CNS Lesions and HIV

Recently in Morning Report at both TGH and TWH, we heard about cases in which patients with HIV presented with CNS symptoms consistent with meningitis. In each case, we had a discussion about the differential diagnosis for space occupying lesions in the brain in patients with HIV. 

To CT Head or not to CT Head?

First, let's start off with an overview: Which patients presenting with signs and symptoms of meningitis require a CT Head prior to LP? Keep in mind that the purpose for the CT Head is not to diagnose meningitis, but to make rule out contraindications for LP, namely increased ICP due to a mass/bleed in the brain. Performing a CT Head should not delay the initiation of treatment - antibiotics should be started prior to the completion of a CT Head in those where indicated:

                       

The following risk factors are listed in the IDSA recommendations because these patients are more likely to have space-occupying lesions:

                              

As you can see, one of the indications to performing a CT Head prior to LP is HIV, due to the higher than average probability that patients will have a space-occupying lesion. These lesions can all also present with fever, seizure, focal neurological deficits, and decreased LOC. If one is found, what is the differential for such a mass? There are 3 main differentials:

1) Toxoplasmosis - Usually multiple ring-enhancing lesions. Seen in patients with a CD4 count less than 100 and localized to frontal or parietal lobes (corticomedullary junction), and basal ganglia.

2) Primary CNS Lymphoma - Single or sometimes multiple homogeneously or ring-enhancing lesions near the subependymal surfaces. Lesions that cross the corpus callosum are suspicious for this diagnosis.

3) Abscess - Ring-enhancing capsule with central low attenuation (pus) in the late capsular stage of abscess formation. Most common pathogens include Staphylococcus, Streptococcus, Aspergillus, and Nocardia. Rarely, but more often than in non-HIV patients, the lesions can include cryptococcomas, tuberculomas, and syphillis (gummas).

 

       CNS Lymphoma in an HIV patient

                                                                                   Abscess in an HIV patient

What do I do next?

Investigate!

If a space-occupying lesion is found, the next step in management may include performing an MRI to better delineate the etiology of the lesion (e.g. abscess vs. lymphoma). A biopsy (the gold standard) may also be required, depending on the clinical status of the patient. Less invasive testing may also help differentiate the problem - such as serum and CSF analysis. Once an LP can safely be done, helpful CSF tests include bacterial cultures, fungal cultures, AFB staining, PCR for JC virus/Toxoplasmosis/EBV, cryptococcal antigen, VDRL, and opening pressure (may be high in cryptococcal meningitis). 

Treat!

Again, antibiotic therapy should not be delayed when a suspected CNS infection is found, and empiric therapy in an HIV patient may include ceftriaxone (to cover usual meningitis organisms), flagyl (protozoal infections), pyrimethamine and sulfadaizine (both to treat toxoplasmosis), and possible quadruple therapy for suspected CNS TB.

One last point...

Keep in mind that not all infections of the CNS in HIV patients will present with large masses and mass effect. Some will be seen as white matter changes on MRI with no mass effect:

1) PML- Demyelinating disease due to the JC virus. Can present with rapidly progressive focal deficits such as hemiparesis, field deficits, ataxia, and aphasia. Asymmetric multifocal demyelination.

2) CMV encephalitis - seen in patients with CD4 counts less than 50. Periventricular white matter changes with possible enhancement.

3) HSV encephalitis -  Affects the medial temporal lobes, insular cortex, and inferolateral frontal lobes along with the brain stem.

4) HIV encephalopathy -  Present with memory and psychomotor slowing, depression, movement disorders. Symmetric periventricular white matter changes, possibly with cerebral atrophy.

But wait, there's more....

There are also some entities which have no CNS lesions on imaging, such as any cause of meningitis (eg. bacterial, TB, cryptococcal) and neurosyphillis. 
Ok. All done!

Resources:

A recent NEJM article reviewed the management of brain abscess in HIV and non-HIV patients.
Click here for IDSA Guidelines for Meningitis from 2004.

