Another Mind Boggling Case

Dear Bloggers

The following case has, as always, been anonymised to safe guard patient confidentiality and anonymity.  International physicians are also welcome to answer this case history. Please feel free to send in your answers which I will then publish.

This 61 year old male presented with a six-week history of

• Cough
• Fever
• Fatigue and Malaise
• Numbness and pain in the right hand
• Pain in the proximal lower limbs, buttock pain and dragging of the left leg

The cough commenced six weeks before admission and the patient considered this to be due to a common cold. The cough was non-productive. There was no associated sinus pain, rhinorrhoea, throat or ear pain. 

The fever had started gradually and had reached up to 38 degrees. There was no associated chills or shaking with the fever. No associated sweats.

The fatigue and malaise had been of relatively rapid onset and the patient had lost his appetite only being able to eat half of his food.

The numbness in the right hand had developed just prior to admission into the hospital. The numbness initially affected the thumb, index and middle finger but then became confluent over the entire palmar aspect of his hand. He did not complain of numbness on the back of his hand. He also described joint pain and was unable to make a fist. 

The pain in the proximal lower limbs was described as a dull ache in the back of his thighs. It was not worsened by movement or coughing. There was no history of any previous spinal pathology and no history of trauma. There was no 'shooting' quality to the pain. The patient had also developed a heaviness of the left leg and he was dragging it when walking. Although he was able to walk  he preferred to be prostrate because of the fatigue and malaise. 

The buttock pain was described as an ache and was localised without radiation. The patient preferred not to lie on his buttocks in bed and instead, laid on his side.

Prior to admission, the patient had sought medical advice from a local clinic on several occasions and several courses of antibiotics had been prescribed which had not resolved the problem.

On further questioning (Body Systems Review):

CVS: No chest pain, no palpitations, no breathlessness.

RESP: No sputum, no haemoptysis, no history of lung disease or TB exposure.

ABDO: No abdominal pain, no nausea or vomiting. No diarrhoea or constipation. No jaundice, normal coloured stool and urine.

MUSC-SKEL: No bone pains, no back pain, no joint swelling or stiffness. 

UROGEN: No urinary symptoms e.g. dysuria, haematuria, frequency, nocturia, urgency, hesitancy, incontinence, feeling of incomplete voidance etc...

CNS: No headaches, no pulsating head pains, no visual disturbance, no jaw claudication or tongue pain on eating. No description of facial numbness or pain. No dizziness or vertigo. No visual disturbance. No auditory disturbance.

ENDO: No thirst, no polyuria, no changes in ability of concentration, no tremor, no sweating, no previous fractures, no recent weight gain  or weight loss. 

SKIN: No complaint of skin rashes or ulceration.

Previous Medical History

Appendicectomy when aged 15 years

Left sided weakness at age of 30 years. No formal diagnosis made. Recovered within 6 months.

Medications- nil

No know drug allergies (NKDA)

Family History

No IHD, no AMI, no HTN, no hyperlipidemia, no diabetes mellitus, no connective tissue diseases.

Social history

The patient was normally well and independent and he worked part-time in a grocery store. He had not been able to work for 1 week prior to admission because of the worsening symptoms.

He was a non-smoker and drank occasional alcohol. He lived with his wife and had two adult sons.

On Examination-- please pay careful attention to the detail here!

General Impression: The patient looked unwell but not seriously ill.

Vital Signs: Temp 38.4 C, BP 140/80, Pulse 110/min (regular), respiratory rate 14/min, SpO2 98% breathing ambient room air. BMI 38.2

General: No clubbing, no splinter hemorrhages, no Janeway lesions or Osler nodes. No conjunctival hemorrhages.  No lymphadenopathy.

CVS: Apex not displaced. No heaves or thrills. Heart sounds 1 + 2. No systolic or diastolic murmurs. No lower limb swelling or evidence of deep vein thrombosis (DVT)

RESP: trachea central and no tracheal tug. Expansion, percussion and auscaultation were normal. Palpation of the chest revealed tenderness along the anterolateral aspect of the ribs bilaterally.

ABDO: Subcutaneous fascia ++. Soft, non-tender, no obvious masses or hepatosplenomegaly. No abdominal bruits and normal bowel sounds. No renal angle tenderness. 

