SECTION 1
A 19-year-old man with no significant medical history noted 3 weeks of right facial numbness and slurred speech. On examination, he had decreased sensation in the right middle and lower trigeminal nerve distributions, right tongue deviation, and bilateral facial weakness. A lumbar puncture yielded CSF with a lymphocytic predominant pleocytosis (50 leukocytes/mm3, 95% lymphocytes), elevated protein (260 mg/dL), and normal glucose (49 mg/dL), without other evidence of inflammation or infection, while serum studies were normal. Brain MRI with gadolinium demonstrated a subcentimeter left frontal subcortical white matter lesion on fluid-attenuated inversion recovery images and a nonenhancing pineal cyst.
Question for consideration:
What is the differential diagnosis?
In an otherwise healthy young person, diagnostic considerations would include tumors, demyelinating conditions, infectious processes such as CNS borreliosis or fungal meningitis, and systemic inflammatory conditions including neurosarcoidosis. A nonenhancing pineal cyst raises concern for a germ cell tumor, pineal parenchymal tumor, and low-grade glioma.
SECTION 2
Over 6 months, the patient developed right horizontal jerking nystagmus, bilateral hearing loss, dysarthria, and dysphagia. Two lumbar punctures demonstrated a persistent lymphocytic pleocytosis (37 leukocytes/mm3, 87% lymphocytes, and 60 leukocytes/mm3, 77% lymphocytes) with elevated protein (197 and 377 mg/dL) and elevated glucose (69 and 70 mg/dL) in the CSF with negative infectious studies and atypical lymphocytes on flow cytometrics. Serum studies were unremarkable.
Question for consideration:
What additional tests/studies should be considered?
Repeat brain MRI with gadolinium and detailed imaging of the midbrain, pons, and medulla; whole-body CT; CSF fungal cultures; CSF acid-fast bacilli stain and culture; 3 large volume (>30 mL) CSF collections for cytopathology; serum and CSF α-fetoprotein (αFP); and β-human chorionic gonadotropin (βHCG).
SECTION 3
Repeat MRI of the brain with gadolinium demonstrated enhancement of cranial nerves V, VII, IX, X, XI, and the pineal gland cyst. Cervical and thoracic spinal MRI was normal. PET demonstrated hyperplastic marrow but no metastatic disease. He had been treated with a slow oral taper of prednisone, IV glucocorticoids, and IV immunoglobulin (IVIg).
On transfer to a tertiary facility, he endorsed dyspnea, weak cough, difficulty managing secretions, progressive weakness in the legs, diminished sensation in the left arm and leg, and 1 month of urinary incontinence and constipation. His medications on transfer were oral prednisone as well as antibiotics for an aspiration pneumonia, gastric ulcer prophylaxis, and symptom management for nausea and oral secretions. There were no notable medical conditions in his family history. He was a high school graduate with no significant substance use or travel history.
His neurologic examination was remarkable for visual sensation only for light and movement, fixed dilated pupils, downgaze in primary position, upward and lateral eye movement paresis, bilateral ptosis, diminished bilateral facial sensation, bilateral facial weakness, diminished hearing, poor soft palate elevation, weak cough, and absent gag reflex. His left leg was externally rotated with otherwise antigravity strength throughout the bilateral legs. He demonstrated resistance to movement which could be overcome throughout the bilateral arms. His reflexes were brisk throughout with plantar flexor responses bilaterally. He was well coordinated in all extremities except for slow and dysrhythmic left foot tap. Gait could not be assessed.
Repeat brain MRI with gadolinium (figure 1A) and dedicated fast imaging employing steady-state acquisition series (figure 1B) demonstrated multiple areas of cranial nerve enhancement, including the bilateral oculomotor, trigeminal, abducens, facial, and spinal accessory nerves as well as enhancement of the pineal gland and soft tissue masses in the bilateral trigeminal caves. Spine MRI (figure 1, C and D) with gadolinium demonstrated multiple focal lesions within the spinal cord and central canal as well as a heterogeneously enhancing intradural, extramedullary thoracolumbar mass.
