John Engstrom, MD February 14, 2020 A 61 yo man with low back pain - - PDF document

John Engstrom, MD February 14, 2020 A 61 yo man with low back pain (LBP) presented to the neurology outpatient practice in December 2017 with bilateral (R > L) leg pain, weakness, numbness since April 2017. His LBP was worse with sitting and best when supine. There was no nocturnal LBP pain, fever, chills, or sweats. There was no history of head

• r spine trauma, MVA or whiplash, IVDU, steroid use, or cancer. There was no

history of chronic infection of the lungs, skin, urinary tract, or teeth. The patient had noticed diminished bulk of his bilateral calf muscles. There was weakness when pushing off with his feet while walking up stairs or uphill. There had been no falls, but he reported occasional tripping. He reported tingling below the knees bilaterally. Meloxicam and Lyrica provided modest pain relief. Referral records provided additional information. An EMG was interpreted as showing polyneuropathy. Spinal fluid analysis revealed the following: wbc 29 (66L/34M), rbc 1325, glucose 42, and protein 165 mg/dl. Flow cytometry was negative for neoplasm. CRAG was negative. Bacterial and fungal stains and cultures were negative. The CSF results were thought to reflect a possible chronic, low grade infection. His past medical history was notable for NAION (non-arteritic ischemic optic neuropathy) that had left him legally blind in both eyes. He is a retired, college- educated citrus farmer who has traveled the world and asks good questions. On general examination, there were no straight-leg raising signs or no palpation tenderness over the lumbar spine. On neurologic examination, mental status and cranial nerve assessments (in detail) were normal. On motor examination, there was normal tone in the limbs and mildly reduced bulk in the calves and feet. FFM were normal bilaterally and pronator drift was

• absent. Power testing in the arms and proximal legs was normal including

deltoid, biceps, triceps, IP, quads, hamstrings, leg adductors, and leg abductor

• muscles. Power in the distal legs (R/L) was as follows: TA 4-/4-, EHL 4-/4-, toe

flexors 4/4, and peronei 5/5. Deep tendon reflexes were absent except for 1+ right biceps brachii. He walked with a slight steppage gait bilaterally, and was unable to heel or toe walk bilaterally. Sensory examination was abnormal for decreased light touch sensation distal to the knees and impaired vibration sensation at the great toes bilaterally. There was a Romberg sign present with swaying in all directions when his eyes were closed. Additional diagnostic studies were performed.

References

• 1. Alderazi YJ, Coons SW, Chapman K (2012). J Child Neurol. doi:

10.1177/0883073811422831

• 2. Amariglio N, Hirshberg A, Scheithauer BW, Cohen Y, Loewenthal R, Trakhtenbrot L,

et al. (2009) PLoS Med. doi: 10.1371/journal.pmed.1000029

• 3. Bauer G, Elsallab M, Abou-El-Enein M (2018) Stem Cells Transl. Med. doi:

10.1002/sctm.17-0282

• 4. Berkowitz AL, Miller MB, Mir SA, Cagney D, Chavakula V, Guleria I, et al. (2016) N.
• Engl. J. Med. doi: 10.1056/NEJMc1600188
• 5. Hurst RW, Peter Bosch E, Morris JM, Dyck PJB, Reeves RK (2013) Muscle and
• Nerve. doi: 10.1002/mus.23920

.

John Engstrom, MD February 14, 2020 n-SCIPT: Case Discussion The name of the syndrome represented by this patient and the five other patients is n-

• SCIPT. The acronym stands for Neuroglial Stem Cell derived Inflammatory Pseudotumor. The

cardinal features include primitive neuroglial tissue that encases the nerve roots or presents with a mass-like appearance. The tissue is derived from stem cells infused into the subarachnoid space and is near the site of infusion. The CSF results reveal an inflammatory

• profile. The appearance of the tissue raises the diagnostic possibility of a neoplasm, but the low

mitotic index and other features indicate partially differentiated primitive neuroglial tissue only. The rise of loosely regulated stem cell clinics nationally and unregulated stem cell clinics internationally have given rise to mythical promises about the benefits of such infusions in the complete absence of proof. These false promises are the 21st century equivalent of the 19th century snake oil salesmen who promised snake oil as a panacea “for what ails you.” For example, if you perform a google search of “stem cell and blindness” you will see an extensive list of stem cell therapy options for a list price of up to $50,000 per infusion.