Lyme Disease

This week we discussed an interesting case of Lyme Disease in Morning Report.

Briefly, a middle-aged lady presented with signs and symptoms of meningitis following recent exposure (5-10 days prior) to a tic bite. The patient was at a cottage in southern Quebec when she found a tic on their leg. A rash developed at the site of the tic bite that had the classic appearance of erythma migrans (EM) (aka erythema chronicum migrans, ECM), which is pathgnomonic for early localized Lyme Disease. 

An interesting issue was raised with this case - can Lyme Disease present with meningitis? And if it does, at what stage might you expect to see this?

For this case, it is important to understand the stages of Lyme Disease, as features of Lyme infection present according to a specific timeline of the disease. Notably, earlier features do not necessarily have to appear in order for the later features of the disease to manifest. Also, in a quarter of cases, patient do not even recall having a tic bite.

Fun Fact - The northward spread of Lyme into southern Ontario and Quebec may be linked to warmer temperatures (i.e. Global Warming). (Lyme Disease is named after the town where the earliest cases were discovered - Lyme, Connecticut). See below for reference.

Here are the three stages of Lyme Disease:

1. Early Localized Disease:
- Marked by erythema migrans, seen in more than 80% of patients, appears within 1-2 weeks after exposure.
- EM is often described as an erythematous circular rash having a central clearing; however, it may be uniformly erythematous in up to 50% of patients, especially when the lesion is small.
- Multiple lesions may be present
- Additional features may include lethargy, headache, mild neck stiffness, myalgias, arthralgias, and lymphadenopathy. Rarely can it present as aseptic meningitis. More likely is that these symptoms are confused with meningitis.

2. Early Disseminated Disease
- Occurs weeks-months after exposure if early disease has gone untreated.
- In this phase, systemic features of the disease are seen:

- Therefore, neurological manifestations such as meningitis are far more likely to appear >2 weeks after exposure to the infection.

3. Late Disseminated Disease
- Defined by prominent worsening  neurological and MSK symptoms 
- MSK: Arthritis of one or more joints, often the knee
- Neurological: Persistent neuropathy, myelitis

Treatment

The treatment for Lyme Disease includes either doxycycline, amoxicillin, or cefuroxime. All are safe and effective for early Lyme disease. Treatment should be started on detection of EM lesions in the case of early disease. In disseminated disease, treatment is started on the basis of compatible clinical picture with serology.

Back to the case....
Our patient's LP showed few cells and normal protein. Therefore, her clinical picture was consistent with possible aspetic meningitis, and not due to direct infection of Lyme into the CSF. She was treated for her early localized disease with amoxicillin and improved rapidly with conservative management. 

An excellent NEJM article from 2014 summarizes the diagnosis and treatment of Lyme Disease.
Click here for an interesting paper suggesting that Global Warming is contributing to the spread of Lyme Disease.

Polyarthitis

Diagnosing Polyarthritis

This past week we discussed the approach to polyarthritis. Here are the key points to keep in mind:

Key Lessons:

1. History of the Arthritis

The pattern, timing, and location of the joints affected are key to determining a diagnosis. Establish whether the complaint is articular (pain in all directions of movement, pain on passive movement) or peri-articular (pain in some ranges of motion, no pain on passive movement). Establish whether the arthritis is inflammatory (morning stiffness, systemic symptoms, joint swelling, limited range of motion) or non-inflammatory. Document the affected areas carefully on a diagram, for example:

1. Symmetric large joint: Seronegative arthropathy, rheumatoid arthritis

2. Asymmetric oligoarthritis: Seronegative arthropathy, infectious, or crystal induced

3. Symmetric small and large joints (non-inflammatory): Osteoarthritis

4. Symmetric small and large joints (inflammatory): Seropositive arthropathy, psoriatic arthritis

2. Establish a Differential Diagnosis:

Inflammatory conditions:

Seropositive conditions: Rheumatoid Arthritis, MCTD, Systemic Lupus Erythematosus, DM/PM

Seronegative condtions (Spondyloarthritidies): Anklyosing Spondylitis, Reactive Arthritis, Psoriatic arthritis, and IBD associated.

