Answer to August 2009 Case

Dear Bloggers

Thanks for waiting for the answers to this exciting case.

I would like to apologise for the typing error with the PNS exam which should have been like this

RUL LUL RLL LLL

Supin +/- ++ n/a n/a
Bicep +/- ++ n/a n/a
Tricp +/- ++ n/a n/a
Knee n/a n/a +/- +/-
Ankle n/a n/a +/- +/-

RUL = Right Upper Limb
LUL = Left Upper Limb
RLL = Right Lower Limb
LLL = Left Lower Limb

This month Prof Alan Lefor (Surgeon, USA) and Professor Gerald Stein (Rheumatologist, USA) have kindly answered the case. Their comments follow on below:

Professor Lefor

Question 1: From the history and examination, please make an appropriate problem list. Problem List:

1. History of LOC with urinary incontinence 2. Changes in bowel habits (loose stool, black stool) 3. Neurology symptoms (double vision, dizzy, tingling, reflexes asymmetric) 4. Hx of adrenal tumor 5. PAF 6. Hx of previous Htn 7. Abnormal physical exam with axillary nodes, hypotension and tachycardia

Question 2: Please provide a differential diagnosis (es).

It would be nice to tie all of this together in one package, which may be possible, but there are other possibilities with multiple diagnoses. 1. GI tumor with brain mets, anemia 2. Other primary tumor (e.g. melanoma) with GI, brain involvement 3. GI bleeding from a non-malignancy and significant anemia 4. New onset seizures from tumor or from metabolic disturbance 5. Metastatic adrenal tumor (someone should get the details of this tumor from old records, it is essential).

Question 3: What would you immediately do for this patient?

Immediate actions: 1. Complete the physical exam with a stool guaiac test 2. IV fluid resuscitation with catheter placement to follow urine output 3. If her anemia is significant, given her LOC, tachycardia and hypotension, then transfusion is indicated.


Question 4: What tests would you perform and why?

1. I think the stool guaiac will probably be positive. She needs a colonoscopy. If that is negative then upper endoscopy especially if an NG tube shows bloody drainage 2. She has enough neurological symptoms to mandate a CT of the head for ischemic damage or mets as a cause 3. I would check a CBC (?anemia) and electrolytes (?cause of seizures, etc) 4. If all of this is uninformative, especially the endoscopy, then the axillary lymph nodes should be biopsied in the search for a primary tumor.


Question 5: What other bedside physical examination test(s) could provide additional information to aid your diagnosis?

1. Stool guaiac 2. Fundoscopy looking for signs of increased intracerebral pressure 3. Pass NG tube to R/O upper GI bleeding

Professor Stein Question 1: From the history and examination, please make an appropriate problem list.

1. Transient Loss of Consciousness with urinary incontenence need duration
2. Loose BLACK stools
3. Parathesias LUE, diplopia (Cr N 6), proptosis L eye, LUE & LLE ??? DTR
4.Adrenal tumor>-ectomy
5. HTN
6. PAF
7. 2 anti plat Rx + NSAID
8. Anemia
9. Lymphadenopathy
10. Hypotension
11. Tachycardia

Question 2: Please provide a differential diagnosis (es).

1. R/O GI bleed/hypovolemia/hypotension 2. R/O Subdural hematoma 3. R/O Midbrain or Brain stem infarct 4. R/O Brain emboli [PAF] 5. R/O arrythmia 6. R/O AMI & PE 7. R/O DM/Addison???s 8. R/O causes of hyperuricemia: renal, lymphoma 9. R/O seizure

Question 3: What would you immediately do for this patient?

1. Fluid resuscitation-hourly urine output 2. Capillary Glucose 3. STOP anti plat & NSAID Rx

Question 4: What tests would you perform and why?

Stool & NG fluid occult blood; if + EGD/colonoscopy, ECG for PAT/hidden flutter CBC, electrolytes, Blood glucose, BUN/creat, cardiac markers, D-dimer, cortisol, Chest xp, Brain CT Cardiac, ECHO, EEG-later if needed

Question 5: What other bedside physical examination test(s) could provide additional information to aid your diagnosis?

Stool occult blood, Fundoscopy, Ausculate neck for carotid bruits and Bilat upper limb BP???s/pulses

Thank you to Professors Lefor and Stein for such excellent answers. I will now reveal the case answer below!

Question 1: From the history and examination, please make an appropriate problem list.