• Dr. Arnold Kriegstein, a senior stem cell scientist at UCSF and a faculty member in

Neurology, has testified before congress regarding the real and potential dangers of unregulated stem cell transplantation. In common with the patient presented today, the source

• f the stem cells and the stem cell screening process is unclear to the patient and poorly
• documented. Even in the United States, allogenic stem cells may be included in these infusions

about 15% of the time. No reliable information regarding these parameters is are available from international sources of stem cell infusions. As a result, we can expect to see more unusual neurologic complications of intrathecal stem cell therapy over in the future. It is important for the clinical neurologist to be aware of this syndrome for several

• reasons. First, we need to be comfortable telling our patients that unregulated stem cell therapy

is an expensive scam. Second, we need to be prepared to give patients examples of the serious risks or complications known to be caused by unregulated stem cell therapies. Third, all our patients are susceptible to false promises of cure for untreatable illnesses. The patient presented today is an outstanding example of how this principle applies to all patients. Fourth, we need to be prepared to ask our patients if they have had stem cell therapies in the setting of thickened lumbar nerve roots and lumbar polyradiculopathy or the presence of unexplained abnormal tissue in the lumbar subarachnoid space. Many issues regarding the neurologic complications of intrathecal stem cell therapy are

• unresolved. The timeline over which neurologic complications of intrathecal stem cell therapy

might present is unknown. The long term prognosis of n-SCIPT is unknown. The extent to which the inflammatory cerebrospinal fluid is beneficial or injurious is unknown. The utility of immunomodulation therapy is unknown. While n-SCIPT is one complication, we will almost

certainly see others. Close follow-up of these patients will further define the natural history and

• ptimal management of N-SCIPT.

References

• 1. Alderazi YJ, Coons SW, Chapman K (2012) Catastrophic demyelinating encephalomyelitis

after intrathecal and intravenous stem cell transplantation in a patient with multiple sclerosis. J Child Neurol. doi: 10.1177/0883073811422831

• 2. Amariglio N, Hirshberg A, Scheithauer BW, Cohen Y, Loewenthal R, Trakhtenbrot L, et al.

(2009) Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Med. doi: 10.1371/journal.pmed.1000029

• 3. Bauer G, Elsallab M, Abou-El-Enein M (2018) Concise Review: A Comprehensive Analysis of

Reported Adverse Events in Patients Receiving Unproven Stem Cell-Based Interventions. Stem Cells Transl. Med. doi: 10.1002/sctm.17-0282

• 4. Berkowitz AL, Miller MB, Mir SA, Cagney D, Chavakula V, Guleria I, et al. (2016)

Glioproliferative lesion of the spinal cord as a complication of stem-cell tourism. N. Engl. J. Med. doi: 10.1056/NEJMc1600188

• 5. Hurst RW, Peter Bosch E, Morris JM, 5. Dyck PJB, Reeves RK (2013) Inflammatory

hypertrophic cauda equina following intrathecal neural stem cell injection. Muscle and Nerve. doi: 10.1002/mus.23920

• 6. Julian K, Yuhasz N, Hollingsworth E, Imitola J (2018) The Growing Reality of the Neurological

Complications of Global Stem Cell Tourism. Semin Neurol. doi: 10.1055/s-0038-1649338

• 7. Kuriyan AE, Albini TA, Townsend JH, Rodriguez M, Pandya HK, Leonard RE, et al. (2017)

Vision loss after intravitreal injection of autologous “stem Cells” for AMD. N Engl J Med. doi: 10.1056/NEJMoa1609583

• 8. Lee BS, Achey RL, Yeaney GA, Bosler DS, Aly Z, Ontaneda D, et al. (2018) Stem cell

injection180 induced glioneuronal lesion of the cauda equina. Neurology. doi: 10.1212/WNL.0000000000005219

2/14/2020 1

UCSF Neurology Outpatient Conference John Engstrom, M.D. February 14, 2020 Just Another Lumbar Polyradiculopathy?