Systemic vasculitis

Crystal disease

Non-Inflammatory:

Osteoarthritis

Hemochromatosis

Acromegaly

Infectious:

Bacterial: S. aureus, Group G strep, Neisserial infections

Viral: Rubella, Parvovirus, HIV, Hepatitis B/C

Tick borne disease: Lyme disease (Borrelia burgdorferi)

Rheumatic Fever

Endocarditis 

Other Rarer Inflammatory Causes

Sarcoidosis

Palindromic rheumatism

Serum sickness

3. Associated symptoms

In order to narrow down your differential diagnosis, inquire about associated (extra-articular) symptoms:

Seropositive Disease: Malar rash, photosensitive rash, oral ulcers, sicca symptoms, nodules, Raynaud's phenomenon

Seronegative Disease (Spondylarthritis): low back pain, uveitis, diarrhea, enthesitis, psoriatic plaques, dactylitis.

Infectious: diarrhea illness, recent STI, recurrent fevers, cellulitic rash.

Osteoarthritis: No associated or systemic symptoms.

4. Investigations

- Bloodwork: CBC (screen of inflammatory or systemic disorder), serum urate (if gout is suspected), creatinine and urea (can help establish systemic involvement of a disorder), rheumatologic tests such as complement/ANA/ANCA/ESR (should only be ordered if a rheumatologic condition are highly suspected).

- Arthrocentesis: Can very be very helpful in establishing a diagnosis if fluid is present in one of the affected joints. Would likely be helpful in an acute on chronic process

- Imaging: Plain films are helpful if process is longstanding and underlying changes have developed.

Resources;

Click here for a review article on polyarthritis from CMAJ in 2000.

Click here for a review article on polyarthritis and fever from the NEJM from 1994. 

Asthma Exacerbation

Today in morning report we discussed an important case of a patient presenting with an asthma exacerbation.

This is an emergency and that your history/physical/investigations and management are all going to happen almost simultaneously. And of course, get help.

Some key points to consider on:

1. History:
- Questions around severity: 
# of ICU admission, # of exacerbations, # of MD visits. 
Adherence. Beta agonist use (2 more cannisters / month is sign of severity)
Other psychosocial issues
- Questions around control:
Daytime symptoms 
Nighttime symptoms
Physical exercise 
Inhaler/rescue use 
Absence work/school 
PEF 

- Triggers: 
Infection, allergen, adherence

2. Physical Examination:
Appearance, # of word dyspnea
Vitals including a pulsus if possible
Peak Flow
Chest exam. Silent chest is a bad sign

3. Labs
ABG: beware the "normal" CO2

4. Treatment:
-Bronchodilation
MDI via spacer just as good as nebulizer (and issues around infection control)
Beta-agonists, anticholinergics (in the acute setting for anticholinergics, and especially consider if due to beta-blocker)
Remember that HR may actually get better with treatment as you improve the hypoxia and constriction.
IV magnesium in severe exacerbations
- Corticosteroids
Likely longer duration than in COPDE
- ICU
Earlier assessments important, especially if ventilation needed. 
- NIV: Considerations around non-invasive ventilation discussed, may be helpful, but be mindful of delaying needed intubation.
- Intubation: tricky, if needed should be done by experienced, skilled MD (ie Anesthesia, ICU).
- Others: Heliox discussed, still probably needs more evidence.

A word on Peak Flows:
Important. Don't forget to do them. Will help to guide treatment response and disposition.
Pre-treatment of less than 25 percent personal best or less than 100 L / min should be admitted
200-300 L/min consider admission. more than 300 consider home
(These are only guidelines and need to take into consideration all other factors of the patient to best decide if admission, ICU, or home).

See this review article on management of asthma exacerbations.

Your analysis?

An inside joke entitles today's post from morning report where we actually discussed a patient who presented with a "sickle cell crisis".

