J Med Cases

Journal of Medical Cases, ISSN 1923-4155 print, 1923-4163 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Med Cases and Elmer Press Inc

Journal website http://www.journalmc.org

Case Report

Volume 9, Number 9, September 2018, pages 296-302

A Rare Case of Paraneoplastic Encephalitis in Association With Breast Cancer

Figure 1. (a) MRI of brain with and without contrast showing T2/FLAIR hyperintensity along the medial temporal lobe involving portions of the hippocampus and amygdala. (b) CT of chest with contrast showing markedly enlarged axillary lymph nodes. (c) Ultrasound of right breast and axilla showing 4 × 4 × 3 mm hypoechoic lobulated nodule at 2 o’clock axis. (d) MRI of bilateral breast with and without contrast showing clumped enhancement in the upper outer quadrant of the right breast. (e) MRI of bilateral breast with and without contrast showing a small 8 mm area of patchy non-mass enhancement in the lower outer right breast.

**Table 1.** Laboratory Data
Test	Results	Reference range
Workup for neuropathy and encephalitis
Vitamin B12	760	193 - 986 ng/dL
Folic acid	65.7	4 - 18 ng/mL
TSH	0.86	0.340 - 4.820 µIU/mL
Homocysteine	8.6	5.0 - 12.0 µmol/L
Gliadin IgAb	9.0	Negative < 20
Ganglioside antibody panel	Negative
Zinc	0.73	0.66 - 1.10 µg/mL
Erythrocyte sedimentation rate	27	0 - 30 mm/h
Rapid plasma regain	Non-reactive
Lyme disease antibody, serum	0.02	< 0.90 index
Blood parasites	Negative
Epstein-Barr virus antibody panel	Negative
Spotted fever antibody IgG, IgA, IgM	Negative
Bartonella antibody panel	Negative
Ehrlichia antibody panel	Negative
Babesia microti antibody IgG, IgM	Negative
Antinuclear antibody (ANA)	Positive 1:640 speckled
ANA reflex antibodies	Negative
Rheumatoid factor	< 10	0 - 15 IU/mL
Cardiolipin antibody IgA, IgG, IgM	Negative
Neuromyelitis optica NMO/Aqua4-IgG	Negative
Heavy metals screen, serum
Arsenic	2.0	0 - 12 ng/mL
Lead	< 1.0	0.0 - 4.9 µg/mL
Mercury	< 1.0	0.0 - 9.0 ng/mL
Cadmium	0.2	0.0 - 4.9 ng/mL
Copper	1.36	0.75 - 1.45 µg/mL

Table 1. Laboratory Data

Test

Results

Reference range

Workup for neuropathy and encephalitis

Vitamin B12

760

193 - 986 ng/dL

Folic acid

65.7

4 - 18 ng/mL

TSH

0.86

0.340 - 4.820 µIU/mL

Homocysteine

8.6

5.0 - 12.0 µmol/L

Gliadin IgAb

9.0

Negative < 20

Ganglioside antibody panel

Negative

Zinc

0.73

0.66 - 1.10 µg/mL

Erythrocyte sedimentation rate

0 - 30 mm/h

Rapid plasma regain

Non-reactive

Lyme disease antibody, serum

0.02

< 0.90 index

Blood parasites

Negative

Epstein-Barr virus antibody panel

Negative

Spotted fever antibody IgG, IgA, IgM

Negative

Bartonella antibody panel

Negative

Ehrlichia antibody panel

Negative

Babesia microti antibody IgG, IgM

Negative

Antinuclear antibody (ANA)

