Turning the Differential on Its Head: A Case of Rhombencephalitis

Rebecca Bystrom, MDInternal Medicine, PGY-2

ACP Maine Chapter Meeting 2018

Transfer SummaryNovember 2017

62 year old woman with minimal past medical contact was transferred to our institution with rhombencephalits.

10 days prior to presentation• Symptoms of nasal congestion, sinus

pressure, cough, and sore throat• Double vision• “Dizzy spells”

3 days later …• Fever, Chills, Diaphoresis• Photophobia

Presented twice to a local clinic:• Diagnosed with new COPD exacerbation• Treated with ciprofloxacin, prednisone and

albuterol

1 week later…• Dysphagia• Drooling• Fall• Right-sided facial droop• Word-finding difficulty

Concern for CVA Presented to outside hospital ED

Outside Hospital Admission• CT Head: unremarkable• CXR: unremarkable• CT C/A/P w/o contrast: Limited study. No intra or

retroperitoneal mass or lymphadenopathy. • MRI brain: high attenuation of the periventricular

white matter with brainstem and cerebellar inflammation vs. demyelination.

• Initial LP: 8 WBCs (85% lymphocytes) and elevated RBCs. Gram stain, protein and glucose were not sent. Negative cytology and flow cytometry.

Initial ManagementOutside Hospital Management:• Treated with Ceftriaxone, Acyclovir,

Fluconazole, Steroids• Addition of Ampicillin

2 days later transferred to our institution with signs and symptoms suggesting involvement of CN VII, VIII +/- IX, X• Added Vancomycin

Further History• Past Medical History: None• Allergies: Sulfa antibiotics• Medications: None• Herbal supplements: Calcium, cranberry, vitamin

D, milk thistle, apple cider vinegar, probiotic, oil of oregano

• Family History: Mother (unknown cancer; died at 52), Father (early-onset Alzheimer’s, CVA; died at 59), brother (lymphoma, multiple myeloma)

Social History• Smoking: Current (25 pack years)• Drugs: Recreational marijuana use • Sexually active with one male partner• No sick contacts • No recent travel• No alcohol use• Enjoys walking in the woods near her home.

Encounter with a tick 5 months prior.• Lives at home with husband and golden

retriever. • Concern for mould at home.

General Physical ExamBP 133/95 | Pulse 95 | Temp 36.6 °C (97.9 °F) | Resp 31 | SpO2 98%

General: Awake, alert, oriented. Mild respiratory distress. Ill-appearing. HEENT: Mucous membranes dry. No oral lesions. No scleral icterus. No conjunctival injection.Neck: Full painless ROM. No lymphadenopathy, masses or thyromegaly.Cardiovascular: Regular rhythm, normal rate. No murmurs, clicks, or rubs. 2+ pulses. No JVD.Chest: Mild tachypnea with diffuse rhonchi throughout and occasional musical end expiratory wheeze. No egophony or dullness to percussion.Abdomen: Non-distended. Normoactive bowel sounds. Soft, non-tender. No hepatosplenomegaly. Extremities: Full painless ROM. No joint swelling or erythema.Skin: No rashes or lesions.

Neurological ExamCranial Nerves: Mild right-sided facial droop, nystagmus, CN VI palsy. Remainder intact.Motor strength: 5/5 in all muscle groups. Tone: Fluid. DTRs: 2+ in upper extremity and 3+ in lower extremity. Babinski equivocal, no clonus. Coordination: Poor finger to nose on the right but without past pointing or intention tremor. Good coordination on the left upper extremity and bilateral lower extremities. Rapidly alternating movements: Intact. Gait: Deferred. Speech: Dysarthric and gravelly. Repetition intact. Interprets abstract phrases.

Initial InvestigationsCBC: WBC 12.4 | HGB 13.9 | PLAT 222DIFF: 55% Neutrophils, 33% lymphocytes, 9% monocytes,2% eosinophils, 1% immature granulocytesCMP: NA 138 | K 4.5 | CL 104 | HCO3 17 | BUN 14 | CREAT 0.72 | GLUC 105 | ALB 3.7 | CALCIUM 9.1 | BILI 0.4 | AST 29 | ALT 27ABG: PH 7.54 | PCO2 19 | PO2 75 | HCO3 16CRP 28.5ESR 16Fungal culture negative at 48 hrsLactate wnlLP: 61 WBC, 98% lymphs, protein and glucose wnl.Negative cytology and flow cytometry.

