author Filippi).  Arch Neurol 2009; 66:1144-1150.

Authors studied 70 patients with multiple sclerosis and 22 normal controls .  They used the Rao BRB and used a cutoff of 2 SD's below mean on at least one test of, version A of BRB to define cognitive impairment.  They also looked at T2 lesion volume, contrast enahncing lesion number, cortical lesions using double inversion recovery sequences, volume, and normalized grey matter volume.  Finding was that T2 lesion number and enahncing lesions were not important, but that cortical lesions, cortical and brain volume and gray matter involvement predicted cognitive impairment. 

Tests used in BRB were"  SRT and delayed recall, spatial and delayed recall (10/36 cutoff), PASAT 3 and SDMT, and word list generation.  See Camp et al, Brain, 1999 for normative values. (see article anyway). 

24 patients were listed as cognitively impaired.  The rate of impairment was, for SRT delayed, 12.9%; PASAT and word generation 10 %, SDMT 8.6 %, EDSS also predicted. 

Authors discussed the "cognitive impairment index" as discussed in Brain article above.  This is a continuous variable obtained by a grading system applied to each patient's score on each test, depending on number of SD's below mean normal.  Grade 0 means index was above mean for normal controls.  Grade 1 was given for mean to 1 SD below normal.  Grade 2 was 1-2 SD's  below normal.  Grade 3 was given for more than 3 standard deviations below.  The results for all tests were added to give an overlal measure of cognitive dysfunction.

Authors discussed that the CL (cortical lesion) number and volume correlated with CI index score, and deficits in attention, concentration, speed of processing, and memory. 

Neuropsychological effects of interferons

Fischer JS, Priore RL, Jacobs LD et al.  Neuropsychological effects of interferon B-1a in relapsing multiple sclerosis.  Neurology 2000; 48: 885- 892.

Study looked specifically at Avonex to 166 patients 104 weeks apart.  The neuropsych battery was divided into Set A (information processing and learning/memory) ,  Set B ( visuospatial and problem solving), and Set C (verbal abilities and attention span).  Avonex benefitted A set, with a trend in B set and no effect on C.  Secondary analysis showed a treatment effect on time to worsening with PASAT. 

Subject selection-- disease duration at least one year, at least 2 relapsed in 3 years, and EDSS 1-3.5 inclusive.  age 18-55. Study was placebo controlled.  Actual tests used were , for Set A, signnificant group, CalCap Sequential reaction time (information processing), Ruff Figural Fluency Test error ratio, and CVLT Trials 1-5 (total).

Set B tests were WMS-R Visual Memory Span (forward), WCST perseverative responses, visual search number of trials, TOL % planning time. 

Set C tests were WAIS-R information, and digit span forward.

Secondary outcomes were RFFT error ratios, RFFT unique designs, CVLT trials 1-5 (total), PASAT processing . 

Results-- on set A, the CVLT test was most important.  On Set B, Tower of London was most important.  Set C was negative tests.  In secondary outcomes, slopes were correct direction in all variables, RFFT appeared significant, and  practice effects were noted in all groups. 

Authors contrast to 2 other studies of cognition with treatment for MS.  One was a copaxone study (Weinstein et al, Arch Neurol, 1999) which was negative, and one was for Betaseron, that showed an effect for visual memory  (Pliskin et al, Neurology, 1996).  However, neither of those was as good of a study. 

MIMS Study for Novantrone in MS

Hartung H-P et al.  Mitoxantrone in progressive multiple sclerosis: a placebo controlled, double blind randomised multicentre trial.  The Lancet 2002; 360: 2018-2025.

194 patients with worsening RRMS or SPMS were given MTX or placebo  q 3 months for 24 months (5 mg/meter squared).  at end, the treated group had a benefit in five clinical primary outcome measures:  change in EDSS, change in ambulation index, adjusted total number of treated relapses, time to first treated relapse, and change in standard neurological status. 

Shortened version of PASAT is effective discriminant in MS

Solari A, Motta A, Radice D, Mendozzi L.  A shortened version of the PASAT 3 is feasible.Multiple Sclerosis 2007

Authors studied PASAT in 105 persons with multiple sclerosis and controls using PASAT 3 regular and shorrtened version.  They used the first 20 items.  The first 20, 30 and 50 items of the PASAT 3 retained discriminant value for MS

Notes study did not norm for age (highly sensitive) or practice effect (important). 

Note:  A review of the PASAT Tombaughh TN Arch Clin Neuropsychol 2006; 21:53-76.

Effect of copaxone on fatigue in MS

Metz IM, Patten B, Archibald CJ et al.,The effect of immunomodulatory treatment on multiple sclerossi fatigue.  JNNP 20 04; 75: 1045-7. 