Problem List

1. Loss of Consciousness
2. Dizziness on standing
3. Urinary incontinence
4. Loose stools
5. Pins and Needles of the left arm
6. Double vision
7. Right adrenalectomy
8. Paroxysmal AF
9. Hyperuricaemia
10. Disopyramide / Aspirin / Voltarol / Allopurinol / Ranitidine/ Lactulose / Senna
11. Large, rubbery, smooth, multifocal lymphadenopathy
12. Tachycardia
13. Hypotension
14. Rectal Examination - Black stool
15. Proptosis of Left Eye
16. Abduction Palsy of Left Eye
17. Left arm relative Hyper-reflexia

Question 2: Please provide a differential diagnosis (es).

In the under 50s it is often desirable to try and use Okham's Razor to bring all elements of the problem list together to try and make one unifying diagnosis. However, in the over 50s although Okham's Razor can still be used, Hickham's Dictum is perhaps more relevant. This means that patients are allowed to have as many diagnoses as '...they well please' ! :-) This was described by Hickham in the 1950's when it was said that patients are statistically more likely to have several distinct illnesses / diseases then one rare disease (re Okham), which logically becomes more likely as the patient ages.

Hence, when looking at this case, it should be considered that there are multiple diseases rather than one. Let's first consider why the patient collapsed.

The fact that the patient experienced dizziness on standing, has vital signs consistent with shock (when the patient is usually hypertensive) and has a rectal examination consistent with malaena (despite the patient saying no to this) makes an upper GI bleed the most likely cause of the collapse. The cause of such bleeding is the combination of Aspirin and NSAID despite the use of Ranitidine (H2-blocker). H2-blockers are not as effective as PPI medication and even the latter cannot always prevent GI bleeding. However, one should also consider other causes:

• Infection - sepsis can result in collapse from shock. Remember that sepsis can cause DIC with low platelets and a coagulopathy. This can result in GI bleeding too. The fact that the patient was unconscious should alert us to intracerebral infection such as acute bacterial meningitis. Of course, other bacterial infections can cause septic shock e.g. gram negative UTI, GI infection
• Endocrine - remember that this patient has had a previous adrenalectomy and may therefore be relatively hypoadrenal. Hence, under a period of stress of any cause, hypoadrenalism can result with collapse (from hypotension), loss of consciousness / confusion (hypoglycaemia) etc. One might also observe a rise in the K+ and a low Na+ level. One should also consider thyroid disease e.g. thyrotoxicosis, which is a precipitator of AF.
• Trauma - no evidence to support this but the patient is taking anti-platelet agents so minimal head trauma could conceivably cause intracranial bleeding.
  
• Inflammatory (connective tissue disease) - no evidence to support this
• Neoplastic - see later. Gastric Ca with bleeding (possibly metastatic to brain), metastatic adrenal tumour -> cerebral mets ->seizure
  
• Haematovascular - SAH, intracerebral bleeding/infarction, subdural, extra-dural bleeding (less likely due to the PNS exam)
• Metabolic - Hyponatraemia, Hypoglycaemia, Hypercalcaemia
• Cardiovascular - cardiac dysrhythmia e.g. underlying worsening of PAF, other dysrhythmia induced by the disopyramide (!!!Remember that Class I drugs are also arrythmogenic!!!), Pulmonary embolism (always on the differential diagnosis list for collapse!) Vascular: Hypovolaemia / Sepsis / bleeding
• CNS - Seizure (as a result of metastatic tumour / metabolic / electrolyte / structural / vascular abnormalities)

The second set of problems we must assess are the cause of the tingling left arm with hyper-reflexia, diplpopia and proptosis with a impairment of abduction of the left eye. The lymphadenopathy may also be relevant here along with the hyperuricaemia. Although the CNS manifestations are physically presenting on the same side of the body, the fact that there is proptosis of the left eye strongly suggests a space occupying lesion in the left orbit. The hyper-reflexia of the left arm with tingling suggests a right sided cerebral lesions possibly affecting the sensory (post-central) cortex. Hence, the intracranial lesions are on different sides suggesting a multifocal pattern!

The fact that there are lymph nodes makes one consider the possibilities of:

• Infection e.g. Tb
  
• Neoplasia e.g. Ca stomach, lymphoma
  
• Connective tissue disease
• Granulomatous disease e.g. sarcoid

The raised uric acid might simply be 'idiopathic' perhaps related to her diet or alcohol consumption (which we are not told about). On the other hand, high turnover of cells might suggest the presence of a tumour e.g. lymphoma (as suggested by Professor Stein)

However, the description of 'smooth and rubbery' usually points towards the idea of a lymphoma as the cause. If there are indeed multifocal intracranial space occupying lesions, common things should be considered first e.g. malignancy (metastatic disease), intracerebral lymphoma, tuberculosis, etc. Hence, the differential diagnoses on admission have been separated into the causes of collapses and the causes these odd neurological symptoms and signs with some of the causes certainly over-lapping.