CNS: normal cranial nerve examination.

PNS: tone, reflexes and coordination were all within normal limits. Gross sensation of the upper and lower limbs was normal except the right hand. Sensation of the hand was reduced over the entire palmar aspect including the fingers and the distal dorsal aspects (nail area). The dorsal aspect of the hands had normal sensation. Babinski sign negative bilaterally.

MUSC-SKEL: The right hand was held open in extension. The patient was unable to make a fist because of pain. Examination of each small hand joint revealed pain in the metocarpophalangeal joints of the index and middle finger. There was no increased warmth or swelling. Several of the proximal interphalangeal joints were also painful but not obviously swollen. The wrist joint was not painful or swollen. 

Movements were reduced in extension but particularly flexion of the fingers. The patient was unable to grip paper between his thumb and index finger (pincer grip) or between the index and middle and the middle and ring finger. Testing these movements was not painful.

Power (MMT) of the other remaining limbs was 5/5 (normal)

Examination of the left hand was normal.

Examination of hip movements revealed a normal range of movements which was non-painful. Straight leg raising test was non-painful bilaterally.

Springing of the pelvis with the patient lying on his front elicited pain over the sacro-iliac regions.

Other joints e.g. elbow, shoulders, spine, knees and ankles were within normal examination limits.

ENDO: no tremor, no exopthalmos, no goitre, no pretibial myxoedema, no necrobiosis lipoidica diabeticorum, no acromegallic features, no Cushingoid features (moon face, shoulder hump, striae etc), normal genital size and testicular volume.

SKIN: no focal abnormality identified. No evidence of alopecia.

Questions:

1. From the history and physical examination, please make a problem list.
2. What are the possible differential diagnoses in this case?
3. What tests would you undertake to investigate this patient's problem including both simple and advanced tests?
4. Give your top three differential diagnoses.

GOOD LUCK !!!

Muscle fasciculation

Dear Bloggers

Muscle fasciculation is something that we have all read about but which we rarely see---unless you actively look for it.

This patient developed a peripheral neuropathy with wasting of the thigh, anterior lower leg and calf muscles causing a foot drop as a result of a vasculitis.

As can be readily seen in the video below, with this patient sitting at rest (hence not using the lower limb muscles), there is spontaneous, involuntary, gross muscle contraction and fasciculation. Please pay close attention to the trough formed between the quadraceps and medial thigh muscles.

   

B's Clinical Images in Medicine- A Quick Case-- The Answers

Dear Bloggers

Here are the answers to the recent blog case.

Professor Alan Lefor, Professor of Surgery at Jichi Medical School, Japan has provided an excellent set of answers to the case below:

It appears that with a history of dyspnea, cough, fever, poor dental hygiene and the attached x-rays, as well as hx of smoking, that this is a lung abcess. It looks like the superior segment of the left lower lobe. It could be a tumor with overlying infection, but there is an air-fluid level in the lung mass which to me suggests at least infection. It could be from Tuberculosis, or oral flora. Aspiration of oral flora is most common, and they typically occur in the posterior segments of the upper lobe or the superior segments of the upper lobe.

I would suggest a bronchsocopy for further evaluation, with cytology etc. Also AFB studies to r/o TBc. The pt needs a transtracheal aspiration to get definitive dx.

The treatment of this, at the least, would be antibiotics, but it may require surgical drainage if the pt does not respond to antibiotics, which should be done using a minimally invasive approach (VATS).

Thank you Professor Lefor.

Professor Tierney, Professor of Medicine, USCF, commented on a similar case some time ago on lung abscesses and I would like to share his words of wisdom with you today.

A lung abscess without teeth is cancer of the lung until proven otherwise.

The notion here is that edentulous patients have a much smaller oral burden of anaerobic organisms, which ordinarily originate in the teeth, and thus a cavitary, abscess-like lesion virtually always implies bronchial obstruction. In a series of several hundred similar infections reported from the West Los Angeles Veterans Hospital this rule was never broken. In general, drainage is as important as antibiotics in such patients, performed by sequential rigid bronchoscopies.

Thank you Professor Tierney.

Gurpreet Dhaliwal, M.D., Associate Professor of Medicine, UCSF, has also kindly commented on this case.