In Calgary 218 MS clinic studied patients with initially comparable levels of fatigue who were treated with glatiramer (copaxone) v. interferons using fatigue impact scale.  2x as many started on copaxone and 2x as many reported greater reductions in fatigue.  This was true for all MS patients and RRMS patients.  The difference affected total FIS, the physical and cognitive subscale but not the social subscale.  The authors used one SD as the cutoff. 

Cognitive dysfunction in patients with CIS or newly diagnosed MS

Glanz BI, Holland CM, Gauthier SA et al.  Multiple Sclerosis 2007; 13:   senior author Howard Weiner BWH

Authors studied 92 patients with CIS/new MS and fouund 49 % impaired on one or more tests of the battery.  There was not correlation with MRI measures of disease including T2 lesion volume, NAWM, grey matter volume or brain parenchymal fraction.

Tests given were Rao's brief repeatable battery including SRT, 10/36 Spatial Recall test, SDMT, PASAT, COWAT, CES Depression Scale.  PASAT, SDMT, and SRT were the clear tests that showed abnormalities in MS v healthy controls. 

Authors contrast their results to Achiron and Barak (JNNP 2003) who found visual learning and recall , COWAT and SDMT to be most abnormal tests.  Other studies were Feinstein (Brain, 1992; 115: 1403-15) and Callanan MM et al (Warrington) Brain 1989; 112: 361-74.   

main references for Zamboni procedure for MS

• Zamboni P, Menegatti E, Salvi F, et al. Intracranial venous haemodynamics in multiple sclerosis. Curr Neurovasc Res 2007;4:252–258.




• Zamboni P, Galeotti R, Salvi F, et al. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 2009;80:392–399.



• Zamboni P, Galeotti R, Salvi F, et al. Endovascular treatment of chronic cerebrospinal venous insufficiency: A prospective open-label study. J Vasc Surg 2009; 50:1348–1358.

Q & A AAN 2010

COMMENTS
1.  possible association of seminoma and demyelination disorder
2.  dural av fistula lesions identified by stepwise progression and involvement of conus, angiography can miss it
3.  Rabies case of Weinshenker-- rabies is increasing in bat population, catch the bat, give everyone a shot even if they don't have a bite, only have a week or so to get a shot
4.  NMO CSF may be positive with negative serum studies, but is rare.  Antibody arises in blood and leaks into CSF, does not get produced in CSF.  Could be a question of CSF is cleaner with less noise of other antibodies in blood interfering with test.
5.  Persistent black holes at onset is a good sign of non-ADEM; rarely if ever seen all enhancing lesions with ADEM more common to see none of lesions enhance.

Superficial siderosis

check 2009 article Neurology

check cerebellar folia
do myelogram look for extradural defect
consider fixing it

ADEM and atypical demyelinating disease pearls

1. Occurs more in childhood than adulthood
2.  Occurs post infection, infection may include VZV, EBV, HSV 6, measles, influenza
3.  Acutely, all lesions enhance rather than being of different ages (MAY occur)
4.  Pathologically perivenous inflammation with very little tissue or axonal destruction
5.  Hurst's hemorrhaghic leuokoencephalitis is sometimes considered as part of spectrum of ADEM, with severe course, may be fatal, hemorrhage may be petechial, with pathological and MRI diagnosis and severe demyelination
6.  Marburg's MS -- severe and unrelenting MS even within one year. Otto Marburg, 1906
7.  Tumefactive MS--may be monophasic course or develop into MS, typical or otherwise
8.  Balo's concentric sclerosis with concentric rings of demyelination alternating with remyelination, described 1927, variable course, more common in Southeast Asia, high level if inducible nitrous oxide synthase similar to hypoxia.
9.  Isolated optic neuritis without MS--half may not progress to MS without associated MS lesions
10  CRION chronic relapsing inflammatory optic neuritis disease is restricted to optic nerves
11.  NMO spectrum disease with isolated and recurrent optic neuritis

For above, treatment algorithm is five days of solumedrol, then plasma exchange (at Mayo Clinic) then cytoxan.

Weinshenker on Acute Myelopathies from AAN 2010 pearls

1.  Most myelopathies are undetermined cause at initial diagnosis, then infectious, then CVA, then systemic disease eg. lupus

2. NMO may have a central cord syndrome

3.  Initial functinal score and a central lesion on MRI are predictors at outcome, as is systemic disease or NMO at outcome.

4.  Paraneoplastic case with CRMP 5 in a 42 year old man with positive vep, cigar shaped faintly enhanicng lesions improved with removal of papillary thyroid cancer.  One radiographic sign not well known is owl eye sign with 2 "eyes"  suggests cancer or paraneoplastic.

