A case of progressive headache and cranial neuropathies

We’ve gotten a lot of feedback recently about the styles of our podcasts, and the overwhelming favorite is the case presentations (which are fictionalized…). So we’ll be doing more of those in the coming weeks, including this episode–our first one of 2017!

Case presentation: A 59 year-old actress presented to your urgent care clinic with 5 days of progressive headache. She had taken off work the preceding two days due to such severe symptoms. The headache began insidiously, was associated with photophobia but not phonophobia, and nausea with vomiting this morning. It did not improve with NSAIDs or sleep. She tells you her headache has been associated with neck pain and stiffness as well as generalized fatigue. She came to urgent care this morning because of new diplopia, which she confirms is binocular, present in the horizontal and vertical planes, and gets better when she tilts her head backward and to the right. She denies any prior history of headache, focal neurologic deficits, recent illnesses, sick contacts, travel, tick bites, pets, or new medications. She has a history of well-controlled diabetes (not on insulin) and cold sores. No family member has ever had prior symptoms, and there is no personal or family history of autoimmune disease. Her mother had breast cancer. On examination, she is uncomfortable but in no acute distress. Her general medical examination is only remarkable for the absence of fever. Her neck resists passive flexion. The neurologic exam is notable for a complete third nerve palsy on the left and a partial sixth nerve palsy on the right.

A left third nerve palsy.

In localizing the lesion, the combination of headache plus multiple cranial neuropathies localizes either to the orbit, subarachnoid space, and midbrain/upper pons. A number of infectious, neoplastic, inflammatory, and vascular etiologies can explain her symptoms. Diabetes is a risk factor for infarction to the brain parenchyma and to cranial nerves, and stroke can present with headache in a small proportion of cases. But symptoms are not progressive or insidious. A history of herpes may suggest an HSV-1 meningitis/encephalitis, but she lacks a fever, and patients often present with altered mentation or seizure. To cut to the chase here, in the absence of any other pertinent past medical or family history, it is most likely that our patient has developed a subacute meningitis.

We should all have a basic understanding of meningitis, which is an inflammation of the CSF and meninges. The meningitides are usually categorized into bacterial and aseptic. But calling meningitis aseptic is technically a misnomer. It literally means “not septic”, which means not infective or infectious. But many of the cases are infectious, and most identifiable causes of meningitis are viral. More specifically, aseptic meningitis indicates a meningitis not caused by a bacterial infection. So the differential diagnosis can be frustratingly broad (viral, fungal, drug-induced, inflammatory, neoplastic…), but in most instances, thankfully, it heralds a more favorable prognosis for the patient than a bacterial cause.

Our patient likely has an aseptic meningitis given the subacute clinical course. In contrast, a bacterial meningitis often evolves over 24-48 hours, and these patients look sick. The exception to this acuity seen in bacterial meningitis is when listeria is the responsible pathogen. Listeria can cause a meningitis, meningoencephalitis, rhombencephalitis, myelitis, or central nervous system abscess, but when it causes a meningitis, the clinical course is slow and progressive, evolving over several days. That being said, our patient’s clinical course is not typical for a bacterial pathogen, nor is this patient all that susceptible to listeria. So, an aseptic meningitis it is.

It’s important to get the LP early, and before antibiotics if possible in order to increase the yield of identifying a bacterial or fungal pathogen. Features suggestive of an aseptic meningitis are white blood cell count >10/mm3 with a negative bacterial culture. That being said, a pleocytosis is not necessary to make the diagnosis, and WBC counts may be normal in up to 20% of patients. A WBC greater than several hundred or thousand would be more consistent with a bacterial cause of meningitis. An assumption I’ve seen frequently is that aseptic meningitis produces a lymphocytic pleocytosis, however it can be neutrophil predominant in over half of cases. The CSF protein is often elevated in aseptic meningitis, but only mildly so. Protein >200 mg/dL would be less consistent with most causes of aseptic meningitis except for things like tuberculous or carcinomatous meningitis, and it can also be seen in spinal block. The glucose is often normal or close to it, except in cases of TB or other fungal causes where hypoglycorrachia may be present. A large number of red blood cells which do not clear, or more specifically xanthochromia, can be seen in subarachnoid hemorrhage masquerading as aseptic meningitis, and it can be seen in HSV1 encephalitis or meningoencephalitis as well.

Laboratory data is notable for a hemoglobin of 9.8 mg/dL, platelet count of 233, calcium of 11.3 mg/dL and a serum glucose of 215. A non-contrast head CT was unremarkable for any acute pathology. An LP showed an opening pressure of 29 cm water, so 30 cc’s were removed. Her closing pressure was 18 cm water. The CSF was remarkable for 2 red blood cells and 128 white blood cells per microliter in the fourth tube, 73% of which were lymphocytes, a protein of 110 mg/dL, and a glucose slightly low at 35. Gram stain and HSV PCR were negative. Cryptococcal antigen was checked because of the intracranial hypertension, and it was negative. AFB stain was also negative, but an AFB and routine fungal cultures were sent.