Positive 1:640 speckled

ANA reflex antibodies

Negative

Rheumatoid factor

< 10

0 - 15 IU/mL

Cardiolipin antibody IgA, IgG, IgM

Negative

Neuromyelitis optica NMO/Aqua4-IgG

Negative

Heavy metals screen, serum

Arsenic

2.0

0 - 12 ng/mL

Lead

< 1.0

0.0 - 4.9 µg/mL

Mercury

< 1.0

0.0 - 9.0 ng/mL

Cadmium

0.2

0.0 - 4.9 ng/mL

Copper

1.36

0.75 - 1.45 µg/mL

**Table 2.** Cerebrospinal Fluid Analysis
CSF	Results	Reference range
*CSF IgG index: CSF IgG to CSF albumin ratio compared to the serum IgG to serum albumin ratio. An increase in the index is an indicator of IgG production in the central nervous system. In our patient serum albumin 3.5 g/dL and serum IgG 814 mg/dL (Reference: https://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/8271)
Appearance	Clear	Clear
WBC	44	0 - 5/UL
Lymphocytes	90	63-99%
Monocytes	10	3-37%
RBC	< 1,000	/UL
Glucose	110	40 - 70 mg/dL
Protein	58	12 - 60 mg/dL
Cytology	Negative for malignant cells
Oligoclonal bands	14	< 4 bands
IgG index, CSF*	1.22	≤ 0.85
IgG	9.4	≤ 8.1 mg/dL
Albumin	33.9	≤ 27.0 mg/dL
IgG/albumin	0.28	≤ 0.21
Synthesis rate	28.77	≤ 12 mg/24 h
Meningitis/encephalitis panel, PCR
Escherichia coli K1	Not detected
Hemophilus influenzae	Not detected
Listeria monocytogenes	Not detected
Neisseria meningitidis	Not detected
Streptococcus agalactiae	Not detected
Streptococcus pneumoniae	Not detected
Cytomegalovirus	Not detected
Enterovirus	Not detected
Herpes simplex virus 1 and 2	Not detected
Human herpesvirus 6	Not detected
Varicella zoster virus	Not detected
Cryptococcus neoformans/gatti	Not detected
Paraneoplastic panel
Amphiphysin antibody	1: 15,360	< 1:240 titer
ANNA-1, S	Negative	< 1:240 titer
ANNA-2, S	Negative	< 1:240 titer
ANNA-3, S	Negative	< 1:240 titer
AGNA-1, S	Negative	< 1:240 titer
PCA-1, S	Negative	< 1:240 titer
PCA-2, S	Negative	< 1:240 titer
PCA-TR, S	Negative	< 1:240 titer
CRMP-5-IgG	Negative	< 1:240 titer
Striated muscle Ab	Negative	< 1:120 titer
P/Q-type calcium channel Ab	Negative	≤ 0.02 nmol/L
N-type calcium channel Ab	Negative	≤ 0.03 nmol/L
Ach receptor binding Ab	Negative	≤ 0.02 nmol/L
ACHR ganglionic neuronal Ab, S	Negative	≤ 0.02 nmol/L
Neuronal (V-G) K⁺ channel Ab, S	Negative	≤ 0.02 nmol/L
GAD65 Ab assay, S	Negative	≤ 0.02 nmol/L

Table 2. Cerebrospinal Fluid Analysis

CSF

Results

Reference range

*CSF IgG index: CSF IgG to CSF albumin ratio compared to the serum IgG to serum albumin ratio. An increase in the index is an indicator of IgG production in the central nervous system. In our patient serum albumin 3.5 g/dL and serum IgG 814 mg/dL (Reference: https://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/8271)