Sickle cell disease results from a point mutation at position 6 of chromosome 11 leading to a glutamate to valine substitution. There are 3 main forms of SCD and these are:

HbSS- typical form of SCD

HbSC- one S genotype, and one C genotype that results from a different mutation. Less severe

HbSBeta-thal- one S and one beta thal trait.

Others include HbE, HbD, Hb Lepore.

Clinical manifestations are broad in SCD and include vaso-occlusive crises (VOC) that result from sickled RBCs obstructing capillaries resulting in ischemia and necrosis. VOC include bony pain crises, and include one of the most severe complications of SCD which is an Acute Chest Syndrome (ACS). Other complications include priapism, stroke (cause of "stroke int the young"), painful leg ulcers, AVN, as well as aplastic crises, hemolytic crises, sequestration crises,and pulmonary hypertension, to name a few.

Principles of management include fluid rehydration, appropriate analgesia, antibiotics if indicated, plasma exchange for certain circumstances such as ACS

What about hydroxyurea (HU)?

HU increases HBF concentrations, and was shown in a landmark NEJM study in 1995 by Charache et. al to reduce morbidity by decreasing the number of painful crises from a median of 4.5 to 2.5 per year. Rates of ACS, blood transfusions also decreased, and time to painful crises also increased in the HU group. An observational follow up of 233 out of 299 of these patients 9 years later by Steinberg et. al from JAMA showed a mortality reduction of 40%. Lastly, one clue that might point to adherence, is that due to its effects, HU should cause an elevated MCV, and so certainly a low MCV might suggest non-adherence. 

What about infection?

Infection is another important consideration in patients with sickle cell disease. Patient with HbSS by adulthood will be functionally asplenic because of autoinfarcting their spleen. Thus one clue that perhaps a patient dose not have HbSS disease is if they have a history of splenectomy in their PMH. Patients with HbSbetathal can have associated splenomegaly. 

As a result of either no spleen, or no functioning spleen, patients will be at risk of infection with encapsulated organisms - S.pneumo, H.influenzae, N. meningitidis - and other Gram negatives such as E.Coli, Salmonella species, and Pseudomonas. As a result, patients should be vaccinated. See this CMAJ article that discusses optimal management of patients pre-splenectomy, the vaccine aspect applies to SCD patients. 

Other principles of management

Folic acid - due to chronic hemolysis and high requirements.

Medic alert bracelet

Patient education

Click here for the original 1995 NEJM article and also here for a 2008 NEJM review on HU and SCD

Pulmonary Hypertension 

In morning report today we discussed the case of an elderly patient who presents with dyspnea. Specific points include an echocardiogram that showed a normal LV, with no significant diastolic dysfunction, but reported a very elevated RVSP (over 100). 

Given the absence of obvious left sided heart disease as the cause and suggestions of high right sided pressures, the diagnosis of pulmonary hypertension was raised. 

Approach to pulmonary hypertension

An anatomical approach is useful and from this come the 5 major categories of disease.

1. PAH (pulmonary  artery hypertension)

-idiopathic, hereditary ((bmpr2, alk (alk mutations, not the ones that cause cancer, can lead to PAH, and HHT))

-secondary to CTD (scleroderma more often CREST, anticentromere…whereas anti-scl70 is systemic, causes ILD), HIV, 

-hemoglobinopathies (ie sickle cell, anything with hemolysis leads to binding of NO that prevents vasodilation), drugs (amphetamines, cocaine, fen-phen)

1 prime: PVOD (pulmonary veno-occlusive disease)

PVOD vs PAH: one defining feature is that if PVOD receives PAH treatment, they will get significantly worse.

2. Cardiac: CHF, LV dysfunction, AS, MR, diastolic

3. Lung disease: Chronic hypoxemia eg COPD, OSA, hypoventilation syndrome or parenchymal lung disease eg ILD

4. CTEPH: treated with endarterectomy (surgery)

5. Miscellaneous: sarcoid, langerhan’s, splenectomy, mpd, glycogen storage diseases

Workup

History, physical 

-looking for consequences of and causes of pulmonary hypertension:

O/E

-Elevated JVP, CV, loud P2, palpable P2, RV heave, SOA, pulsatile liver.

