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Department of Medicine

Morbidity and Mortality Conference

January 9, 2018

“A 76 year old male with acute lower extremity weakness”

Presenter: Rachel Rome, MD

Internal Medicine Resident, PGY3

Prepared by Malorie Simons, MD

Chief Medical Resident

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Panel Discussants Adam Olszewski, MD

Hematology and Oncology

Jaroslaw Hepel, MD

Radiation Oncology

Thomas Kosztowski, MD

Neurosurgery

Dariusz R Stachurski, MD

Pathology

Contributions from Dr. Sairah Sharif and Dr. Eric Kerns from Nephrology

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Disclosures

There are no disclosures.

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Chief Complaint: lower extremity weakness

History of Present Illness: 76 M who presented to Tobey Hospital with

bilateral LE weakness 2 days prior to admission. His symptoms suddenly,

and gradually worsening until he was unable to ambulate.

• ROS positive for inability to bear weight due to weakness.

• ROS negative for recent illness, sensory changes, bower or bladder

dysfunction, back pain, chest pain, shortness of breath, nausea,

vomiting, upper extremity weakness of dysphagia, back pain.

Case Presentation

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PMHx Diagnosed with IgG lambda multiple myeloma 8 months prior

(10/2016) after PCP found abnormal renal function and anemia

on routine laboratory results.

Has been on chemotherapy since that time.

– CyBorD (Cyclophosphamide, Bortezomib, Dexamethasone)

– Completed 9 cycles.

– Lambda light chains nadired to 15, but over the past few

months increased to 320 (one week prior to admission).

Outpatient oncologist planned to switch his chemotherapy

regimen

– Did not complete infusion the week prior 2/2

thrombocytopenia.

Dr. Olszewski: Multiple Myeloma is now referred to as “Plasma Cell Myeloma

(PCM)” based on new definitions published in 2015. It is now recognized that all

patients with myeloma are preceded with monoclonal gammopathy. Indolent myeloma

is one subset of this disorder.

PCM is defined based upon

• Symptoms

• Anemia

• Presence of lytic lesions

• Renal Failure

• Visible lesions on MRI

• >60% plasma cells on bone marrow biopsy

• Free light chain kappa/lambda ratio has replaced urine immunoelectropheresis to

diagnose PCM.

This patient’s major gammopathy is in production of free light chains, which are not

seen on SPEP but are tested for specifically.

Treatment is quite good for PCM. Patients who undergo bone marrow transplant can be

expected to have an average survival of 10 years, while those treated without transplant

have an average survival of 5 years. Chemotherapy, as in this patient, consists of a

steroid, an antimetabolite such as cyclophosphamide and a protease inhibitor such as

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Bortezomib. All 3 of these medications may be used without modification in patients

with renal failure.

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Past Medical History:

•HTN

•Gout

Past Surgical History:

•Remote right orbital fracture requiring

surgery after MVA

•Remote removal of pleural cyst c/b post

surgical empyema

Allergies: None

Family History:

•Mother with heart failure

•Father with lung cancer and bladder

cancer

History (Continued)

Medications:•Allopurinol

•Bisacodyl

•Acyclovir

•Dexamethasone 4 mg

•Metoprolol tartrate

•Pantoprazole

•Furosemide

•Docusate

•Calcium with vitamin D

•Zolendronic acid

Social History:

• Quit smoking 46 years ago

• Drinks 8 oz alcohol per week.

• Lives at home, independent

with ADL’s prior to admission.

•No other recent travel, no pets

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Physical Examination –Vital Signs: T 98.2 HR 116 BP 159/98 RR 18 O2 sat: 96% RA

General: No acute distress. Well appearing but anxious about his symptoms.

HEENT: no scleral icterus, PERRLA, EOMI Neck: No JVD Cardiovascular:

tachycardic, regular rate and rhythm, normal s1/s2, no r/m/g Pulmonary: Clear

bilaterally. Abdominal: soft, non-tender throughout; no rebound or guarding.

Extremities: no cyanosis, clubbing, or edema. Skin: No rash or ulcers

Neuro:

• Abnormal Reflexes: bilateral + Babinski. 0 patellar and Achilles reflexes

bilaterally. bilateral clonus

• Strength: 1+ strength beyond the knee. 2+ at knee.

• Sensation: no saddle anesthesia, LE sensation intact.

• No urinary incontinence, retention or fecal retention.