5.  Cord compression can produce abnormal signal mimicking transverse myelitis clue check axials, and clinically symptoms did not progress over 3 weeks. Signet ring pattern of enhancing signal is c/w compression

6.  Case zoster leading to myelitis indistinguishable from NMO by MRI abnormalities.  Infections that cause acute myelopathy include:  Schistosomiasis (esp in Mideasterners), rabies virus, TB, lyme, syphilis, HSV, VZV, West Nile Virus, dengue, polio, coxsackie and Echovirus, actinomyces, blastomyces, >50 % none found, MAY HAVE OCB's

7. 71 yo woman with recurrent TM after 6 months, then paratonic spasms, TPO antibodies, letm, was NMO

8.  ADEM can be NMO positive and turn out to be NMO


Summary- conclusions  Algorithm: 1) is it compressive (subtle types included such as lipomatosis, spondylosis)  2)  is it really a myelopathy (parasagittal meningioma, CIDP)  3)  is it an acute presentation of a metabolic disorder (eg. B12 deficient patient exposed to nitrous oxide)  4) Is image quality and timing adequate?  (too early, too late)   5)  Is it functional?

New MRI Montalban criteria for diagnosis of multiple sclerosis

Neurology 2010; 74: 427-434.  called MAGNIMS proposal

* An MRI at any time showing dissemination in space (DIS) and showing 1 or more asymptomatic lesions enhancing and nonenhancing thus meeting criteria for dissemination in time (DIT) is sufficient to diagnose MS

*  An MRI showing DIS but without enhancing lesions, or with all lesions enhancing (thus no DIT), would require a new MRI to demonstrate additional lesions

*  An MRI at any time showing lesions but not DIT or DIS requires new MRI's

One DIS criterion: need one or more asymptomatic lesions in 2 of 4 locations considered characteristic for MS: juxtacortical (JC), periventricular (PV), infratentorial (IT), and spinal cord (SC).

Two DIT criteria:  1)  presence of one or more enhancing and nonenhancing lesions irrespective of the time of the scan and 2) presence of a new T2 and/or Gd+ lesion compared to a previous scan, irrespective of the time of the scan

The above apply only to those with CIS, ie symptomatic patients. 

fatigue components

Nocturnal jerks and phasic spasms
Nocturia multiple NGB
Depression
Deconditioning
increased energy requirements to move-- due to spasticity, balance
lots of drugs that contribute to fatigue
anemia
low vitamin levels, b12, D
temperature effects especially perimenstrual
effects of interferons. Try Naprelan, the long acting naprosyn, treximet,or pentoxifylline to prevent AE's before injections.

pearls symptoms management elliott froman

This summary is not available. Please click here to view the post.

differential diagnosis of longitudinally extensive spinal cord lesions

sarcoid
neuromyelitis optica
lupus
Sjogren's
multiple sclerosis
glioma (don't biopsy these patients deteriorate over weeks to months not days)

Pearls

evaluation includes

CSF
ESR
HIV status
CXR
MRI with contrast
B12
copper
Gallium scan for sarcoid
? Ace level
noncontrast CT chest to screen for  neurosarcoid (even in whites)

differential diagnosis of ring enhancing lesions on MRI

h/t Benjamin Greenberg AAN 2010

metastasis
abscess
glioma
lymphoma
infarction
contusion
demyelination
resolving hematoma
radiation necrosis

MS 12 item walking score

• These questions ask about limitations to your walking due to MS during the past 2 weeks.




• For each statement, please circle the one number that best describes your degree of limitation.



• Please answer all questions even if some seem rather similar to others, or seem irrelevant to you.



• If you cannot walk at all, please tick this box.









In the past two weeks, how much has your MS ... Not at all

--------------------------------------------------------------------------------

A little

--------------------------------------------------------------------------------

Moderately

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Quite a bit

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Extremely

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1. Limited your ability to walk? 1 2 3 4 5

2. Limited your ability to run? 1 2 3 4 5

3. Limited your ability to climb up and down stairs? 1 2 3 4 5

4. Made standing when doing things more difficult? 1 2 3 4 5

5. Limited your balance when standing or walking? 1 2 3 4 5

6. Limited how far you are able to walk? 1 2 3 4 5

7. Increased the effort needed for you to walk? 1 2 3 4 5

8. Made it necessary for you to use support when walking indoors (e.g., holding on to furniture, using a stick, etc.)? 1 2 3 4 5

9. Made it necessary for you to use support when walking outdoors (e.g., using a stick, a frame, etc.)? 1

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2 3 4 5

10. Slowed down your walking? 1 2 3 4 5

11. Affected how smoothly you walk? 1 2 3 4 5

12. Made you concentrate on your walking? 1 2 3 4 5



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Please check that you have circled ONE number for EACH question

© 2000 Neurological Outcome Measures Unit.

Infliximab and central and peripheral demyelination

Neurology AAN 2010 S47:002.  NozakiN, Judson M. Charleston.  2 cases of suspected sarcoid that became worse (central or peripheral demyeination) due to infliximab,  The case of peripheral demyelination improved with plasma exchanges.