Question 3: What would you immediately do for this patient ? & Question 4: What tests would you perform and why?

• This patient has shock vital signs and she requires volume resuscitation and glucocorticoid therapy until such time that hypoadrenalism has been ruled out.
• In view of the malaena, it is advisable to cross match 6 units of blood for possible transfusion immediately or to use later if the patient bleeds more extensively. Large bore venous lines should be placed in each antebranchial fossa of the upper limbs for the purpose of rapid fluid transfusion.
  
• In order to guide fluid status, it is often advisable to place a central venous line to maintain the CVP at 8-12cmH2o and place a urinary Foley catheter to ensure adequate urinary output e.g. >30ml urine/hour. In Japan, CV pressure is estimated using echo measurements of IVC compliance that can estimate whether the CV pressure is raised or decreased. Remember that both methods are fraught with inaccuracy and hence, repeated physical examination is ALSO required to gauge when fluid rehydration is inadequate, adequate or excessive.
  
• Venous glucose should be checked and if in any doubt, 50ml 50% glucose should be given to treat for hypoglycaemia. Remember that peripheral and CNS glucose have a poor correlation. Hence, even if the peripheral glucose is normal, the CNS glucose can be low!
• Blood, sputum and urine culture should be obtained to investigate causes of sepsis. Remember that ranitidine and allopurinol drugs can affect the haemopoietic system causing immune dysfunction. If in doubt about the focus of infection, please treat accordingly with antimicrobial agents until infection has been fully excluded by negative cultures or another definitive diagnosis has been established.
• This patient should have basic laboratory data checked to establish haematological or biochemical abnormalites (as discussed) and a chest Xray which could be a clue for the cause of cerebral lesions e.g. cancer, Tb
• To investigate upper GI bleeding, an NG tube can be passed to aspirate blood. A negative test does not exclude GI bleeding but supports it if it positive. There is not evidence that passing an NG tube makes variceal and non-variceal bleeding any worse and it can be helpful diagnostically to know if there is fresh active bleeding. Once haemodynamically stabilised (and not before!) an EGD (gastroscopy) can be performed to look for a cause of possible upper GI bleeding. Intravenous PPI should be given e.g. omeprazole 80mg stat, followed by continuous infusion for 72 hours. Consider tranexamic acid which also reduces GI bleeding. Assess patient's Rockall score for potential of rebleeding AFTER the gastroscopy. This will help to know if the patient requires a 'bleeder bed' -- high input care on a GI ward.
• STOP ANTI-PLATELET AGENTS and CORRECT ANY COAGULOPATHY
  
• Remember, never do procedures on an unstable patient. Moving the patient to the GI room could prove catastrophic with a 'bleed out' on the way. Better if you can take the gastroscopy machinery to the patient!
• Once stabilised, this patient will need a CT head scan to look for SOLs, edema, bleeding, etc. If normal, a lumbar puncture would be very reasonable to exclude meningitis / bleeding. Remember, you have already given the antibiotic to cover infection. CSF can remain positive for up to 4 hours after injection of intravenous antibiotic. Even if the CSF is visibly negative for organisms, PCR can be performed.
• Lymph node biopsy should be performed as soon as possible to look for the underlying cause e.g. lymphoma.
• Remember to check the ECG and if there is still concern, a 24 hour Holter ECG can be performed. The disopyramide might need to be stopped until the cause of the collapse can be fully elucidated.
• Checking of cardiac enzymes (e.g. CK-MB, Troponin I/T) and D-Dimer should be performed. The fact that there may be underlying sepsis or malignancy can give a false + D-Dimer result and hence, as part of the work-up, a cardiac echo may be required. If the pressures are normal, then a life threatening pulmonary embolism (PE) can be ruled out whereas if they are elevated, proceeding to Spiral CT would be necessary. An Echo would also be useful to exclude large intra-cardiac clot that could give rise to cerebral emboli resulting in stroke and collapse.
  
• The fact that the collapse was unwitnessed and the patient has multi-focal neurological signs warrants an EEG to look for a focus of seizure. The patient might require intravenous medication -- remember though, disopyramide and pheytoin (the usually IV drug for seizures) are both Class I drugs. Phenytoin induces liver enzyme induction and can reduce the effective levels of disopyramide.
  