1) What is the diagnosis from the history, physical examination and X-ray findings?

There is an irregular air-fluid level and cavity in the mid-left lung, perhaps in direct communication with the bronchus. Differential diagnosis is listed below. If forced to choose among them, the reported fever provides modest weight for an infection (lung abscess), as does the poor dentition and the diabetes mellitus. Putrid sputum and weight loss, which also characterize abscess, are not mentioned. There is no reason it can not be TB or malignancy, both of which bacterial lung abscess is known to mimic, and vice-versa. The ischemic ulcer on the right lower limb is quite common in a smoker with diabetes, but could be a portal of entry for a blood-borne infection.

2) List the likely cause(s)

Common offenders are lung abscess (aspiration or hematogenous), tuberculosis, lung cancer or metastases, and autoimmune syndromes like RA or Wegeners. Uncontrolled DM (and its associated nonspecific immunodeficiency) might expand the possible list of infections.

3) What other tests would you do?

A sputum study for cytologic, mycobateriologic, and bacterial examination. CT imaging, bronchoscopy, or both may be required if sputum is unrevealing.

4) What is the current evidence based treatment of such a condition?

I don’t know the latest with regards to lung abscess (if that’s the correct dx). Usually prolonged treatment with antibiotics will suffice, with some very old data favoring clindamycin over PCN. Lung abscesses are “drained” by their communication with the bronchial tree.

Thank you Dr Dhaliwal

What happened with the patient?

The patient deteriorated with an increasing size of the abscess despite standard antibiotic treatment for this condition. At presentation, the abscess diameter by chest xray measurement was 6.5 cm (a poor prognostic feature). The patient did not receive a bronchoscopy.

Several days into the hospital admission, the patient developed sudden chest and abdominal pain. Radiological investigations revealed breakdown of the abscess with a resulting pyopneumothorax which required intervention by chest drainage.

Usual cultures of the fluid remained negative.

However, the pleural examination revealed the following: LDH 5021, total protein 4.2 and Adenosine Deaminase (ADA) was 70 U/L.

The above results are mainly consistent with the presence of either an abscess, empyema, carcinoma, rheumatoid lung or tuberculosis. However, the ADA level was >60 U/L making tuberculosis a more likely candidate.

As can be seen by the above observation chart, following drainage with a chest tube, the fever and pulse began to settle (red- pulse, blue- temperature).

As a physician, in a case such as this, I would rely more heavily on the observation chart such as the pulse and fever rather than watching the C-reactive protein. Remember, CRP is not a vital sign and is expensive whereas, pulse and temperature ARE vital signs and can be measured for free and actually show how the patient is improving!

The Current Evidence

In a recent review of the literature from UpToDate version 16.1 the vast majority of abscesses are caused by anaerobic organism inhaled into the lungs when in a recumbent position i.e. when sleeping.

Various organisms are involved in the infective process including peptostreptococcus, Prevotella, Bacteroides species and Fusobacterium species. There are other bacteria that can also cause lung abscess e.g. streptococcus, Tb, but the anaerobic organisms are by far the most common.

Indeed, as Prof Lefor mentions, the infection tends to affect posterior lung segments or upper segments of lung lobes where there can be infection in the recumbent position.

The history is usually one of cough, sputum, chest pain, fever and sometimes a foul putrid smell to the breath or a bad taste in the mouth.

It is important to try and obtain sputum for gram stain and culture. Tracheal aspirates are performed in Japan via the nasal cavity but can be uncomfortable and cause localised trauma to the nasopharyngeal mucosa. Bronchoscopy to obtain a specimen is considered controversal and should be performed by an experienced operator because spillage of fluid from the abscess cavity can result in further lung infection.

However, in cases where the abscess is unresolved by antibiotic therapy, bronchoscopic placement of a pigtail catheter to drain the abscess may be of use or percutaneous drainage can also be performed. In unresolving cases, surgery is sometimes required.

Antibiotic therapy is aimed at the underlying cause. The common antibiotic therapy for anaerobes is Clindamyin 600 mg IV Q8h, followed by 150 to 300 mg PO four times daily. The duration of therapy is at least 3 weeks and/or until there is symptomatic and radiological resolution.

