John Betjemann, MD February 14, 2020 Patient Presentation A 17 - - PDF document

John Betjemann, MD February 14, 2020 Patient Presentation A 17 year-old young man presented with altered mental status and depressed respiratory effort. The patient has no known medical history and takes no medications. On the day of admission he was with friends who noted that he may have used some substances and by report he has a history of alcohol and alprazolam (Xanax) abuse. They noted that he was sleeping for a prolonged period of time and became concerned when he appeared to stop snoring. EMS was called and administered naloxone without effect. Upon arrival to the emergency room he was noted to be breathing spontaneously but had a Glasgow Coma Scale of 3. On his initial neurologic exam he was intubated, sedated and paralyzed. He underwent routine laboratory testing that revealed a mildly elevated creatinine, creatine kinase and liver function tests. A non-contrast CT scan of the head was unremarkable. On repeat examination following extubation he was noted to be conversant with fluent

• speech. He was oriented to the year but not his location or the remainder of the date

and frequently answered “I don’t know” when asked other simple orientation questions. The remainder of his neurologic exam including cranial nerves, motor, reflexes, sensation and coordination was unremarkable. Diagnostic procedures were performed. References

• 1. Somerville NJ, et al. Morb Mortal Wkly Rep 66:382-386, 2017.
• 2. Barash JA, Somerville N, DeMaria A Jr.. Morb Mortal Wkly Rep 66:76-79, 2017.
• 3. Barash JA, et al. N Engl J Med 378:1157-1158, 2018.
• 4. Barash JA, Ganetsky M, DeMaria A Jr. N Engl J Med 378:2247-2248, 2018.
• 5. Khatri UG, Viner K, Perrone J. N Engl J Med 379:1782, 2018.
• 6. Frank RG, Pollack HA. N Engl J Med 376:605-607, 2017.
• 7. Bhattacharyya S, Gholipour T, Colorado DA, Klein JP. J Neuroimaging 27:300-

305, 2017.

John Betjemann, MD February 14, 2020 Case Discussion The patient presented with acute encephalopathy for which the differential diagnosis very broad. Once extubated it became clear that he primarily had an acute amnestic syndrome as well as some disorientation. The MRI was the biggest clue to his

• diagnosis. The symmetric nature of the MRI changes involving the hippocampi raises

suspicion for hypoxia, toxic or metabolic etiologies. The hippocampi are particularly vulnerable to hypoxic-ischemic injury. Neuroimaging studies have demonstrated that bilateral reduced diffusion in the hippocampi often results from hypoxic-ischemic injury, but the underlying causes can be quite varied and include substance abuse (cocaine,

• pioids, benzodiazepines), cardiac arrest, nonconvulsive seizures and hypoglycemia.

Ultimately our patient was diagnosed with fentanyl overdose leading to respiratory compromise, hypoxia, and the hippocampal changes seen on MRI. It is worth noting that in our clinical lab, and likely in many others, it requires an extended toxicology screen to detect fentanyl. Fentanyl overdoses have risen dramatically throughout the country, including in the Bay Area, such that public health interventions are warranted. Fentanyl is being used to cut

• ther illicit drugs such as heroin because it is relatively cheap and potent but is also

being used to cut counterfeit oxycodone, alprazolam and hydrocodone/acetaminophen (Norco), often times unbeknownst to the person taking the drug. People who have witnessed a fentanyl overdose describe that symptoms occur rapidly and include blue discoloration of the lips, gurgling sounds, stiffening of the body, foaming at the mouth and confusion. Often a single dose of naloxone is insufficient to reverse the effects of fentanyl. As in this case, fentanyl overdose often causes an acute amnestic syndrome with other areas of cognitive impairment including attention and

• rientation. The MRI findings in the case presented have been well described in other

fentanyl overdoses. The exact mechanism of injury is not known but potential mechanisms include cerebral ischemia, hypoxemia, or excitotoxicity. Other than naloxone, treatment is largely supportive and the amnestic syndrome has been reported to last months or even longer. References

• 1. Somerville NJ, et al. Characteristics of fentanyl overdose – Massachusetts, 2014-
• 2016. Morb Mortal Wkly Rep 66:382-386, 2017.
• 2. Barash JA, Somerville N, DeMaria A Jr. Cluster of an unusual amnestic

syndrome – Massachusetts, 2012-2016. Morb Mortal Wkly Rep 66:76-79, 2017.