Appearance

Clear

WBC

0 - 5/UL

Lymphocytes

63-99%

Monocytes

3-37%

RBC

< 1,000

/UL

Glucose

110

40 - 70 mg/dL

Protein

12 - 60 mg/dL

Cytology

Negative for malignant cells

Oligoclonal bands

< 4 bands

IgG index, CSF*

1.22

≤ 0.85

IgG

9.4

≤ 8.1 mg/dL

Albumin

33.9

≤ 27.0 mg/dL

IgG/albumin

0.28

≤ 0.21

Synthesis rate

28.77

≤ 12 mg/24 h

Meningitis/encephalitis panel, PCR

Escherichia coli K1

Not detected

Hemophilus influenzae

Not detected

Listeria monocytogenes

Not detected

Neisseria meningitidis

Not detected

Streptococcus agalactiae

Not detected

Streptococcus pneumoniae

Not detected

Cytomegalovirus

Not detected

Enterovirus

Not detected

Herpes simplex virus 1 and 2

Not detected

Human herpesvirus 6

Not detected

Varicella zoster virus

Not detected

Cryptococcus neoformans/gatti

Not detected

Paraneoplastic panel

Amphiphysin antibody

1: 15,360

< 1:240 titer

ANNA-1, S

Negative

< 1:240 titer

ANNA-2, S

Negative

< 1:240 titer

ANNA-3, S

Negative

< 1:240 titer

AGNA-1, S

Negative

< 1:240 titer

PCA-1, S

Negative

< 1:240 titer

PCA-2, S

Negative

< 1:240 titer

PCA-TR, S

Negative

< 1:240 titer

CRMP-5-IgG

Negative

< 1:240 titer

Striated muscle Ab

Negative

< 1:120 titer

P/Q-type calcium channel Ab

Negative

≤ 0.02 nmol/L

N-type calcium channel Ab

Negative

≤ 0.03 nmol/L

Ach receptor binding Ab

Negative

≤ 0.02 nmol/L

ACHR ganglionic neuronal Ab, S

Negative

≤ 0.02 nmol/L

Neuronal (V-G) K⁺ channel Ab, S

Negative

≤ 0.02 nmol/L

GAD65 Ab assay, S

Negative

≤ 0.02 nmol/L

**Table 3.** Clinical Features and Investigations Associated With Various PNS [5]
Syndrome	Clinical feature	Investigations
Paraneoplastic encephalomyelitis (PEM)	Subacute involvement of more than one area of the CNS includes cortical, limbic or brainstem encephalitis, cerebellar dysfunction, myelitis	MRI of the relevant part. CSF - pleocytosis, elevated protein and oligoclonal bands
Limbic encephalitis (LE)	Memory problems, seizures, mood and sleep abnormalities	MRI brain T2/FLAIR hyperintensity involving limbic structure. Abnormal CSF as above. EEG epileptiform abnormality/focal slowing
Paraneoplastic cerebellar degeneration (PCD)	Severe pan cerebellar ataxia developing in less than 12 weeks, onset appendicular	Initial MRI brain usually normal. Later cerebellar atrophy
Chronic gastrointestinal pseudoobstruction	Subacute progressive nausea, vomiting, abdominal distention, pain and constipation	GI motility study and autonomic reflex screen, thermoregulatory sweat test for associated autonomic dysfunction
Opsoclonus myoclonus	Involuntary chaotic saccades in all directions of gaze, associated with myoclonus and ataxia frequently	MRI brain usually normal. EMG diagnosis of myoclonus
Chronic gastrointestinal pseudoobstruction	Subacute progressive nausea, vomiting, abdominal distention, pain and constipation	GI motility study and autonomic reflex screen, thermoregulatory sweat test for associated autonomic dysfunction
Subacute sensory neuronopathy	Numbness and pain onset in upper extremity, asymmetric. Progression in less than 12 weeks	Nerve conduction studies (NCS) - absent or reduced SNAPs, MRI spine enhancing nerve roots. Abnormal CSF as mentioned above.
Lambert-Eaton myasthenic syndrome (LEMS)	Proximal weakness with ocular and bulbar involvement. Hypoactive deep tendon reflexes and mild dysautonomia helps clinical differentiation from myasthenia gravis	EMG-incremental response on repetitive stimulation

Table 3. Clinical Features and Investigations Associated With Various PNS [5]

Syndrome

Clinical feature

Investigations

Paraneoplastic encephalomyelitis (PEM)

Subacute involvement of more than one area of the CNS includes cortical, limbic or brainstem encephalitis, cerebellar dysfunction, myelitis

MRI of the relevant part. CSF - pleocytosis, elevated protein and oligoclonal bands

Limbic encephalitis (LE)

Memory problems, seizures, mood and sleep abnormalities

MRI brain T2/FLAIR hyperintensity involving limbic structure. Abnormal CSF as above. EEG epileptiform abnormality/focal slowing

Paraneoplastic cerebellar degeneration (PCD)

Severe pan cerebellar ataxia developing in less than 12 weeks, onset appendicular

Initial MRI brain usually normal. Later cerebellar atrophy

Chronic gastrointestinal pseudoobstruction

Subacute progressive nausea, vomiting, abdominal distention, pain and constipation

