Aseptic Meningitis

Today we discussed a case of decreased level of consciousness and confusion in a 35-year old man.

We started by discussing the relatively young population we serve on general medicine we see here at St. Mike's. There are important factors that cause illness in this young patient population (more broadly social or societal determinants of health):

• Poverty
• Mental illness
• Substance use (often on the basis of mental illness)
• HIV prevalence in the community we serve
• An "early hit" - for example, traumatic brain injury or spinal cord injury leading to chronic illness.

The patient underwent a CT head and lumbar puncture, which demonstrated a lymphocytic pleocytosis. The differential diagnosis for a lymphocytic pleocytosis is actually broader than just viral meningitis:

• Viral meningitis (most commonly enteroviridae, arboviridae, HIV-1, and HSV-1 & 2)
• Less common viral etiologies include lymphocytic choriomeningitis virus and mumps, as well as EBV, CMV, influenza, measles, rubella, and VZV
• Mycobacterial and listeria infections
• Neurosyphilis
• Leptospira, toxoplasma, and fungi such as cryptococcus
• Lymphomatous meningitis & meningeal carcinomatosis
• Drug-induced aseptic meningitis

Diagnosis is made primarily with CSF analysis with cell count and differential, glucose, protein, CSF culture, and viral PCR (nucleic acid amplification of viral specific DNA or RNA, especially looking for HSV-1 and enteroviridae).

Polyuria

Today we discussed an interesting case of a patient with hypercalcemia, presenting with polyuria. Remember, polyuria has a specific definition - technically >3L/24h. However, we must remember that a volume less than this may be inappropriately high (ie the patient is still "polyuric") if the patient is volume deplete. There is relatively limited differential diagnosis: the problem is either too much solute or too much volume. See here for a previous post on polyuria.

Diabetes insipidus can be central or nephrogenic, depending on whether this is insufficent production/release of ADH, or inadequate response to ADH at the level of the kidney. Central diabetes is related to pituitary dysfunction, such as due to tumour, infiltration, inflammation, or trauma. Nephrogenic DI is often related to lithium use, congenital, or (as in our case) due to hypercalcemia.

Testing requires: urinalysis, 24hour urine for volume, urine electrolytes, and osmolarity, serum lytes and serum osmolarity. DI is suspected with a high serum osmolarity but low urine osmolarity (ie an inappropriately dilute urine). The response to DDAVP, often done with or without a water deprivation test (arguably not needed if they are already hypernatremic/high serum Osm), indicates the difference between central and nephrogenic DI. In central DI, the kidney should respond by concentrating urine (ie rising urine osmolarity), while in nephrogenic DI there will be no change with exogenous DDAVP.

See here for a previous post on hypercalcemia.

Mycoplasma Pneumoniae and Hemolytic Anemia

Today we had the pleasure of a guest visit from Dr. Ho Ping-Kong, who walked us through a fascinating case of cold-agglutinin hemolytic anemia secondary to mycoplasma pneumoniae infection in a young man presenting with jaundice.

Mycoplasma pneumoniae is a common cause of community-acquired pneumonia in younger patients. It can cause both upper and lower respiratory tract infections. It typically has a prolonged and gradual onset, with prolonged paroxysmal cough. Its incubation period can be up to three weeks. Of note, although one of the most common causes of pneumonia in people younger than 40, only 10% of patients with mycoplasma pneumoniae infection will develop pneumonia.

Typically patients complain of fever, malaise, persistent dry cough, headache, chills, and coryza. Tracheal tenderness, chest soreness and pleuritic chest pain can occur, all because of the protracted cough. Patients typically do not appear unwell, and have nonspecific findings like pharyngeal injection and usually normal lung fields. Imaging can show bronchopneumonia, interstitial or reticulonodular infiltrates bilaterally (lower lobe predominance), and atelectasis.

Mycoplasma pneumoniae is associated with many extra-pulmonary manifestations, including acute hepatitis, ITP, cold-aggulitinin mediated autoimmune hemolytic anemia, arthritis, Stevens-Johnson syndrome, conduction abnormalities and transverse myelitis. These can occur before, during, after, or even in the absence of respiratory symptoms.

It is difficult to culture and, lacking a cell wall, cannot be seen on gram stain. Mycoplasma serology and PCR testing can be done. Cold agglutination testing is often positive, even in patients not actively hemolyzing. Often these cold agglutinants result in subclinical hemolysis and reticulocytosis.