Of course, malignancy should always be ruled out especially in a smoker. Hence, sputum should also be sent for cytology. In uncertain cases, a bronchoscopy and obtaining brushings, aspirates and bronchoalveolar lavage may provide helpful clues to the underlying cause.

Moreover, ruling out tuberculosis must be considered in 'at risk' patient e.g. from high risk areas, immune suppression e.g. HIV, and should prompt the physician to check a ZN stain on 3 daily sputa, TB PCR, a Tuberculin Skin test and Adenosine Deaminase in the pleural fluid. Fluid should be sent for long term TB culture and if still undecided, a Quantiferon test may help.

For a more indepth discussion on this subject I would suggest reading the current evidence in UpToDate 16.1

Please Consider....

Rheumatology, oh joy, rheumatology

Dear Bloggers

Professor Stein joined us for two-days to do his famous teaching through case examples.

Being an expert in rheumatology, he was presented with various difficult cases covering rheumatology and general internal medicine. Cases, that were presented in English by the Japanese 1st, 2nd and 3rd year residents, included:

• Infective endocarditis due to streptococcus bovis
• Rheumatoid arthritis-systemic sclerosis overlap syndrome
• Churg-Strauss syndrome

Professor Stein then instructed the residents how to take a rheumatologic physical examination and how to understand the problems of the history, physical examination, lab data and radiology in order to construct a problem list and assessment to decide on what would be the best way to proceed with further tests and / or treatment.

Here are some photos of his current visit.

B's Clinical Images in Medicine- A Quick Case

Dear Bloggers

Below is a set of radiographs of a patient who presented with increasing cough, dyspnoea and fever.

The patient had long-term untreated diabetes mellitus and there was a history of chronic, heavy smoking.

On examination, dental hygiene was poor and the physical examination of the chest revealed no abnormalities to percussion or auscaultation. Abdominal examination was normal.

The patient had an ischaemic ulcer present on the right lower later limb.

Questions:

1) What is the diagnosis from the history, physical examination and Xray findings?

2) List the likely cause(s)

3) What other tests would you do?

4) What is the current evidence based treatment of such a condition?

Chest Pain-- Oh What A Pain !

Dear Bloggers

Sorry for almost a week of absence from this blog.  I hope this entry makes up for the short hiatus.

Today I would like to discuss about chest pain.

Chest pain is one of those things that is either something innocuous or on the other hand may be extremely serious. It is up to us as doctors to decipher the 'chaff from the wheat', or in other words, determine whether we need to do lots of tests and treatments or not.

Chest pain is a big topic in itself and too much to go into in detail in this blog. However, when we ask about chest pain we should not just rely on the patient saying that they just have chest pain and we as physicians should not just leave it at that. Chest pain needs thorough investigation through history, examination, radiological, laboratory and electrocardiographic modalities.

If we simply accept the phrase 'chest pain' and do nothing more, then we are short changing the patient and maybe missing a life threatening diagnosis.

So, when we ask about chest pain, we need to know what type of pain.

Cardiac pain is classically heavy / pressing / squeezing -- like someone standing on your chest. It is usually the worst pain ever and patients may say it is 10/10 on the pain scale. The location is usually central chest and may radiate through to the back or into the abdomen especially if it is an inferior MI.  Patients may mention or may have to be asked if the pain radiates to the jaw, neck or either arm or whether there is numbness in the fingers. Associated symptoms of nausea, vomiting, breathlessness and sweating are other classic features of ischaemic chest pain.

Other cardiac causes of chest pain can be aortic dissection which can present with very similar symptoms as patients with acute coronary syndrome. However, patients can develop tearing interscapular pain (between the shoulder blades), cardiovascular collapse from tamponade, limb weakness from arterial occlusion as the dissection occludes the vessels derived from the arch of the aorta. If the dissection moves distally, abdominal organ ischaemia can occur resulting in pain, renal failure and ischaemic bowel. Hence, a patient who starts off with chest pain that then migrates to neck / shoulder blades, lower back and abdomen should be suspected of a dissected aorta until proven otherwise.