GI motility study and autonomic reflex screen, thermoregulatory sweat test for associated autonomic dysfunction

Opsoclonus myoclonus

Involuntary chaotic saccades in all directions of gaze, associated with myoclonus and ataxia frequently

MRI brain usually normal. EMG diagnosis of myoclonus

Chronic gastrointestinal pseudoobstruction

Subacute progressive nausea, vomiting, abdominal distention, pain and constipation

GI motility study and autonomic reflex screen, thermoregulatory sweat test for associated autonomic dysfunction

Subacute sensory neuronopathy

Numbness and pain onset in upper extremity, asymmetric. Progression in less than 12 weeks

Nerve conduction studies (NCS) - absent or reduced SNAPs, MRI spine enhancing nerve roots. Abnormal CSF as mentioned above.

Lambert-Eaton myasthenic syndrome (LEMS)

Proximal weakness with ocular and bulbar involvement. Hypoactive deep tendon reflexes and mild dysautonomia helps clinical differentiation from myasthenia gravis

EMG-incremental response on repetitive stimulation

**Table 4.** Paraneoplastic Antibodies Associated With Cancers and PNS [6, 7]
Antibody	Neoplasm predicted by autoantibody	Neoplasm (%)/frequency of coexisting antibody (%)	Clinical features
Nuclear antibodies
Anti-neuronal nuclear antibody-1 (ANNA-1) (anti-Hu)	Small cell lung cancer (SCLC), neuroblastoma, thymoma	81/43	PEM- limbic, cortical, brainstem encephalitis, PCD, myelitis, PSN, autonomic dysfunction
ANNA-2 (anti-Ri)	Lung cancer, breast cancer	86/73	Brainstem encephalitis, opsoclonus - myoclonus, PCD
ANNA-3	Lung cancer, upper airway cancer	90/30	Sensory/sensorimotor neuropathy, cerebellar ataxia, myelopathy, brainstem and limbic encephalopathy
Anti-glial nuclear antibody (AGNA 1)	SCLC	90/50	LEMS, PCD, sensory neuronopathy, limbic encephalitis, sensory motor neuropathy
Anti-Ma2	Germ cell tumor of testis, lung, GIT, breast, non-Hodgkin’s lymphoma	Unknown	Cerebellar/brainstem syndrome, limbic encephalitis. Narcolepsy like, cataplexy, hypnogogic hallucination
Zic 4	SCLC	92/27	Limbic encephalitis, cerebellar/brainstem syndrome
Cytoplasmic antibodies
Purkinje cell cytoplasmic antibody (PCA-1)	Ovarian, fallopian, endometrial and breast cancer	90/9	PCD
PCA-2	SCLC	80/63	Brainstem/limbic encephalitis, PCD, LEMS, motor neuronopathy
PCA-Tr	Hodgkin’s lymphoma	90/unknown	PCD, limbic encephalopathy
Amphiphysin	Breast cancer, lung cancer	80/38	Stiff-man syndrome, PEM
CRMP-5 (collapsin response mediated protein)	SCLC, thymoma, thyroid, renal cancer	80/57	PEM, PCD, chorea, optic neuropathy, myelopathy and peripheral neuropathy
Striational (sarcomeric proteins)	SCLC, thymoma, breast cancer	Unknown	Myasthenia gravis
Cell membrane antibodies
Voltage gated calcium channel (VGCC) N	Lung, breast, ovarian cancer	Unknown	LEMS, cerebellar degeneration
VGCC P/Q	SCLC	Unknown	LEMS, cerebellar degeneration
AchR, muscle	Thymoma, SCLC	Unknown	Myasthenia gravis
AchR, ganglionic	Thymoma, SCLC	Unknown	Autonomic neuropathy
Voltage gated potassium channel (VGKC) related protein	Thymoma, SCLC	Unknown	Limbic encephalitis, Morvan’s syndrome, PCD, GI dysmotility, parkinsonism, tremor, chorea, sensory motor neuropathy, hyponatremia, dyssomnia and hyperphagia
NMDA receptor	Ovarian teratoma	59/unknown	Psychiatric features and memory loss, orofacial dyskinesia, choreoathetoid movements, abnormal posturing or increased tone, catatonic state and central hypoventilation
AMPA receptor	SCLC, thymoma, breast	Unknown	Limbic encephalitis, atypical psychosis
GABA B receptor	SCLC	Unknown	Limbic encephalitis
Glycine receptor	Lung cancer	Unknown	Progressive encephalomyelitis with rigidity and myoclonus (PERM)
MgluR1	Hodgkin’s lymphoma	Unknown	PCD

