Severe B12 Deficiency

During morning report this past week, we were introduced to a patient with severe alcoholism who presented with a hemoglobin of 24 g/L due to B12 deficiency, whose only presenting symptom was 'fatigue.' That's pretty low. Low enough to hear orbital bruits. It is important to note that it takes months to years to deplete one's Vitamin B12 stores as it did in this patient's case.

On physical examination, the patient appeared "pale and yellow," ( a lemony yellow) due to the combination of anemia and hemolysis, a classic appearance of patients with severe B12 Deficiency. Let's go over the important pieces of diagnosing and treating B12 deficiency:

Causes
To develop a differential diagnosis of B12 deficiency, think of the anatomic components necessary for B12 absorption, from mouth to terminal ileum:
Mouth (Diet) - Vegans, alcoholics, patients with eating disorders
Stomach - Pernicious anemia results from autoantibiodies to parietal cells due to Autoimmune Atrophic Gastritis. This is the most common cause of B12 deficiency in adults.
Proximal Small Bowel - Post Roux-en-Y, Celiac Disease, Chronic Pancreatitis,
Terminal Ileum - IBD is a disease with classic TI manifestations.

Physical Examination
Aside from the above mentioned finding of "pale and yellow," another important aspect of physical examination is looking for risk factors for B12 deficiency, such as manifestations of alcoholism, general malnutrition, IBD, and other autoimmune disease.

The neurological examination is unique in patients with B12 deficiency. It is one of the very few diseases that can manifest with both upper and lower neuron lesions. Manifestations classically include subacute combined degeneration of the dorsal (posterior) and lateral spinal columns. SCD manifests as symmetrical primarily lower limb neuropathy with loss of vibration and position sense, which can result in ataxia. Other neurologic findings in B12 deficiency include axonal degeneration of peripheral nerves and central nervous system symptoms including memory loss, irritability, and dementia. Notably, not all patients with neurologic abnormalities secondary to B12 deficiency have hematologic manifestations. 

Investigations
Aside from macrocytic anemia, the other findings on investigation that are suggestive of B12 deficiency include a low or undetectable serum B12 level, and megaloblastic anemia.

Blood films from patients with severe B12 deficiency will also show hemolysis, due to improper RBC production in the bone marrow. Low platelets may also be seen because B12 is necessary for the production of megakaryocytes. The finding of anemia, hemolysis, and thrombocytopenia on a blood film may be confused with a MAHA. The distinction is that the patients with B12 deficiency will also megaloblastic anemia:
- Megaloblasts (immature RBCs) in the bone marrow
- Hypersegmented neutrophils (>5  nuclear lobes) on their peripheral blood film,  

Important tests to help diagnose the etiology of B12 deficiency include antibodies to IF, the Schilling Test, and endoscopy.

Important Tips for treatment outlined during our discussion with Dr. Wayne Gold:

1) Use B12 Injections to Supplement B12 - Once a diagnosis of Vitamin B12 deficiency is made, use injection rather than oral supplements to replete patients. This will allow you to bypass the entire GI tract and will reliably provide patients with your supplement.

2) Watch out for Hypokalemia - When treating patients with severe B12 deficiency, new RBCs are being produced and numerous building blocks are consumed. This includes potassium, which is a major intracellular electrolyte. Remember to carefully replace patient's potassium during treatment.

3) Watch out for folate deficiency - As new RBCs are being produced, folate is rapidly consumed and so when patients are receiving B12 supplementation they will also require folate supplementation as well.

4) Don't transfuse too much - Patients with severe, chronic anemia compensate slowly over time with a hyperdynamic cardiac state, and will have no symptoms of hemodynamic instability. Over-treatment by physicians to rapidly transfuse these patients to a normal hemoglobin values can lead to cardiac failure due to volume overload in an already stressed cardiovascular system.

Here are some good review articles:
Click here for a good article on the treatment of B12 deficiency from Blood.
And a good review from NEJM is found here from 2013.

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.