• 3. Barash JA, et al. Acute amnestic syndrome associated with fentanyl overdose. N

Engl J Med 378:1157-1158, 2018.

• 4. Barash JA, Ganetsky M, DeMaria A Jr. More on acute amnestic syndrome

associated with fentanyl overdose. N Engl J Med 378:2247-2248, 2018.

• 5. Khatri UG, Viner K, Perrone J. Lethal fentanyl and cocaine intoxication. N Engl J

Med 379:1782, 2018.

• 6. Frank RG, Pollack HA. Addressing the fentanyl threat to public health. N Engl J

Med 376:605-607, 2017.

• 7. Bhattacharyya S, Gholipour T, Colorado DA, Klein JP. Bilateral hippocampal

restricted diffusion: same picture many causes. J Neuroimaging 27:300-305, 2017

John Betjemann, MD February 14, 2020 Patient Presentation A 37 year-old transgender woman presents with vision loss, cognitive complaints, and jerking movements that have caused falls. She initially presented with 2 weeks of progressive vision loss of the left eye and was diagnosed with neuroretinitis and macular edema of unclear etiology. She was subsequently lost to follow up. Three years later she presented to clinic with depression, memory complaints and falls. She had a Montreal Cognitive Assessment of 26/30 and was diagnosed with major depressive disorder. Five months later she was seen in the emergency room for worsening depression, worsening cognitive impairment, and new

• nset insomnia. Reversible causes of dementia labs (B12, HIV, TSH and RPR) were
• unremarkable. MRI showed trace periventricular T2/FLAIR hyperintensities. She was

discharged without a diagnosis. She then returned one month later with continued worsening of all of her symptoms. She was no longer able to work and had noted new gait instability. In particular, she noted jerking movements that would cause her to fall. On her neurologic exam at that time she scored a 13/30 on Montreal Cognitive Assessment (0/5 executive function, 3/3 naming, 3/6 attention, 0/3 language, 1/2 abstraction, 0/5 delayed recall, 6/6 orientation). She was also noted to have hypomimia and hypophonia. Motor exam demonstrated only trace weakness in left hip flexion and rigidity in the left leg. She had diffuse, nonstimulus-dependent myoclonic jerks approximately every 30 seconds. Repeat MRI showed interval worsening of the previously seen periventricular T2/FLAIR hyperintensities bilaterally. Diagnostic procedures were performed. References

• 1. Holmes BB, Conell-Price J, Kreple CJ, Ashraf D, Betjemann J, Rosendale N.

The Neurohospitalist 2019. doi: 10.1177/1941874419869713

• 2. Garg RK, Mahadevan A, Malhotra HS, Rizvi I, Kumar N, Uniyal R. Rev Med

Virol 29(5), 2019. doi: 10.1002/rmv.2058

• 3. Raut TP, Singh MK, Garg RK, Rai D. BMJ Case Rep 2012. doi: 10.1136/bcr-

2012-007052

• 4. Colpak AI, Erdener SE, Ozgen B, Anlar B, Kansu T. Curr Opin Ophthalmol

23(6):466-471, 2012

John Betjemann, MD February 14, 2020 Case Discussion The patient initially presented with ophthalmologic symptoms and was diagnosed with neuroretinitis and chorioretinitis of unclear etiology. She then returned numerous times

• ver the next few years with nonspecific cognitive decline, depression/behavioral

changes, and falls. Labs testing for reversible causes of dementia were unremarkable and MRI brain showed nonspecific changes. She was initially misdiagnosed as having major depressive disorder. Given the nonspecific nature of the initial symptoms it is not unusual for patients with subacute sclerosing panencephalitis (SSPE) to be misdiagnosed or remain undiagnosed for some time, particularly adult patients in whom SSPE is even more rare. It wasn’t until the patient presented with profound cognitive decline, myoclonus and rigidity that a more extensive work up was undertaken. Her CSF was inflammatory with an elevated IgG index and numerous oligoclonal bands unique to the CSF. However, her EEG was the real diagnostic clue. The high amplitude, bilateral periodic complexes seen ever 5-7 seconds are typical of SSPE and serve as one of the Dyken criteria to diagnose SSPE. The EEG prompted CSF rubeola testing and when the IgG returned elevated the patient met 4/5 Dyken criteria:

• 1. Clinical presentation of subacute cognitive decline and myoclonus
• 2. Periodic discharges on EEG
• 3. Elevated CSG IgG index of oligoclonal bands
• 4. Raised rubeola titer in serum or CSF
• 5. Brain biopsy (not pursued given that 4/5 criteria were already met)

SSPE is a rare, chronic, progressive encephalitis caused by persistent mutant measles virus and involves both gray and white matter. Typically, the disease presents in childhood or adolescence, but rare cases have been described in adults with a prolonged latent period between initial measles infection and the onset of SSPE-related

• symptoms. SSPE often presents with nonspecific cognitive complaints but in up to 50%
• f cases ocular manifestations are also present. The most common findings are

chorioretinitis, retinal vasculitis and papillitis, though other findings have been described including cortical vision loss. While these changes often occur along with the neurologic symptoms, they can precede neurologic symptoms by years and should have served as a clue in this particular case. As the disease progresses myoclonus appears and can

• ften present with falls. Pyramidal and extrapyramidal feature commonly develop as the

disease progresses. The diagnosis of SSPE is based on the Dyken criteria (see above). Accordingly, CSF and EEG are very helpful while neuroimaging is often nonspecific. Antimeasles antibody titers of >1:256 in the serum or >1:4 in the CSF are considered diagnostic of SSPE.

Treatment involves the use of antiviral agents including Interferon-α or Interferon-β. These are often combined with Ribavirin. The prognosis is poor and death often occurs within 1-3 years. There are reports of patients surviving longer in cases of spontaneous disease remission. Accordingly, the emphasis needs to be on public education regarding the importance of vaccination. References

• 1. Holmes BB, Conell-Price J, Kreple CJ, Ashraf D, Betjemann J, Rosendale N.

Adult-onset subacute sclerosing panencephalitis with a 30-year latent period. The Neurohospitalist 2019. doi: 10.1177/1941874419869713

• 2. Garg RK, Mahadevan A, Malhotra HS, Rizvi I, Kumar N, Uniyal R. Subacute

sclerosing panencephalitis. Rev Med Virol 29(5), 2019. doi: 10.1002/rmv.2058

• 3. Raut TP, Singh MK, Garg RK, Rai D. Evolution of certain typical and atypical

features in a case of subacute sclerosing panencephalitis. BMJ Case Rep

• 2012. doi: 10.1136/bcr-2012-007052
• 4. Colpak AI, Erdener SE, Ozgen B, Anlar B, Kansu T. Neuro- ophthalmology of

subacute sclerosing panencephalitis: two cases and a review of the literature. Curr Opin Ophthalmol 23(6):466-471, 2012

• 5. Garg RK. Subacute sclerosing panencephalitis. Postgrad Med J 78(916):63-

70, 2002.

2/14/2020 1

RAIN 2020: Cases from ZSFG

John Betjemann, MD Associate Professor of Neurology

Disclosures

• Dr. Betjemann has received consulting fees

from Marinus Pharmaceuticals for work related to status epilepticus

ZSFG

• Relationship with UCSF since 1873
• San Francisco’s main public safety net hospital and
• nly level 1 trauma center

ZSFG (%) CCSF 2010 Census (%) White 23 42 African American 17 6 Hispanic 31 15 Native American <1% n/a Asian/PI 23 33 Other/Unknown 5 4

Case 1

• History
• 17 yo young man presented with altered mental status

and depressed respiratory effort

• Friends noted he had been sleeping for a prolonged

period, became worried when he stopped snoring.

• He has used drugs (alprazolam) and alcohol in the past
• GCS 3 but was breathing. Received naloxone without

effect.

• Meds
• Takes no medications

1 2 3 4

2/14/2020 2

Case 1

• CBC normal
• Creatinine 1.2
• Lactic acid 5.6
• AST 188, ALT 151, Alk P 93
• CK 633
• Ammonia 16
• TSH 0.88
• B12 723
• RPR nonreactive
• HIV nonreactive
• Acetaminophen, Salicylate,

Ethanol all unremarkable

• Utox pending

On initial exam he is afebrile, intubated, sedated and paralyzed. A head CT is obtained and is unremarkable

Case 1: Question 1

On initial exam he is intubated, sedated and paralyzed. What would you like to do next?