Repeat MRI with gadolinium of brain demonstrates symmetric enhancement of (A) bilateral trigeminal nerves within trigeminal cave. (B) Fast imaging employing steady-state acquisition series demonstrates enhancement within bilateral cavernous sinuses, bilateral jugular foramen, as well as facial and vestibulocochlear nerves. MRI of thoracolumbar spine (C) T2 and (D) T1 postgadolinium sequences demonstrate heterogeneously enhancing intradural, extramedullary thoracolumbar spinal mass.
Question for consideration:
What is the differential diagnosis for an intradural, extramedullary spinal cord mass?
Primary tumor considerations include meningioma, schwannoma, neurofibroma, dermoid tumor, and lipoma. The differential also includes drop metastases of medulloblastoma, ependymoma, glioma, and germ cell tumor.
SECTION 4
Bilateral first and second lumbar vertebrae laminectomies were performed with resection of the thoracolumbar mass. A lumbar puncture was performed to assay CSF levels of αFP βHCG for comparison to serum levels. βHCG levels were elevated in both serum (1,123 mIU/mL) and CSF (4,104 mIU/mL). αFP levels in the CSF (<1 ng/mL) and serum (7 ng/mL) were normal. The thoracolumbar mass contained multiple germ cell layers with differentiated tissue (figure 2, A–C). Several OCT-4 and c-kit positive germinoma cells with focal staining for αFP and βHCG were also noted (figure 2D).1,2 Final pathologic and oncologic diagnosis was immature teratoma with germinoma cells.
Hematoxylin & eosin–stained histopathologic samples from intradural extramedullary thoracolumbar mass demonstrate multiple germ cell layers including (A) keratinized skin with hair follicles, (B) smooth muscle, (C) bronchiolar tissue, and (D) germinoma cells with striated muscle.
He was subsequently transferred to the pediatric oncology service and completed the first 2 courses of induction chemotherapy with carboplatin, etoposide, and ifosfamide prior to transfer to his local medical facility. At time of transfer, his serum βHCG was markedly reduced (15 mIU/mL). At his local medical facility, he completed induction and consolidation chemotherapy. In time, he regained his hearing to a conversational volume, and the ability to partially open his eyes, speak with partial occlusion of his tracheotomy site, and walk with assistance. After 18 weeks of chemotherapy and a prolonged inpatient course, he died due to cardiac arrest.
DISCUSSION
Multiple cranial neuropathies are common in neurology, with etiologies ranging from the relatively benign and treatable to malignant and life-threatening (table 1).3,–,5 This presentation still poses a formidable diagnostic challenge, as cranial nerves can be disrupted at any site along their course from the brainstem to the superficial soft tissues.3 The differential diagnosis is extensive, with the patient's age, immunocompetence, and tempo of progression all key considerations for clinical evaluation (table 2). The basic evaluation includes assessment for evidence for metabolic derangements suggestive of systemic processes. Our understanding of the etiologies for multiple cranial neuropathies has been limited to case reports and case series.4 In the largest series, cancer accounted for 30% of cases.5
Differential diagnosis of etiologies of multiple cranial neuropathies3–5
Basic evaluation with additional considerations for evaluation of patients with multiple cranial nerve palsies
CNS germ cell tumors (GCT) are rare primary brain tumors, accounting for 0.6%–3% of all brain tumors, with an incidence of 0.16 per 100,000 person-years among pediatric patients 0–19 years of age.6,7 Typically, CNS GCT present in the second decade of life.7,8 GCT are broadly classified as germinomatous (composed solely of germinoma cells) or non-germinomatous (NGGCT). This distinction is clinically relevant as germinomas, like gonadal GCT, are highly curable with 5-year survival rates greater than 90%.7,–,9 In contrast, NGGCT portend a worse prognosis, with survival of 30%–40% with radiation alone. The addition of platinum-based chemotherapy regimens and surgical resection has boosted survival rates in NGGCT to 90% at a mean of 96 months.9