Sometimes, fast dysrhythmias can result in chest pain because of rate-related ischaemia and can be due to non-sustained VT, Atrial fibrillation-flutter, Wolff-Parkinson-White syndrome etc. Hence, asking the patient whether they have a fast, regular or irregular pulse may give you a clue to the cause before putting a hand upon the patient.

Another cause of chest pain is pericarditis which is usually infective although non-infective causes are also well known e.g. connective tissue disease, post-AMI, Dressler Syndrome. Such acute pericarditic symptoms include sharp localised pain over the area of the heart, worse on lying flat and better when sitting forwards. Patients may also develop tamponade if severe and especially if taking anti-coagulants or if they are mistakenly given thrombolysis for suspected AMI. However, pericarditis can masquerade as an AMI and hence, it is not always possible to decipher the two conditions without further investigations and intervention.

Pulmonary Embolism is something that should never be forgotten but is not usually high up on physicians differential diagnosis lists in Japan. It should be. Although I have indeed seen far fewer DVTs and pulmonary emboli in patients in Japan, I have nevertheless seen such cases. Symptoms include sudden or gradual onset of dyspnoea, chest pain- typically pleuritic, cough, haemoptysis, palpitations, collapse etc. Sometimes patients will have a classically swollen lower limb containing a DVT although I have found this to be the exception rather than the rule. Remember that patients with pneumonia, cancer, UTI, bed ridden etc can get DVT-PE and just thinking of a single pathology can catch you out. For example, a patient with a pneumonia who remains hypoxic and who may also, for example, have persistent AF despite resolving pneumonic changes should be considered to have a PE until proven otherwise.

Chest pain can also be from lung conditions such as pneumonia, pleurisy and malignancy where the pathology involves the parietal pleural which is innervated by peripheral intercostal nerves and the phrenic nerve of the diaphragm. Hence, such pleuritic pain is a lancinating pain (stabbing) when the patient breathes or moves/coughs etc. This may limit the patient taking a deep breath. Patients may also experience shoulder tip pain on one side and may signify inflammation  of the diaphragm with radiated pain via the phrenic nerve especially around the area of the central tendon of the diaphragm. Inflammation on the other side of the diaphragm e.g. peri-hepatitis, abscess etc can also result in shoulder tip pain.

Pneumothorax and pneumomediastium can result in sudden onset of chest pain. These may produce pain during respiration. The latter may only be considered if there is trauma or gastro-oesophageal symptoms (?? rupture of the oesophagus) and may only then be considered if there is crepitus in the supra-clavicular fossae or air is seen tracking up the mediastinum on chest X-ray.

The ribs of the thorax may also give rise to pain especially if there have been fractures or if there are metastases and asking about bone pain or symptoms of hypercalcaemia are also worthwhile. 

Of course, a common and innocuous cause of chest pain is muscle damage from heavy lifting and this can cause the patient anxiety. 

Back pathology may also cause central chest pain !! Vertebral collapse, fractures, osteoarthritis etc, can irritate the intercostal nerves and produce a lacinating pain over the distribution of these nerves and is worse when the patient moves. This kind of pathology should always be investigated. Many years ago I saw a patient with typical unstable angina who also had pain lacinating round his chest wall who on more detailed examination, had a tender spine. He had two pathologies causing his chest pain!

There are several serious causes of "chest pain" that originate in the abdomen too. 

As mentioned oesophageal rupture is one. Others include pancreatitis, gastric ulceration, cholecystitis, cholangitis etc. 

Because the nerve supply to the abdominal viscuses is from the slower unmyelinated nerves, there is poor localisation of pain unless there is inflammation of the overlying parietal peritoneum. Hence, patients with, for example, pancreatitis can experience lower chest pain / upper epigastric pain and may have some ease of discomfort when sitting forwards. 

Patients with gastric / duodenal ulceration may experience epigastric pain and may also have GERD symptoms such as reflux, retrosternal burning especially when lying flat, flatulence, bitter taste in the back of the mouth and lots of saliva (waterbrash). Patients may not offer up such symptoms unless asked !

Cholecystitis / cholangitis typically gives right hypochondrial or epigastric pain and this can radiate the infrascapular area on the right side. Patients can have fever and jaundice too. However, the patient may define the pain as chest or even back pain and hence, such a diagnosis should always be borne in mind.