• A. Lumbar puncture: I’m concerned for meningitis/CNS

infection

• B. EEG: I’m concerned for status epilepticus
• C. MRI: I’m concerned for acute multifocal strokes

missed on CT

• D. Wean sedation and repeat exam: I’m not sure what is

going on here

L u m b a r p u n c t u r e : I ’ m c

• n

c e . . . E E G : I ’ m c

• n

c e r n e d f

• r

s t a t u . . . M R I : I ’ m c

• n

c e r n e d f

• r

a c u t . . . W e a n s e d a t i

• n

a n d r e p e a t . . .

28% 30% 12% 29%

Case 1

• Sedation weaned and extubated the day of admission
• Neuro exam
• MS: Conversant with fluent speech. Oriented to year but not

month, date or hospital. Knows president. Able to name and

• repeat. Follows commands. Unable to recite months of the year

backwards past November. Says “I don’t remember” to most questions.

• CN: VFF, EOMI, PERRL, face symmetric, sens intact, no
• dysarthria. Full shoulder shrug
• Motor: Normal bulk and tone. 5/5 throughout
• Reflexes: 2+ and symmetric, toes down
• Sens: intact to LT
• Coord: intact FNF and HKS

Case 1:

• Utox: + oxycodone
• Started thiamine 500mg IV TID
• MOCA: 19/30 (-3 executive/visuospatial, -1 language

fluency, -5 delayed recall, -3 orientation)

• MRI…

5 6 7 8

2/14/2020 3 Case 1: MRI

DWI ADC

Case 1: Question 2

What would you like to do next?

• A. Lumbar puncture
• B. Extended toxicology screen
• C. EEG
• D. Initiate multifocal stroke work up

L u m b a r p u n c t u r e E x t e n d e d t

• x

i c

• l
• g

y s c r e e n E E G I n i t i a t e m u l t i f

• c

a l s t r

• k

e w

• .

.

55% 4% 21% 20%

Case 1: Question 3

The patient’s clinical picture of depressed mental status, acute amnestic syndrome and MRI findings are most consistent with an overdose of?

• A. MDMA (Ecstasy)
• B. Methamphetamine
• C. Fentanyl
• D. Alcohol

M D M A ( E c s t a s y ) M e t h a m p h e t a m i n e F e n t a n y l A l c

• h
• l

58% 10% 21% 11%

9 10 11 12

2/14/2020 4 Case 1: Fentanyl Overdose

• Potential mechanisms of fentanyl-related hippocampal injury
• Cerebral ischemia, hypoxemia, excitotoxicity
• Has been shown to cause hippocampal damage in rats
• Fentanyl used to cut heroin, counterfeit oxycodone, Xanax

and Norco

• Fentanyl is potent and cheap
• Heroin: $65,000 per kg
• Fentanyl: $3,500 per kg
• From 2012-2014 Fentanyl deaths have more than doubled

Case 1: Question 4

Have you ever treated a fentanyl overdose similar to this patient?

• A. Yes
• B. No

Y e s N

• 96%

4%

Case 2

• 37 yo transgender woman from the Philippines

presented with 2 weeks of progressive, painful vision loss in the left eye.

• Diagnosed with chorioretinitis,

neuroretinitis and macular edema

• Lost to follow up

Holmes BB, et al. The Neurohospitalist 2019. doi: 10.1177/1941874419869713

13 14 15 16

2/14/2020 5 Case 2: 3 years later…

• Presents to clinic with depression, memory complaints

and falls.

• MOCA 26/30, otherwise unremarkable neurologic exam
• Diagnosed with major depressive disorder
• 5 months later worsening depression, cognitive

impairment, new-onset insomnia and left leg weakness

• B12, HIV, ANA, TSH and RPR are unremarkable
• MRI brain shows trace periventricular T2/FLAIR hyperintensities
• Discharged without a diagnosis

Case 2: one month later…

• Frequent falls
• Cognitive decline: word-finding, fluency
• Gait instability, dysphagia
• Jerking movements causing her to fall and have trouble

with self care

• Exam
• 13/30 MOCA
• Hypomimia, hypophonia
• LE rigidity
• Diffuse myoclonic jerks approximately every 30 seconds

Case 2

 Repeat MRI 38 days after prior MRI

Holmes BB, et al. The Neurohospitalist 2019. doi: 10.1177/1941874419869713

Case 2: Question 1

Which category of rapidly progressive dementia are you most concerned for?