In patients presenting with jaundice found to have hemolytic anemia, it is important to think of other potential causes of hemolysis - our patient had incidental G6PD deficiency! Similarly, mycoplasma pneumonia has been associated with chest crisis in sickle cell disease, making this an important entity to rule out as well.

Macrolides or doxycycline can be used against this atypical pneumonia. The complications of the pneumonia can be treated supportively. Patients who are hemolyzing should not be transfused if possible, as this can worsen the hemolysis. While admitted, patients should be under droplet precautions.

See here for a quick case report and review.

Vertigo in a hypertensive patient

Vertigo as a presenting complaint can be challenging diagnostically, but not when approached in a systematic, rational way. We discussed a case of a hypertensive patient of Western African origin who presented with vertigo, ultimately found to have a cerebellar stroke.

This case highlights a few key principles in the approach to vertigo:

1) Verify that this is truly vertigo - ie a sensation of oneself or the room spinning, as compared to presyncope or lightheadedness. The diagnostic approach for these 2 entities can be quite different.

2) Once you have decided that this is vertigo, decide whether it is of central (ie CNS) or peripheral (ie vestibular) etiology.

First, let's discuss what the central and peripheral causes are:

Peripheral

Benign positional paroxysmal

vertigo (transient, positional, caused by otoliths)

Ménière’s disease (recurrent vertigo, aural fullness, tinnitus, nausea, vomiting)

Acute labyrinthitis (typically viral)

Acute vestibular neuronitis (inflammation of the nerve, typically viral)

Cholesteatoma

Herpes zoster oticus (Ramsay Hunt syndrome)

Medication-related

Central

Cerebellopontine angle tumor

Cerebrovascular disease (TIA, Stroke, hemorrhage)

Migraine

Multiple sclerosis

Medication-related

There are several key features on history that can help differentiate between peripheral and central causes, in over 75% of cases.

Central:

• Longer duration of symptoms without relief
• Less severe nausea and vomiting
• More likely purely horizontal, rotatory, or vertical nystagmus that is not alleviated by fixing on an object
• Sudden only if cerebrovascular in nature
• Associated neurological symptoms/findings
• Cardiovascular risk factors
• Short latency after performing Dix-Hallpike before nystagmus

Peripheral

• Rotatory illusions
• Much more likely to have nausea and vomiting
• Nystagmus is often both horizontal and rotational, improving with fixing gaze, and usually triggered by some provoking factor (ie position)
• Often sudden onset
• Often associated with other symptoms: tinnitus, ear pain/fullness, hearing loss, recent viral illness
• Long latency after performing Dix-Hallpike before nystagmus

Physical examination should pay special attention to a full neurological examination (including gait), H&N examination looking at the tympanic membranes, orthostatic vitals, and performing a Dix-Hallpike Maneuver.

See here for a great review.

Lastly, it is important to note that this man was of Western African origin and quite young. Studies have shown that s

mall-vessel cerebrovascular disease and vascular-related cognitive impairment are more prevalent in hypertensive subjects of black African origin compared with Caucasians. This particular study found that

African-Caribbean subjects were typically 4 years younger but had been hypertensive for 3 years longer than Caucasians. They found that mean 24-hour BP was more poorly controlled in African-Caribbean patients and that ethnicity was independently related to

increased hypertensive white matter damage and executive cognitive dysfunction. Another study estimated that the higher BP in hypertensive black patients (as compared to Caucasions) results in 5480 more deaths due to heart disease and 2190 more deaths due to strokes in the US. It is important for us to consider why these differences in both risk factors and outcomes exist - access to healthcare and socioeconomic status being important factors. Interestingly, you may have seen in the news recently - the Annals of Internal Medicine published on culturally-appropriate storytelling (ie African-American patients describing their experiences with hypertension) as an intervention to lower BP - with fascinating results! See here.

Rapidly Progressive Dementia

Today we discussed a fascinating and very sad case of a woman with rapidly progressive dementia over a 3 week period. We discussed the broad differential diagnosis for this phenomenon which includes:

• Neurodegenerative conditions including Creutzfeldt-Jacob disease, other dementias and progressive supranuclear palsy.
• Infectious conditions like HSV encephalitis or HIV dementia, subacute sclerosing panencephalitis following measles infection in young adults, and syphilis.
• Metabolic conditions like B12 deficiency, Wernicke's encephalopathy from thiamine deficiency, and liver/renal failure.
• Toxins like Lead, Lithium, Mercury, Arseni, or bismuth.
• Autoimmune phenomenon like Hashimoto's encephalopathy, CNS vasculitis, or lupus cerebritis.
• Paraneoplastic limbic encephalopathy.
• Metastases or primary CNS malignancies.