Of course, there are several other causes of chest pain that are of no long term consequence. These include the Tietze's "costochondritis" and Bornholme's disease-- coxsackie infection. Elderly patients should also be asked if they have ever had Shingles (VZV dermatomal rash) over the area of the chest pain as post-herpetic neuralgia is occasionally the cause. The give away sign for the diagnosis is the unilateral post-infective scarring of the skin.

Hence, when taking a history about chest pain, it is simply not accepting what the patient says to you. You must ask more detail!!

Thus, a typical set of questions would include:

• What type of chest pain is it? Can you describe it?
• Is it squeezing, sharp, dull, shooting, stabbing or burning?

AMI QUESTIONS

• Is the pain sqeezing or heavy ? Does it feel like an elephant standing on your chest?
• Is it the worst pain you ever experienced? If 10 is the worst pain ever and 1 is almost no pain, where would you place your pain on this scale?
• Is the pain moving anywhere else, for example, into your neck, jaw or arms?
• Are you getting any tingling in your fingers?
• How long does the pain last? Is it continuous or coming on from time to time (intermittent)?
• Does the pain build up to a crescendo or does it stay the same?
• Is there anything that makes it better or worse?
• What happens if you walk? Does the pain get worse too?
• Is there any associated nausea, vomiting, sweating or breathlessness?
• If you use a nitro-spray / tablet, does the pain get better? (This can relieve cardiac pain AND oesophageal spasm so please don't get caught out!) How long does it take for there to be easing of the pain? Minutes? 

PALPITATION QUESTIONS

• Is you heart ever racing? Do you get chest pain at the same time? Is the racing regular or irregular? If you change your body position, such as squatting or bending over, does the racing stop and chest pain stop? 
• Do you drink lots of coffee or alcohol?
• Any history of problem with your thyroid gland in your neck? Any sweatiness? Any tremor of your hands? Increased appetite and weight loss? How are your eyes? Anyone said they look larger recently?

DISSECTION QUESTIONS

• Does the pain go through to your back? Is it severe or tearing?
• Have you noticed any arm or leg weakness or new back or stomach (abdominal) pain?
• Are you feeling breathless?

PERICARDITIS QUESTIONS

• When you breathe, cough or sneeze, does the pain get worse?
• Does the pain get better on sitting forwards or worse on lying flat?
• If you use pain killers, does the pain become less?
• Any recent fever, cough, cold or sniffles? (URTI symptoms--usually viral origin)

PULMONARY EMBOLISM / PLEURISY / PNEUMONIA QUESTIONS

• Do you have sharp chest pain, fever, cough, phlegm, bloody phlegm, palpitations or sudden or gradual onset of breathlessness?
• Any shoulder tip pain?
• Any history of long haul flights, long car journeys or immobility from illness?
• Do you take any medications such as oestrogens? Have you ever had cancer? Do you smoke? Any exposure to asbestos?

GASTRIC / OESOPHAGEAL QUESTIONS

• When you eat or drink, does the pain get better or worse?
• Do you get symptoms of chest burning, flatulence, a bitter taste in your mouth or lots of saliva, especially when lying flat at night? Does milk or antacids make it better?
• Have you noticed a change in the colour of your stool? Is it black like tar? Is it foul smelling? Do you feel dizzy on standing? Do you get breathless or have palpitations?
• Are you under lots of stress? Do you take aspirin or pain killers or steroids? Have you ever had an ulcer?

PANCREATIC / LIVER / GALLBLADDER QUESTIONS

• Have you noticed any change in the colour of your eyes, skin or urine? Have they turned yellow / dark brown? Does the chest pain get better when sitting forwards? Have you been vomiting?
• Does the chest pain come on several hours after eating? Is it mainly when you eat fatty foods? Do you ever get pain under the right shoulder blade or shoulder tip pain ? (sub-phrenic abscess)
• Do you get shivering or shaking with a fever? (may signify gram negative septicaemia e.g. ascending cholangitis, sub-phrenic abscess) 

MUSCULOSKELETAL SYMPTOMS

• Do your bones hurt? If you press on your own chest, do the bones ever hurt? Do you get pain worse at night? Does it ever keep you awake? Have you had any recent injury to your chest? Do you take steroids? Any recent weight loss, night sweats or fever?
• Do you have any back pain? Worse when coughing or sneezing? Is this ever associated with the chest pain?
• Do you get pain in your muscles or chest when you lift something heavy? Have you done any recent heavy lifting at all?