• A. Inflammatory: autoimmune/paraneoplastic encephalitis,

steroid responsive with associated thyroiditis

• B. Infectious
• C. Atypical neurodegenerative: early Parkinson disease etc.
• D. Toxin exposure
• E. Prion

I n f l a m m a t

• r

y : a u t

• i

m m u n e . . . I n f e c t i

• u

s A t y p i c a l n e u r

• d

e g e n e r a t i v e : . . . T

• x

i n e x p

• s

u r e P r i

• n

38% 21% 26% 8% 7%

17 18 19 20

2/14/2020 6

Case 2

• Labs:
• heavy metals, LFTs, renal function, B12, Vit E, Utox
• ANA, Thyroglobulin Ab, thyroperoxidase Ab
• RPR, CSF VDRL, CSF CrAg, CSF Cocci
• ESR 91, CRP >200
• CSF
• 2 WBC, 9 RBC, gluc 95 (serum 165), protein 84, IgG index

1.25, 11 unique oligoclonal bands, 14-3-3 negative

Case 2: Question 2

What to do next?

• A. Repeat MRI brain
• B. Empiric steroids
• C. Empiric antibiotics/antivirals
• D. EEG
• E. Phone a friend

R e p e a t M R I b r a i n E m p i r i c s t e r

• i

d s E m p i r i c a n t i b i

• t

i c s / a n t i v i r a l s E E G P h

• n

e a f r i e n d

12% 44% 13% 23% 8%

Case 2: A friend

Holmes BB, et al. The Neurohospitalist 2019. doi: 10.1177/1941874419869713

Case 2: Question 3

What is your diagnosis?

• A. Creutzfeldt-Jacob disease
• B. NMDA receptor encephalitis
• C. Subacute sclerosis panencephalitis
• D. Progressive myoclonic epilepsy
• E. Gerstmann-Sträussler-Scheinker syndrome
• F. Call Maulik again

C r e u t z f e l d t

• J

a c

• b

d i s e a s e N M D A r e c e p t

• r

e n c e p h a l i t i s S u b a c u t e s c l e r

• s

i s p a n e n c e p . . . P r

• g

r e s s i v e m y

• c

l

• n

i c e p i l e p s y G e r s t m a n n

• S

t r ä u s s l e r

• S

c h e i . . . C a l l M a u l i k a g a i n

41% 8% 3% 2% 9% 37%

21 22 23 24

2/14/2020 7

Case 2: Subacute sclerosing panencephalitis

• Rubeola IgG serum: 4.54 AU (ref <0.7 AU)
• Rubeola IgG CSF: >300 AU/mL (ref <29.9 AU/mL)
• Never immunized and contracted measles at age 10
• Outcome
• Treatment with intravenous ribavirin and intrathecal interferon-
• Ribavirin caused hemolytic anemia
• Patient developed generalized tonic-clonic seizures
• Ultimately passed away from complications 3 months after

diagnosis

Subacute Sclerosing Panencephalitis: Question 4

Which feature is not typical of SSPE?

• A. Bilateral symmetric periodic complexes on EEG
• B. Ophthalmologic findings: chorioretinitis
• C. Age of onset > 30 with a latent period of 30 years
• D. Progressive cognitive decline and myoclonus
• E. Elevated CSF IgG index or oligoclonal bands

B i l a t e r a l s y m m e t r i c p e r i

• d

i . . . O p h t h a l m

• l
• g

i c f i n d i n g s : c h . . . A g e

• f
• n

s e t > 3 w i t h a l a t e . . P r

• g

r e s s i v e c

• g

n i t i v e d e c l i n . . . E l e v a t e d C S F I g G i n d e x

• r
• l

i . . .

3% 19% 15% 3% 60%

Subacute Sclerosing Panencephalitis

Garg RK. Subacute sclerosing panencephalitis. Postgrad Med J 78(916):63-70, 2002.

Case 2: Question 5

Have you ever made the diagnosis of SSPE?

A.

Yes

B.

No

Y e s N

• 90%

10%

25 26 27 28

2/14/2020 8

Thank you

29 30