Initial MRI at MMCAxial with Flair

Problem List• Rhombencephalitis• Cranial nerve palsies: VI, VII, +/- VIII-X• Mixed chronic respiratory alkalosis with

metabolic acidosis• CSF Pleocytosis with normal protein &

glucose• Environmental exposures: tics, mould• +/- Infectious prodrome

InfectiousListeriaEnteroviruses- Enterovirus 71- Bulbar poliomyelitis- Coxsackievirus A16- EchovirusFlaviviruses- Japanese Encephalitis- St Louis Encephalitis- West Nile virusHerpes Viruses- HSV- EBV- HH6- CMV- VZV

Other InfectionsBacterial RE- TB- Pneumococcus- Brucella- Borrellia- Salmonella- Legionella- MycoplasmaViral RE- Rabies Virus- Eastern Equine

Encephalitis- Adenovirus- Influenza AOther - Melioidosis

- Aspergillus- Mucormycosis- Nocardia- Cysticerosis- ToxoplasmosisAutoimmune- Behcet- SLE- Relapsing Polychondritis- Sjogren’s Syndrome- Sarcoidosis- Vogt-Koyanagi-Harada- Paraneoplastic- ADEM- PMLOther- Lymphoma

Differential Diagnoses for Rhombencephalitis

InfectiousListeriaEnteroviruses- Enterovirus 71- Bulbar poliomyelitis- Coxsackievirus A16- EchovirusFlaviviruses- Japanese Encephalitis- St Louis Encephalitis- West Nile virusHerpes Viruses- HSV- EBV- HH6- CMV- VZV

Other InfectionsBacterial RE- TB- Pneumococcus- Brucella- Borrellia- Salmonella- Legionella- MycoplasmaViral RE- Rabies Virus- Eastern Equine

Encephalitis- Adenovirus- Influenza AOther- Melioidosis

- Aspergillus- Mucormycosis- Nocardia- Cysticerosis- ToxoplasmosisAutoimmune- Behcet- SLE- Relapsing Polychondritis- Sjogren’s Syndrome- Sarcoidosis- Vogt-Koyanagi-Harada- Paraneoplastic- ADEM- PMLOther- Lymphoma

Differential Diagnosis for Rhombencephalitis

Listerial Rhombencephalitis• 9% of all cases of CNS listerosis• #1 cause of infectious rhombencephalitis• Initial Sx: flu-like prodrome, HA, fever, n/v • 1-15 days later: Brainstem dysfunction with CN palsies;

ataxia• ½ develop respiratory failure• CSF: elevated protein; low glucose; pleocytosis (>25%

lymphocytes); blood culture positive in only 41% of cases; CSF positive in 51%

• MRI: 100% are abnormal with high signal intensities on T2-weighted and FLAIR images. Exclusively infratentorial.

• Tx: Ampicillin +/- gentamicin

Comparing featuresDiagnosis CSF protein CSF

PleocytosisMRI Ataxia Fever

Listeria Elevated 50% lymphs

Abnormal in 100%

Common Common

Viral Elevated 50% lymphs

Abnormal in 70-90%

Common to uncommon

Common

Behcet Sometimes elevated

43% lymphs

Abnormal Uncommon Common

Para-neoplastic Normal 67% lymphs

Normal in 100%

Uncommon Uncommon

Neurologic Disease in BehçetSyndrome

• <10% Pts; M>F• 3% of cases: Neurologic disease at presentation• Radiologically:

• Can include brainstem (which may extend to the midbrain, basal ganglia, and diencephalon) and include cerebellum.

• Acute and subacute lesions: Hyperintense on T2-weighted, FLAIR, and diffusion-weighted images; commonly enhance with contrast.

• Chronic phase: lesions usually do not enhance. • Cerebrospinal fluid (CSF) may show increased protein

and hyper-cellularity.

CSF• Culture with no growth• Enterovirus• HSV 1+2 QL• Eastern Equine Encephalitis virus• West Nile virus • St Louis Encephalitis virus• Powassan virus • Deer tick virus • HSV PCR• Varicella/Herpes zoster• Enterovirus• Syphilis• Cryptococcus Ag• EBV• JC Virus• IgH Gene Rearrangement (BCGRV)• Multiple Sclerosis Panel, CSF• Lymphoma MDS Flow Cytometry

Autoimmune eval, CSF:• NMDA-R Ab CBA• VGKC-complex Ab• LGI1-IgG CBA• CASPR2-IgG CBA• GAD65 Ab Assay• GABA-B-R Ab CBA• AMPA-R Ab CBA• Anti-Neuronal Nuclear Ab, Type 1• Anti-Neuronal Nuclear Ab, Type 2• Anti-Neuronal Nuclear Ab, Type 3• Anti-Glial Nuclear Ab, Type 1 • Purkinje Cell Cytoplasmic Ab Type 1• Purkinje Cell Cytoplasmic Ab Type 2• Purkinje Cell Cytoplasmic Ab Type Tr• Amphiphysin Ab• CRMP-5-IgG, S

Serum PlasmaAutoimmune eval, serum:

• NMDA-R Ab CBA, s• Neuronal (V-G) K+ Channel Ab, S =

o.o5 nmol/L (ref <=0.02)• LGI1-IgG CBA, S• CASPR2-IgG CBA, S• GAD65 Ab Assay, S• GABA-B-R Ab CBA, S • AMPA-R Ab CBA, S = negative• Anti-Neuronal Nuclear Ab, Type 1• Anti-Neuronal Nuclear Ab, Type 2• Anti-Neuronal Nuclear Ab, Type 3

Anti-Glial Nuclear Ab, Type 1• Purkinje Cell Cytoplasmic Ab Type 1• Purkinje Cell Cytoplasmic Ab Type 2