Dr. Kosztowski: This patient’s neurologic exam reflects deficits in lower as well as

upper motor neuron function. The lesion at the T3 level is likely causing the upper

motor neuron deficit, reflected by clonus and positive Babinski reflexes.

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Laboratory Results

5.5*12.5

68 140 110

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1.0615136.8

4.0

AST 45 Tbili 0.4

ALT 37 Alk Phos 57

Protein 7.1

Albumin 2.6

LDH 614

Free Lambda Light Chain 5,850

Kappa/Lambda Light Chain Ratio 0.00

MCV: 100.2

77% neutrophils

5% lymphocytes

0% plasma cells

*Baseline Hgb 12.5

INR 1.2

Dr. Olszewski: This patient is demonstrating a “serologic

relapse” – his free light chain levels have risen acutely to a high

level indicating aggressive disease. The rise from 300 to 5000 is

alarming. His thrombocytopenia could be due to

cyclophosphamide or to infiltration of bone marrow by plasma

cell. The elevated LDH of 614 indicates a high risk tumor burden

and a poor prognosis. Current standard of care is to review

cytogenetic evaluation of the tissue in order to determine

prognosis and treatment options.

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Diagnostic Imaging

Dr. Hepel: The T3 vertebral body reflects abnormal marrow signal with extension of the

lesion into the epidural space, causing cord compression. There is a second vertebral

lesion higher up in the cervical region.

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Diagnostic Imaging, cont.

Dr. Hepel: These images show that the cord is displaced with very little CSF (white) at

this level due to tumor compression and cord displacement and compression.

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Case Summary

76 M with IgG myeloma who presented to Tobey Hospital with LE weakness, found to clinical and MRI findings concerning for plasmacytoma causing acute spinal cord compression. He was then transferred to RIH for neurosurgical evaluation for decompression.

Dr. Olszewski: This malignancy has progressed despite treatment, thus causing the

clinicians to consider this patient to be refractory to therapy. High dose steroids have

failed to suppress growth.

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Hospital Day 0

Emergency Department Management:

• Administered Dexamethasone 40 mg IV

• Consulted Radiation Oncology

• Consulted Neurosurgery

Dr. Kosztowski: In patients with an acute neurologic decline, steroids are shown to

stabilize this decline through reduction of edema caused by cord compression or tumor

inflammation due to radiation therapy.

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Patchell et al (2005). Lancet.

Dr. Kosztowski: The treatment plan for this patient was to choose radiation (XRT) as

the initial intervention.

The Patchell study from 2005 is an important study, the results of which are used to guide

the initial approach to urgent intervention on malignant cord compression. The study

compares XRT alone versus Surgery plus XRT. The combination of these two modalities

was superior to XRT alone with respect to the primary endpoint of ability to walk four

steps. With respect o our patient here, however, patients with highly radiosensitive tumors

such as myeloma were excluded. If however, a patient presented with cord compression

due to lung cancer, surgical decompression would be the treatment of choice. In myeloma,

the first step is XRT and chemotherapy. The improvement response in many cases is

dramatic. This patient worsened after XRT and steroids, leading us to consider surgical

options and non-malignant causes of compression.

Dr. Hepel: Rapid decompression is critical for preservation and recovery of function. Such

rapid decompression can be achieved with XRT in patients with myeloma, which is highly

radiosensitive. The decision of the best decompression modality is complex and depends

upon the patient’s disease and functional status, the type of tumor and the patient’s

neurologic status. A greater the amount of pain and loss of function reflects a need for

rapid intervention. Cord compression resulting from rapid growth requires a more rapid

intervention

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Hospital Course – HD 1

• Admitted to Neurosurgery Service.

• Radiation Oncology assessment and plan

Dr. Hepel: We planned to radiate C5 and T3 regions

XRT works by delivering a high energy radiation beam (in the range of thousands of

kilovolts) to a specific area, relying on the ability of such energy to damage DNA. In

this way, cells die at time of mitosis. Myeloma, in contrast, responds to XRT through

apoptosis and does not need to undergo mitosis in order for cell death.

Steroids reduce edema caused by compression itself and the resulting cord edema. They

also reduce inflammation and edema resulting from tumor necrosis caused by XRT.

Steroids should be given prior to initiation of XRT.

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Hospital Course – HD 2,3

• Mild improvement in neurologic exam, mostly in strength but still unable to ambulate.

• PT/OT ordered. Plan for rehab facility. Continue plan for radiation therapy as outpatient.