Table 4. Paraneoplastic Antibodies Associated With Cancers and PNS [6, 7]

Antibody

Neoplasm predicted by autoantibody

Neoplasm (%)/frequency of coexisting antibody (%)

Clinical features

Nuclear antibodies

Anti-neuronal nuclear antibody-1 (ANNA-1) (anti-Hu)

Small cell lung cancer (SCLC), neuroblastoma, thymoma

81/43

PEM- limbic, cortical, brainstem encephalitis, PCD, myelitis, PSN, autonomic dysfunction

ANNA-2 (anti-Ri)

Lung cancer, breast cancer

86/73

Brainstem encephalitis, opsoclonus - myoclonus, PCD

ANNA-3

Lung cancer, upper airway cancer

90/30

Sensory/sensorimotor neuropathy, cerebellar ataxia, myelopathy, brainstem and limbic encephalopathy

Anti-glial nuclear antibody (AGNA 1)

SCLC

90/50

LEMS, PCD, sensory neuronopathy, limbic encephalitis, sensory motor neuropathy

Anti-Ma2

Germ cell tumor of testis, lung, GIT, breast, non-Hodgkin’s lymphoma

Unknown

Cerebellar/brainstem syndrome, limbic encephalitis. Narcolepsy like, cataplexy, hypnogogic hallucination

Zic 4

SCLC

92/27

Limbic encephalitis, cerebellar/brainstem syndrome

Cytoplasmic antibodies

Purkinje cell cytoplasmic antibody (PCA-1)

Ovarian, fallopian, endometrial and breast cancer

90/9

PCD

PCA-2

SCLC

80/63

Brainstem/limbic encephalitis, PCD, LEMS, motor neuronopathy

PCA-Tr

Hodgkin’s lymphoma

90/unknown

PCD, limbic encephalopathy

Amphiphysin

Breast cancer, lung cancer

80/38

Stiff-man syndrome, PEM

CRMP-5 (collapsin response mediated protein)

SCLC, thymoma, thyroid, renal cancer

80/57

PEM, PCD, chorea, optic neuropathy, myelopathy and peripheral neuropathy

Striational (sarcomeric proteins)

SCLC, thymoma, breast cancer

Unknown

Myasthenia gravis

Cell membrane antibodies

Voltage gated calcium channel (VGCC) N

Lung, breast, ovarian cancer

Unknown

LEMS, cerebellar degeneration

VGCC P/Q

SCLC

Unknown

LEMS, cerebellar degeneration

AchR, muscle

Thymoma, SCLC

Unknown

Myasthenia gravis

AchR, ganglionic

Thymoma, SCLC

Unknown

Autonomic neuropathy

Voltage gated potassium channel (VGKC) related protein

Thymoma, SCLC

Unknown

Limbic encephalitis, Morvan’s syndrome, PCD, GI dysmotility, parkinsonism, tremor, chorea, sensory motor neuropathy, hyponatremia, dyssomnia and hyperphagia

NMDA receptor

Ovarian teratoma

59/unknown

Psychiatric features and memory loss, orofacial dyskinesia, choreoathetoid movements, abnormal posturing or increased tone, catatonic state and central hypoventilation

AMPA receptor

SCLC, thymoma, breast

Unknown

Limbic encephalitis, atypical psychosis

GABA B receptor

SCLC

Unknown

Limbic encephalitis

Glycine receptor

Lung cancer

Unknown

Progressive encephalomyelitis with rigidity and myoclonus (PERM)

MgluR1

Hodgkin’s lymphoma

Unknown

PCD