Among viral causes of meningitis, HSV1 and 2 are among the few we can pharmacologically treat—the others being HIV, VZV, and lastly CMV in immunocompromised hosts. You should know that meningitis secondary to HIV occurs during the acute seroconversion, unless the patient has AIDS, in which case the meningitis can be caused by many opportunistic and non-opportunistic pathogens. That being said, enterovirus is still the most common identifiable cause of meningitis regardless of the patient’s age. According to the 2006 PICNIC study, enteroviruses accounted for 85-95% of identifiable culprits responsible for non-bacterial meningitis. In addition to testing for enteroviruses by CSF PCR, testing for EBV is routinely performed in suspected viral cases. Depending on travel history and exposures, you may also test for West Nile, St. Louis Encephalitis, Tick-borne encephalitis, or Lymphocytic choriomeningitis virus if they have been exposed to rodents. Each of these viruses can cause meningitis. So I’ll want to know the patient’s HIV status, both PCR and antibody screening, check VZV and EBV from the CSF, and obtain a gadolinium-enhanced MRI of the brain in the meantime to exclude mass lesions in the midbrain/pons as well as rhombencephalitis. An RPR can be checked but syphilitic meningitis is exceedingly uncommon in the US nowadays.

Additional labs are notable for serum HIV PCR and antibodies being negative. VZV PCR was negative. The ratio of CSF to serum VZV antibodies indicated prior immunization and no active intrathecal antibody synthesis. An MRI confirmed mild-to-moderate ventriculomegaly with transependymal flow and diffuse pachymeningeal enhancement without any obvious underlying structural parenchymal lesion.

Sagittal, T1-weighted post-contrast MRI brain with diffuse pachymeningeal enhancement.

Diffuse pachymeningeal enhancement is confirmatory of our suspicion that the patient has meningeal inflammation, but it does not help narrow our differential by much–perhaps it may lower the likelihood of a drug-induced aseptic meningitis. Let’s consider some of her diagnostic testing so far. CSF hypoglycorrhachia, or low CSF glucose, is often observed in cases of fungal, tuberculous, or carcinomatous meningitis—all of which can pick off cranial nerves, produce a radiculopathy from subarachnoid invasion, or cause a communicating hydrocephalus. Sarcoidosis, idiopathic hypertrophic pachymeningitis, IgG4-related disease, granulomatosis with polyangiitis, lupus, and several other inflammatory/autoimmune/rheumatologic conditions can cause pachymeningeal or leptomeningeal enhancement along with infectious and carcinomatous causes. Looking back on some of the serum studies, notably the hypercalcemia and anemia, I would image the chest, abdomen, and pelvis for a malignancy or sarcoidosis.

The next set of results included AFB and fungal cultures from the CSF, which were negative. A CT scan of the chest, abdomen, and pelvis showed a simple renal cyst on the left but no other mass lesions or lymphadenopathy. Incidentally noted were several 1-3 cm lytic lesions of the right 8th rib and 3 thoracic vertebral bodies.

The scattered lytic lesions in conjunction with the prior anemia and hypercalcemia are highly suggestive of a metastatic cancer or multiple myeloma. The primary site of a solid tumor with lytic bone lesions could be thyroid, renal, hepatocellular, melanoma, and tumors arising from the adrenal gland. It would be of low yield to send the remaining CSF from the first LP for cytopathology at this point because the cell viability falls quickly after CSF sampling. Plus, given the communicating hydrocephalus on MRI and the elevated opening pressure, you’re probably going to be repeating the lumbar puncture a few more times during the course of this patient’s hospitalization in order to relieve the pressure.

The CSF cytopathology confirmed the presence of cellular atypia and cytometry identified a clonal population of plasma cells, consistent with the diagnosis of myelomatous meningitis. A serum protein electrophoresis identified an IgG kappa paraprotein.

That’s our final answer: Myelomatous meningitis, aka CNS myelomatosis. For more information on CNS and PNS manifestations of multiple myeloma, I’ll refer you to the full-length episode.

This important thing to take away from this case is that progressive headache with cranial neuropathies has a long differential diagnosis, but localization is rather simple. If you approach it methodically, you’ll be able to cross off the less likely causes of these symptoms quickly and hopefully reach the correct diagnosis. Don’t let this clinical reasoning strategy give you a headache too!

 

[Jim Siegler]


REFERENCES

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Hasbun R, Abrahams J, Jekel J and Quagliarello VJ. Computed tomography of the head before lumbar puncture in adults with suspected meningitis. The New England journal of medicine. 2001;345:1727-33.

Lee BE, Chawla R, Langley JM, Forgie SE, Al-Hosni M, Baerg K, Husain E, Strong J, Robinson JL, Allen U, Law BJ, Dobson S and Davies HD. Paediatric Investigators Collaborative Network on Infections in Canada (PICNIC) study of aseptic meningitis. BMC Infect Dis. 2006;6:68.

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Jolles S, Sewell WA and Leighton C. Drug-induced aseptic meningitis: diagnosis and management. Drug Saf. 2000;22:215-26.

Chamberlain MC and Glantz M. Myelomatous meningitis. Cancer. 2008;112:1562-7.

Nieuwenhuizen L and Biesma DH. Central nervous system myelomatosis: review of the literature. Eur J Haematol. 2008;80:1-9.

Sobol U and Stiff P. Neurologic aspects of plasma cell disorders. Handbook of clinical neurology. 2014;120:1083-99.

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