• Dexamethasone 40 mg PO daily (divided doses)

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Hospital Course – HD 4

• Hematology/Oncology Consulted

• No indication for acute inpatient systemic chemotherapy.

• Emphasized importance of acute rehabilitation.

• Continue dexamethasone taper and palliative radiation.

• Can follow SPEP and FLC as an outpatient

Dr. Olszewski: Ongoing surgery is a relative contraindication to chemotherapy due to

the deleterious effects of chemotherapy agents on post-op healing. The same is true for

ongoing XRT. Chemotherapy enhances the neurotoxicity of XRT to cord or brain and so

we do not administer these agents to patients undergoing XRT. This is in contrast to

head and neck cancer, where we can effect cures by taking advantage of the

enhancement of XRT cellular toxicity by some chemotherapy drugs. Note that if the

patient experiences hypercalcemia, we can interrupt XRT and treat systemically with

chemotherapy until we achieve control

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Hospital Course – HD 5

• Worsening of neurologic exam. LE weakening despite having received one dose of 40 mg IV dexamethasone. Taken to OR for emergent posterior thoracic decompression and fusion.

• Transferred to Neuro ICU with NSGY following.

Dr. Hepel: In such an XRT responsive tumor, it is unusual to see such progression and

decline in function after 3 radiation treatments. Such a clinical deterioration raises

concern for (1) mechanical instability or other source of compression or (2) a bleed or

hematoma. If the above 2 situations arise, the patient may be brought to the OR.

Dr. Olszewski: Continuity of care, handoffs and accuracy of documentation are critical

to the care of this patient so that we may follow and act on changes in neurologic

deficits promptly in the hope of preserving or restoring function.

Dr. Kosztowski: This patient’s decline in function occurred very rapidly from noon to

early evening

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Hospital Course-

Neurology Critical Care Unit

HD 6, Post Op Day 1

HD 6, POD# 1 of T3 corpectomy and t1-5 fusion

– No change in LE exam.

– post operative imaging saw a small piece of anterior

reconstruction that has “popped” backwards towards

the spinal canal (about 5 mm). Returned to OR for

revision.

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Hospital Course- HD 7-9

HD 7, post operative revision

HD 9, POD2- exam stable. Transferred to NSGY service.

Imaging showing extensive dorsal epidural hematoma.

Dr. Kosztowski: A dorsal epidural hematoma is a common post-operative finding after

decompression surgery. Its presence is not usually clinically significant. If the CT or

MRI demonstrates that the hematoma is exerting pressure and effacing the spinal cord,

urgent surgical decompression is warranted. Post-op drains are left in place to evacuate

such collections.

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Hospital course- HD 10,11

HD10, POD3-

Consulted hematology for DVT prophylaxis in setting of

thrombocytopenia and epidural hematoma. Recommended lovenox if

platelets > 50. If

Hospital Course- HD 12

HD 12, POD5

– Neurologic exam declining despite 3 XRT and

decompression. Repeat MRI shows improvement in

hematoma.

– Oncology recommending starting anti-myeloma

therapy. Holding anticoagulation, given platelets 48.

– Radiation oncology – no further XRT treatments given

worsening exam. Will reevaluate in 2 weeks.

Dr. Olszewski: At this point, the patient was not demonstrating improvement despite

treatment and goals of care discussions were held with the family and patient. At this

point, there are limited salvage therapies available for this patient.

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Hospital Course- HD 13-16 HD 13

– Transferred to hematology service.

– Renal Consulted for elevated Creatinine (1.7, admission 1.06),

bladder scan with 1.5 L. Foley catheter placed.

– Corrected Calcium (for albumin 2.1) = 9.6

– Chemotherapy started: Carfilzomib/lenalidomide/dexamethasone.

HD14

– AKI resolved. Nephrology recommended urologic consultation for

obstructive nephropathy, who recommended foley and Tamsulosin.

– Patient reported improvement in LE. Able to move toes bilaterally.

HD15,16

– Improving exam, able to “wiggle toes”. patient reported he had

“best PT session.”

Dr. Olszewski: Note that the patient night have had elevation of creatinine due to

plasma cell infiltrate, hypercalcemia, light chain disease or obstruction by adenopathy.

Carfilzomib has been associated with hematoma formation and bleeding.