• Purkinje Cell Cytoplasmic Ab Type Tr (PCA-Tr)

• Amphiphysin Ab, S• N-Type Calcium Channel Ab• P/Q-Type Calcium Channel Ab • ACh Receptor (Muscle) Binding Ab• AChR Ganglionic Neuronal Ab, S =• CRMP-5-IgG, S • Trinational Muscle Ab

Serum Plasma• West Nile virus• St Louis Encephalitis virus

IgM• RPR and TPPA Syphilis • Babesia• Anaplasma• Lyme • Enterovirus PCR• Arbovirus IgM• HIV 1+2 AB+AG• CRE• Fungitell assay• Cryptococcus Ag• HHV6 PCR• SS-A + SS-B Ab IgG

• ANA = <1:80 (<1:160)• Angiotensin Converting

Enzyme = 26 (ref 8-53 U/L)

• ANTI-MOG AB• Stratify JCV(TM)

Ab(w/Index) w/Rfl to Inhibition

• NMO/AQP4 FACS, S• Vitamin D 25-Hydroxy 25.4

(ref 25-50 ng/mL)• Negative Gram Stain• Powassan virus• Eastern Equine

Encephalitis virus

Lymphocyte Count

Progressive Multifocal Leukoencephalopathy

• Most patients with HIV infection and PML are profoundly immunosuppressed with CD4-positive T-cell counts <200 per mm3

• Isolated cases of immunocompetent patients• Heterogeneous initial symptoms• Radiologically:

• Symmetric or asymmetric multifocal areas • White matter demyelination that do not conform

to cerebrovascular territories • No mass effect • No contrast enhancement

Acute Disseminated Encephalomyelitis

• Autoimmune demyelinating disease of the CNS• Children >> adults• Infectious prodrome (50-75% adult cases) in

days to weeks prior• Acute onset & rapidly progressive• Multi-focal neurological symptoms (brainstem

involvement and ataxia are common)• MRI: bilateral; asymmetric; poorly marginated;

hyper-intense on T2-weighted and FLAIR sequences; heterogenous appearance (may be large and confluent lesions)

Clinical CourseLength of stay: 81 days• Discontinued all antibiotics/antivirals/antifungals by Day 25• Methylprednisone 1 gram (5 day pulse) x2 • Plasmapheresis (5 sessions) x2• ICU admission x2• Tracheostomy and PEG tube

Clinical DeteriorationRadiographic Deterioration

Course complicated by bilateral pulmonary emboli and aspiration pneumonia

Final MRIAxial with Flair

InfectiousListeriaEnteroviruses- Enterovirus 71- Bulbar poliomyelitis- Coxsackievirus A16- EchovirusFlaviviruses- Japanese Encephalitis- St Louis Encephalitis- West Nile virusHerpes Viruses- HSV- EBV- HH6- CMV- VZV

Other InfectionsBacterial RE- TB- Pneumococcus- Brucella- Borrellia- Salmonella- Legionella- MycoplasmaViral RE- Rabies Virus- Eastern Equine

Encephalitis- Adenovirus- Influenza AOther - Melioidosis

- Aspergillus- Mucormycosis- Nocardia- Cysticerosis- ToxoplasmosisAutoimmune- Behcet- SLE- Relapsing Polychondritis- Sjogren’s Syndrome- Sarcoidosis- Vogt-Koyanagi-Harada- Paraneoplastic- ADEM- PMLOther- Lymphoma

Differential Diagnoses for Rhombencephalitis

Any Chance this is Lymphoma?

• 11/2017: Initial LP at OSH negative for malignancy on cytology and flow cytometry

• 11/2017: 2nd LP negative for malignancy on cytology and flow cytometry

• 1/2018: 3rd LP negative for malignancy on cytology and flow cytometry

BUT: Presented with a diffuse, confluent non-enhancing lesion without mass effect

H&E Low Power

H&E High Power

CD‐3

CD‐20

Mib‐1

Diagnosis

Diffuse large B-cell lymphoma

How can this be Primary CNS Lymphoma?

• 3-5% of all primary brain tumors and 1–2% of all lymphomas.

• Gender balance: M:F about 2:5• Age: 50s – 60s• 15% of Pts have an antecedent flu-like or GI illness• MRI:

• Solitary (65%) or multiple (35%) well-defined lesions• Intense homogenous or ring contrast enhancement• Marked restricted diffusion• Variable mass effect

Lymphomatosis Cerebri• 46 cases ever reported (42 in this case report)• Median age: 58 years; F = M• 59% cognitive decline as first presenting symptom• 55% supratentorial and infratentorial infiltration on initial MRI

(remainder = supratentorial)• 30% with patchy enhancement on baseline MRI• 50% basal ganglia involvement • 95% bilateral hemispheric involvement• 76% high CSF protein• 8.3% low CSF glucose• 72% CSF cytology negative for malignancy• 51% CSF pleocytosis• 33% diagnosed on autopsy• 85% were B cell lymphoma

Primary CNS Lymphoma vs Lymphomatosis Cerebri

When to Consider Lymphomatosis Cerebri

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