Thought to originate from primitive embryonal cells, GCT are divided histologically by their resemblance to primordial germ cells (germinoma), embryonic differentiated cells (teratoma), yolk sac endodermal cells (yolk sac tumor), blastocytes (choriocariocarcinoma), or embryonal pluripotent stem cells (embryonal carcinoma).7,8 Mixed GCT are composed of various histologic types, with the most malignant component determining overall prognosis.9
GCT are classically found in the pineal gland but can present anywhere within the CNS. Tumor location governs presenting symptomatology. Patients with pineal lesions often present with obstructive hydrocephalus and Parinaud syndrome (paralysis of upgaze, pupillary light-near dissociation and convergence-retraction nystagmus).9
Differentiating between germinomas and NGGCT directly influences treatment choices. While there are potentially subtle differences in germinomas and NGGCT on MRI, imaging alone is not sufficient to differentiate between the two.7,8 Biopsy is necessary to confirm the diagnosis unless tumor markers are pathognomonic. βHCG and αFP should be checked in both serum and CSF if GCT is on the differential. While germinomas can secrete low levels of βHCG and αFP, βHCG levels greater than 50 IU/L and αFP levels >10 ng/dL in the CSF confirms a diagnosis of NGGCT without the need for biopsy, and markedly elevated levels are associated with more aggressive tumors with worse prognosis.7,–,10 When positive, tumor markers also serve as a sensitive method to monitor therapy response. If a GCT is confirmed, complete craniospinal imaging is recommended as 10%–30% of patients, predominantly NGGCT, have spinal drop metastases or leptomeningeal spread.7,–,10 The patient presented here developed multiple cranial neuropathies from leptomeningeal spread along his cranial nerves and drop metastasis.
We present the case of a young man in his second decade with progressive multiple cranial neuropathies. CSF lymphocytic pleocytosis and elevated protein were persistent features of his evaluation with no other evidence of infectious, hematologic, or rheumatologic conditions. He had no response to antibiotic, steroid, or IVIg therapy. Noted enhancement of the leptomeninges, a midline intracranial structure (pineal gland), and intracranial soft tissue masses were consistent with a GCT. The final diagnosis of NGGCT was made on pathologic examination of an intradural, extramedullary drop metastasis. Comparison of αFP and βHCG in the CSF and blood were also diagnostic. This case emphasizes the utility of assays for αFP and βHCG in the CSF and blood when evaluating an otherwise healthy young person with multiple cranial neuropathies after a basic evaluation fails to present a clear diagnosis.
AUTHOR CONTRIBUTIONS
Dr. Probasco was involved in drafting/revising the manuscript for content, study concept and design, and analysis/interpretation of data. Dr. Munchel was involved in revising the manuscript for content. Dr. McArthur was involved in revising the manuscript for content. Dr. Blakeley was involved in revising the manuscript for content, study concept and design, and analysis/interpretation of data.
STUDY FUNDING
No targeted funding reported.
DISCLOSURE
J. Probasco and A. Munchel report no disclosures. J. McArthur serves on a scientific advisory board for Relevare Services; is an author on patents re: Device for thermal stimulation of small neural fibers and Immunophilin ligand treatment of antiretroviral toxic neuropathy; and receives research support from Biogen Idec, Pfizer Inc., the National Multiple Sclerosis Society, the Foundation for Peripheral Neuropathy, and grant 5P30MH075673 from the National Institute of Mental Health. J. Blakeley receives research support from GlaxoSmithKline, the National Cancer Institute, and the Cancer Therapy Evaluation Program. She has served as an unpaid consultant to Novartis. Go to Neurology.org for full disclosures.
ACKNOWLEDGMENT
The authors thank Dr. Peter Burger and Mr. Norm Baker for preparation of the histopathology images and the patient's family for their help in the preparation of this manuscript.
Footnotes
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
- Received March 19, 2012.
- Accepted September 26, 2012.
- © 2013 American Academy of Neurology
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