PFT’s (also 6 minute walk test for prognostication, not diagnostic)

- looking for lung disease

- normal pft but isolated dlco would be hint to IPAH

ECHO

-Normal RVSP is 35

-RV dilatation, RV hypokinesis, pericard effusion

V/Q scan

-looking for CTEPH

-CT is good for acute, but not chronic. If V/Q positive, CT normal, then think of CTEPH

High res CT with contrast

-for parenchymal lung disease. Contrast is to help look for PE’s

Sleep study

BW: 

-CTD, HIV, Hgb electrophoresis etc.

Right heart catheterization

-mPAP > 25 with PCWP < 15

-Trans pulm grad is mPAP – PCWP  If > 12 then abnormal

Treatment considerations include:

- Oxygen 

- Diuretics 

- Anticoagulation (controversial)

Condition specific treatments include: 

For CTEPH: endarterectomy, Riociguat (recent NEJM link is here)

PAH: endothelin antagonist such as bosentan, vasodilators such as PDE5 inhibitors, IV epoprostenol

Lastly is transplant.

For more check out this BMJ review article on pulmonary hypertension, also where the above figure comes from.

A rash diagnosis

Morning report discussed a case of a patient who presented with non specific symptoms such as nausea, vomiting, subjective fevers, and back pain.

Based on this, proposed diagnoses based on symptom/syndrome recognition included pyelonephritis, vertebral osteomyelitis, epidural abscess. 

If the patient was delirious, how would your consideration change?
Perhaps age factors into this and would be appropriate if this were a patient who was elderly with vascular injury in the past. 

Delirium might invoke CNS infections, or may be secondary to the primary process. 

Physical examination revealed a vesicular rash, in a dermatomal distribution. 

These lesions were de-roofed and sent for analysis, which came back as VZV.

VZV:

Primary infection with VZV = Chicken Pox. Latency develops in dorsal nerve roots.

Reactivation then occurs: 

-Can be with rash = shingles, dermatomal distribution

-Can be without rash = zoster sine herpete

-Reactivation can present with or without visceral involvement eg. pancreatitis, hepatitis

Age is the biggest risk factor on a population basis for reactivation.

Neurologic complications of VZV include:

-         Zoster opthalmicus

-         Bell’s Palsy

-         Ramsay Hunt

-         Immunocompetent: can develop

o       Transverse myelitis

o       Granulomatous angiitis – can present as stroke

-         Immunocompromised:

o       Transverse myelitis

o       Small vessel vasculopathy – present as encephalitis

-         POST HERPETIC NEURALGIA

o       Post herpetic neuralgia defined as pain > 90 days after onset of rash. Age again  is RF.

Zoster associated pain comprises phase of acute neuritis and post herpetic neuralagia

 Antivirals

-         Acyclovir, Famcyclovir, Valcyclovir. (FCV,VCV may be considered over ACV because of activity, dosing)

-         Decrease rash by 0.5 day, decrease fever by 0.5 day, decrease acute neuritis phase

-         Treatment should be within 72 hours of rash. Exceptions include zoster opthalmicus, immunocompromised, one could argue for Bell's Palsy.

Post Herpetic Neuralgia treatment

-         gabapentin, TCA’s...no clear direction over which to choose, which is better. Acetaminophen, NSAIDs may help.

Other points in management include getting an ophtho assessment if V1 is involved. The role of steroids is controversial.

Zostavax

-         Indicated for greater than 60 yo

-         50% reduction in shingles

-         67% reduction in zoster associated pain

-         Similar results greater than 50 yo

-         Cannot give if on immunosupression. Should wait at least 6 months

-         Not clear when to give after acute zoster infection…

For more details see this NEJM review article on Zoster

...and this NEJM article on neurologic complications of Zoster