Thanks and Disclosures

Thanks! Neuropathology-Dr. Emily Sloan,

• Dr. Marta Margeta

Neurosurgery-Dr. Line Jacques Neurology-Dr. Felicia Chow, Dr. Arnold Kriegstein, Dr. Michael Wilson Disclosures I have no conflicts of interest to disclose

Hx: LBP + Bilateral Leg Pain 12/17

• 61 yo man with LBP and bilateral (R > L) leg

pain, weakness, numbness since 4/17

• Pain worse with sitting, best supine
• No nocturnal pain, head or spine trauma, MVA or

whiplash, IVDU, steroid use

• No hx cancer, or chronic infection of lungs, skin,

urinary tract or teeth

• No fever, chills , sweats

Hx: Other Symptoms

• Bilat calf weakness + decr bulk onset 7/17

– Decreased ability to push off with his feet – True calf cramps

• Tingling below knees beginning 8/17
• No falls, but reduced balance with occasional

tripping over right or left foot

• Using Meloxicam and Lyrica for pain with

minimal benefit

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2/14/2020 2

Prior Outside Information

• Initially attributed to lifting incident in 4-17
• EMG-interpreted as polyneuropathy
• CSF wbc 29 (66L/34M), rbc 1325, glucose 42,

protein 165; flow cytometry negative

• CRAG, bacterial and fungal stains and cultures

neg

• CSF thought to reflect a chronic low grade

infection

PMH, FH, Social, ROS

• NAION (non-arteritic ischemic optic neuropathy)

–fuzzy vision, legally blind

• Hypertension
• FH negative for neurologic disease
• SH College graduate; retired citrus farmer
• Lives in a suburb of Sacramento
• Rarely drinks alcohol; never a smoker
• ROS negative

Gen and Neuro Exams

• No straight-leg raising signs or palpation

tenderness over the lumbar spine

• Motor-nl tone and limb coordination

– Power normal in arms, FFMs nl, foot taps slow – Normal power in muscles proximal to knees – Power: TAs 4-, EHLs 4-, toe flexors 4 – Steppage gait (R > L); cannot heel/toe walk

• Reflexes absent except right biceps
• Sensory decr below knees; Romberg present

Normal Lumbar Spine MRI-Sagittal T2

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Normal Lumbar Spinal Canal-Axial T2

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Lumbar Spine MRI June 2017

L4-5

L1-2

L1 L2 L3 L4 L5 S1 Conus Medullaris Cauda Equina Roots

PET May 2018

Presentation Title 1 1

Q1-The Ddx includes which one of the following?

• A. Neoplastic infiltration of the nerve roots
• B. Chronic meningitis due to infection
• C. Arachnoiditis
• D. CIDP (chronic inflammatory

demyelinating polyneuropathy)

• E. All of the above

N e

• p

l a s t i c i n f i l t r a t i

• n
• f

t h e . . . C h r

• n

i c m e n i n g i t i s d u e t

• i

n . . . A r a c h n

• i

d i t i s C I D P ( c h r

• n

i c i n f l a m m a t

• r

y . . . A l l

• f

t h e a b

• v

e

8% 2% 77% 6% 7%

9 10 11 12

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Differential Diagnosis

• Neoplasm-enlarged roots with infiltration of roots

(lymphoma, metastatic disease)

• Infection-undetected fungal/viral/bacterial
• Arachnoiditis-seen with recurrent spine surgery,

chronic infection, hemorrhage, IT chemotherapy

• CIDP (given near areflexia)-demyelination and

remyelination of lumbar nerve roots

Additional Clinical Information

• Found on the web optimistic reports of stem cell

therapy Rx for blindness, inclu NAION

• Traveled to Russia and China where he received

intrathecal chemotherapy

– Source of stem cells unknown – Injections intrathecal in the lumbar spine – Tolerated well