Question 5: What other bedside physical examination test(s) could provide additional information to aid your diagnosis?

• If the patient has an intra-orbital SOL, performing fundoscopy might reveal raised pressure which may be visualised as papilloedema.
• Comfirming the black stool as malaena with the Guaiac test would be supportive of GI haemorrhage.
• As mentioned above, an NG tube could be passed to look for upper GI bleeding.
  

Comments on the Case

Below are the CT pictures that confirm the physical examination findings. Please note the multiple SOLs were considered BEFORE the CT head scan was done. Proptosis and gaze palsy with axillary lymphadenopathy should suggest the possibility of an intra-orbital tumour, as was suspected in this case. Cerebral edema from an SOL was additionally suspected as part of the differential diagnosis. There needed to be careful consideration of using high dose dexamethasone given the possibility of it affecting the GI bleeding by impairing ulcer healing.

The scan shows two mass lesions - one in the left lateral orbit (as suspected) and one in the right cerebrum with edema.

Admission laboratory data was as follows:

Hb 11.o, WCC 8.2, HCT 32.6, MCV 80.1, Plts 135, INR 1.3 Na 132, K 5.3, BUN 60.2, Creat 1.3, Ca 8.7, Glu 160, LDH 290. Normal liver function tests. Albumin 2.8, Total protein 5.9

As can be seen above, the BUN/Creat ratio is 46.3 (hence, more than 20) suggesting an upper GI source of the bleeding. Note the Na 132 and K 5.3 which might signify hypoadrenalism (remember the loss of aldosterone leads to accumulation of K and failure to absorb Na in the kidney). Even though the Hb is 11.0, a normal female Hb level is from 11.5 to 16.o and hence, this patient does have an anaemia. Moreover, the MCV is more than 80 but for the local laboratory measurement it is low! Remember to ALWAYS refer to your own lab's normal range otherwise the microcytic anemia can easily be missed !

The stool examination was +/+ for blood.

As a consequence, the patient underwent a gastroscopy and a large acute gastric ulcer was present (see below) and treated accordingly.

Despite the other mentioned possibilities of sepsis and hypo-adrenalism, unfortunately, these were not followed up by the attending team. The chest x-ray below reveals bulky perihilar areas, which given this case, is suspicious of hilar lymphadenopathy.

Lymph node biopsy revealed Diffuse Large B Cell Lymphoma. Diagnoses in this case:

1. Acute Upper GI Bleed (iatrogenic) from Aspirin and NSAIDs causing collapse and shock
2. Diffuse Large B Cell Lymphoma (multifocal e.g. intracranial, axillary) ? possible seizure due to intracerebral SOL with edema.
3. Possible hypoadrenalism

Take Home Message

• When patients are admitted with loss of conscious, unless there is a reliable witness to the events, search for more than just one cause especially in the elderly.
  
• In loss of consciousness, perform a rectal examination to look for bleeding. Failure to do so may miss GI bleeding!
• In loss of consciousness, perform a full neurological examination if the patient recovers consciousness. Even if unconscious, the GCS/JCS can be performed in addition to pupillary size, corneal reflex, fundoscopy, caloric test, tendon reflexes and Babinski reflex as common examples. In this case, only after asking specific questions did the patient offer up the neurological symptoms and only after a repeat examination did the abnormal neurology come to light. It had been otherwise missed. Hence, you need to have a high suspicion of neurological disease and actively ask additional questions rather than passively relying just on what the patient wants to tell you! Remember, patients don't write the textbooks and they don't know what you want to know (unless they are medical professional themselves!)
  
• Remember that resuscitation of the patient must be done first before considering moving them to have a gastroscopy, a CT or going for surgery etc.
  
• Correct all that can be corrected. This patient's INR was 1.3. That is abnormal. Giving vitamin K will not work to resolve the coagulopathy acutely. It takes several hours to have an effect by which time your patient could have bled out. The quickest treatment is giving factor replacement e.g. factor concentrate (II, VII, IX, X) if warfarin has been used, or Fresh Frozen Plasma (FFP). Even if it is justly slightly abnormal means that it is NOT normal and should be corrected. Don't take risks with your patients. Treat them how you would like to be treated given you being in the same situation.
• If hypoadrenalism is suspected, perform a rapid ACTH test and start appropriate dose steroids e.g. hydrocortisone 100mg iv every 6 hours. Do Not Wait for the results as it can take several days to the detriment of the patient!

Thank you for your consideration.

Many thanks to Prof Lefor and Prof Stein for providing their expert opinions on this month's case.

Thanks to Dr MM, Drs Y, A, Y & U.