We discussed the possibility of prion disease, or Creutzfeldt-Jacob disease at length today. CJD is a transmissible spongiform encephalopathy that is uniformly fatal - variant forms (ie acquired) often within 3 months and sporadic within 6. Although the incubation period is incredibly long (years), CJD progresses rapidly once symptoms appear. It is characterized by:

• dementia, diminished higher-level cortical function, and mood changes
• myoclonus
• extrapyramidal signs like hypokinesia and cerebellar signs like ataxia and nystagmus.

Diagnosis is made with the support of a number of modalities, most of which do not allow for rapid or definitive diagnosis, and lack sensitivity or specificity. These include MRI which often shows increased T2 and FLAIR signal intensity in the putamen and head of the caudate, EEG showing periodic synchronous bi- or triphasic sharp wave complexes (specific, not sensitive), and CSF (normal glucose, often (60%) normal protein levels, and presence of abnormal protein 14-3-3).

Unfortunately there is no treatment for CJD and death invariably occurs within months. This is all the more reason why it is important to search for the other, potentially reversible causes of rapidly progressing dementias. See this great review for a some very helpful algorithms outlining the approach to investigation.

Recurrent pulmonary embolism

On Monday we discussed a patient with recurrent unprovoked DVT/PE. While we often think of venous thromboembolism (VTE) as an acute issue (which it is when we're managing it in the ER!), there is also a chronic component - the risk of recurrence after 5 years is 20–25%. It is more than 25% in patients with unprovoked events, like our patient.

Treatment for VTE is anticoagulation, initially with heparin and for several months thereafter with low-molecular weight heparin or warfarin. Anticoagulation has its own risks - up to 3% per year risk of bleeding, and likely higher rates in "real life". For this reason, it is important that we understand and estimate the risk of recurrence of VTE in our patient population, to avoid unnecessary anticoagulation. Only patients at high-risk of recurrence should be anticoagulated after their initial 3-6 months of anticoagulation therapy - so how do we assess this?

Here are some factors that place patients at higher risk for recurrence:

No predisposing factor (ie unprovoked)

More than two thrombotic events

Continued estrogen use

Pulmonary embolism or proximal deep vein thrombosis

Male (nearly 4x higher than women - with unprovoked VTE!)

Vena cava filter

Cancer (early recurrence)

Lastly, we often discuss (as we did in AM report) the hypercoagulable states and their associated laboratory markers - factor V Leiden, antithrombin III deficiency, protein C and protein S deficiencies, prothrombin mutation, and antiphospholipid antibody syndrome, among others. There is currently no evidence to suggest that testing for these markers (and deciding treatment duration based on the the results) makes any difference in recurrence of events - and it commits some people to lifelong anticoagulation. This seems to suggest that we shouldn't be measuring them routinely - food for thought!

Other markers with some evidence (and ongoing studies) are the utility of the D-Dimer, measured 1-month after discontinuing anticoagulation. High levels are associated with higher risk of recurrence. Other prediction models combining a variety of factors are being investigated.

All this to say - it's not as simple as we thought!

See here for a great review on this subject.

Palpable Purpura

Last week we discussed a young man with IBD, with recurrent episodes of palpable purpura. It was ultimately thought that he had a post-viral leukocytoclastic vasculitis.

Palpable purpura is a rare finding, but can be dramatic. It is important to recognize because it can be a harbinger of serious illness. Purpura is caused by necrosis, antigen-antibody complex deposition, and fibrin deposition on or between endothelial cells. Although it is classically associated with cutaneous small-vessel vasculitis, as in this patient, it is also associated with embolic, infectious, and malignant causes.

Here is a general differential diagnosis (note vasculitidies comprise the bulk of the list):

Inflammatory

Cutaneous vasculitis

Hypersensitivity vasculitis (ie medications-induced)

Henoch-Schonlein purpura

Polyarteritis nodosa

Granulomatous vasculitis (Wegener's granulomatosis, Churg-Strauss vasculitis)

Cutaneous vasculitis associated with a collagen vascular disease (e.g., systemic lupus erythematosus, rheumatoid arthritis)

Giant cell arteritis

Mixed cryoglobulinemia

Hyperglobulinemic purpura

Infectious

Subacute bacterial endocarditis

Meningococcemia (usually petechial)

Noninflammatory

Trauma

Amyloidosis

Senile purpura

Scurvy

Sweet’s syndrome

Kaposi’s sarcoma

Toxins

Unfortunately not available online, here is the reference: Am Fam Physician. 1995 Oct;52(5):1355-62.