• Google: “stem cell therapy for blindness”

– Dr. Kriegstein testified before congress – Cost $2,000-$50,000 per treatment in Mexico

Additional Clinical Information

• EMG-bilateral L5/S1 motor radiculopathies and

no demyelinating polyneuropathy

• Repeat LP glu 40, protein 1164, rbc 720, wbc 195

(61L/37M/2P), VDRL neg

• IgM for West Nile positive
• Neuro ID (Dr. Felicia Chow)-coincident WNV

infection, not cause of this syndrome

• Universal Microbial DNA testing negative
• Neurosurgery for nerve root biopsy

Intraoperative Photo-Dr. Jacques

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Q2: What is the Most Impt Dx Addition to Your Expanded Ddx?

• A. No change in ddx because autologous

stem cells should not produce a problem

• B. This could be an infiltrating tumor arising

from the stem cells

• C. The stem cells induced an immuno-

compromised state

• D. The stem cells produced a mass with
• rgan-specific tissue

N

• c

h a n g e i n d d x b e c a u s e a . . . T h i s c

• u

l d b e a n i n f i l t r a t i n g . . . T h e s t e m c e l l s i n d u c e d a n . . . T h e s t e m c e l l s p r

• d

u c e d a m . . .

4% 51% 9% 37%

Neurofilament Protein (NFP)

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CD3 CD68 CD20

UCSF500 Molecular Analysis: Paired lesional tissue and germline sequencing

• No chromosomal gains, losses, focal amplifications or deletions
• No known pathogenic variants including hotspot mutations important in

glioma pathogenesis

• ~90 nonsynonymous variants present in aberrant glioneuronal tissue

but not in germline sample

• Vast majority are single nucleotide polymorphisms (SNPs) common

in human populations

– Allele frequencies of 20% or 40% likely representing heterozygous and homozygous SNPs

Dx from S1 Sensory Nerve Root Biopsy

Donor-derived glioneuronal proliferation following intrathecal stem cell injection

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N-SCIPT Syndrome

• Neuroglial
• Stem Cell derived
• Inflammatory
• PseudoTumor
• Published in Acta Neuropathologica 12/19
• If you see a patient who received a stem cell

infusion for an unproven indication and who has new neurologic findings of unclear cause, please refer to us!

N-SCIPT Clinical Features

• Hx stem cell injection into CSF
• Subacute-chronic focal neuro symptoms
• Mass lesion, cord, or root thickening near

injection site

• Inflammatory CSF
• Tissue biopsy-glial or mixed neuroglial origin

with or without inflammation

• Molecular studies demonstrating non-patient

tissue

Clinical Course

• In retrospect, patient embarrassed he was taken

advantage of in quest to restore vision

• Supportive of case report and conference, but did

not want to be present

• Follow-up imaging unchanged, but slow

progression of motor deficits in distal legs

• Discussion of Rx with BMT faculty

Q3: What is the Optimal Treatment for this Patient?

• A. Steroids
• B. IVIG
• C. Cytotoxic medications (e.g.-Imuran)
• D. “First do no harm.” No treatment
• E. The optimal treatment is unknown

S t e r

• i

d s I V I G C y t

• t
• x

i c m e d i c a t i

• n

s ( e . g .

• .

. . “ F i r s t d

• n
• h

a r m . ” N

• t

r e a . . . T h e

• p

t i m a l t r e a t m e n t i s u . . .

10% 9% 62% 8% 11%

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2/14/2020 8

Clinical Unknowns

• Is the inflammatory profile in CSF “good

inflammation” or “bad inflammation”?

– Inflammation causing injury to nerve roots? – Inflammation directed against the non-self neuroglial tissue?

• Extent of population at risk for similar

complications unknown

• Prognosis and optimal management unknown

Take Home Points

• Smart patients with untreatable illnesses are

susceptible to sales pitches for unproven Rx

• “First, do no harm”- Discourage pts from

pursuing expensive, risky, unproven Rx

• The history does not end with the first patient

encounter

• Good clinical observations can become great

when neurology is a team sport!

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