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Hospital Course- HD17-19

HD 17-

– Worsening AKI- Cr 2.0

Further evaluation: Spot protein 2.64 gm/gm

+ bence jones proteinuria

HD 18

– Hemoglobin downtrended: 7.8 6.8

Transfused 1 unit PRBC

– Platelets downtrending: 40 22

– Creatinine stable

HD19

– Hemoglobin 6.3 despite 1 unit PRBC

– Given another unit pRBC

– Creatinine stable

Dr. Olszewski: The drop in this patient’s hemoglobin was felt to have occurred too

rapidly for chemotherapy-induced causes. Hematology considered blood loss from

bleeding as a cause of the precipitous drop in hemoglobin, especially in the setting of

thrombocytopenia and anticoagulation. In addition, this patient has renal failure, which

might contribute to a reduced capacity for hematopoiesis in setting of blood loss or

hemolysis.

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HD 20

HD 20

– Worsening mental status: lethargic, confused

– BP 88/58; HR 104, RR 25, 98% R/A

– Numerous hematomas extremities, abdomen distended but soft,

dull to percussion

– Hb 5.3 (from 6.3)

– Given blood, platelets, FFP and vit K.

– CT A/P showed hemoperitoneum.

– Surgery consulted transferred to surgical service

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CTA Acute GI Bleed

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hemorrhage

* Splenomegaly

hemorrhage

surrounding the spleen.

Unable to discern source.

This patient had spontaneous hemoperitoneum. IVC filter rupture of inferior vena cava

wall. Of note is that there is a warning for Carfilzomib relating to its association with

spontaneous bleeding. Splenomegaly is unusual in myeloma.

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HD 20-22, Surgical Service

Review with radiology: has significant splenomegaly but

no evidence of blush to suggest extravasation. Since no

source of bleeding identified and overall high risk, not a

candidate for VIR intervention for empiric splenic artery

embolization

Poor surgical candidate. Patient, daughter wife opted for

nonsurgical intervention, but to remain full code.

Requested transfer to hematology service given no surgical

intervention.

Dr. Rome: The primary team praised the surgical consulting team for their rapid

attention and ongoing communication with the clinicians involved in caring for this

patient.

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HD 23,24– Transferred to

Hematology Service

HD23– worsening mental status, lethargic. Family

meeting resulted in patient’s status to be

DNR/DNI.

HD 24- patient became pulseless and expired.

With permission from the family, the patient

underwent an autopsy.

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Autopsy

Findings

With

Dariusz R Stachurski, MD

With permission from the family, the patient underwent an autopsy.

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Peripheral blood (2016)

There are circulating plasma cells in the peripheral blood – these are mature, with

perinuclear clear zone and clumped “cartwheel” or “clock-face” chromatin in the nuclei,

best seen in the upper right example in this slide. In 2016, this patient had 11%-40%

plasma cells in periphery.

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Epidural mass biopsy

Sheets of plasma cells, consistent with plasmacytoma in the epidural mass

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CD138 (plasma cell marker)

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This tumor was a plasmacytoma in the setting of multiple myeloma

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Left anterior descending artery

On autopsy, the patient was found to have 1.2 liters of blood in peritoneal cavity,

hepatosplenomegaly and atherosclerotic disease.

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Left anterior descending artery

Plasma cell infiltrate in myocardium

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Lung

In the lungs, intra-septal vessels were packed with plasma cells

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Liver

Liver: Intrasinusoidal and periportal tracts demonstrated plasma cell infiltrates.

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Kidney

Kidney stained negative with Congo Red so there was no evidence of amyloid to

account for renal failure. The kidneys themselves did not demonstrate extensive plasma

cell infiltrate.

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Spleen

Gross Pathology at autopsy showed acute rupture of splenic capsule. A normal sized

spleen is between 130-160grams. This patient’s spleen was 900 grams. The entire spleen

was replaced with plasma cells.

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Diagnosis and Cause of Death

“The immediate cause of death is likely

hemorrhagic shock secondary to splenic rupture

associated with splenomegaly and plasma cell

leukemia.”

This patient had plasma cell leukemia , a diagnosis closely related to multiple myeloma.

CD56 cell surface marker presence can be used to distinguish between these two

disorders.

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Learning Objectives

• Understand how to manage acute cord compression (X)

• Recall the specific therapeutic interventions for cord compression, including steroids, radiation and surgery.

• Understand the complications of multiple myeloma (Y), including splenomegaly, plasmacytomas and renal failure.

• Understand how to diagnose Plasma Cell Leukemia (Z).

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Thank You!

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