SKIN AND SOFT TISSUE RELATED QUESTIONS FOR CHEST PAIN

• Have you noticed any recent skin complaints such as a rash? Have you ever had shingles in the area of the chest pain? 
• Have you noticed any breast pain or recent lumps that are of concern to you (especially female patients).

NON-SPECIFIC INFECTION RELATED QUESTIONS

• Any recent foreign travel?
• Any recent contact with another sick person?
• Any recent common cold symptoms?

CONNECTIVE TISSUE RELATED QUESTIONS

• Any pain or swelling of any joints in your body?
• Do they get stiffness? How long for? More or less than one hour in the mornings?
• Anyone in the family with rheumatoid arthritis or other types of immune related diseases?

QUESTIONS FOR INVESTIGATING HYPERCALCAEMIA

• Are you thirsty or passing lots of urine ? (nephrogenic diabetes insipidus)
• Do you get confused or have problems with concentration?
• Do you get constipation or abdominal pains?
• Have you had any recent kidney stones? Have you ever passed a stone in your water?
• Do you get pains in your bones?
• Have you had a recent bone fracture?

The above can be remembered as the 'Bones, Stones, Abdominal Groans and Psychic Moans'.

As you can see from the above, asking about chest pain is not just a five minute chat!! It takes time but must be done if you are to find the true pathology.

Of course, the physical examination may help you a lot. Pressing on the chest may elicit bone pain, percussion may reveal hyper-resonance of a pneumothorax or reduced percussion sound of a pneumonia. Crepitus in the neck may alert you to the pneumomediastinum, or the supraclavicular lymph nodes and unilateral dorsal muscles wasting of the hand may alert you to the Pancoast tumour in the apex of the lung. Of course, the aortic diastolic murmur may be attributed to acute aortic regurgitation and reduced valvular sounds from the ensuing tamponade of a dissection etc....

Therefore, putting together the detailed history with the physical examination is necessary to provide a clearer idea of what the likely underlying process is. Without these two essential and complementary elements, the doctor will have no way to understand the problem and follow on tests will be unfocused and may miss the problem.

Only with the detailed history and physical will one have an idea of what to investigate, and remember from the above non-exhaustive list, there are many potential causes to investigate.

However, a patient with chest pain should have the following basic and cheap examinations despite the underlying cause to exclude serious pathology:

1. Chest roentogen (Chest X-ray) --ERECT TYPE IS BETTER to look for perforation, pneumonia, pneumothorax, widened mediastinum, etc
2. Electrocardiogram (ECG) e.g. AMI, pericarditis, AF
3. Cardiac enzymes, most particularly a Troponin T at a minimum of 6-12 hours after the onset of chest pain (positive in AMI, PE, Myopericarditis, CPR-Trauma, PCI)
4. D-Dimer (positive in DVT-PE; good negative predictive value)
5. Amylase and liver function test (Amylase raised in Pancreatitis, cholecystitis, perforation, dissection, DKA, Macroamylasaemia, etc )
6. Complete blood count to look for signs of a raised white cell count and neutrophil left shift
7. Temperature, pulse oximetry, respiratory rate and blood pressure measurement
8. Corrected Calcium and ALP check in case of bone pathology.

There are many other basic tests that one could do but they would depend on the results of the above investigations e.g. cardiac echo if suspicious of aortic regurgitation, treadmill test. Modalities like CT, MRI should not be launched into without first assessing the underlying cause and determining whether it will give you the appropriate answer.

Of course, patients with non-specific chest pain can end up being over-examined on occasion. However, ruling out serious pathology is necessary. 

Today's discussion is just the tip of the iceberg when it comes to discussing symptoms and how to ask the right questions. My advice to you is to think of the potential serious causes of pathology when thinking in terms of the presenting symptoms. Then once considered, ask yourself how these illnesses present as symptoms and ask those same questions to the patient. Without a deep background knowledge of how diseases present themselves, then one becomes reliant on machines making the diagnosis rather than the doctor. 

Machines are not always right.

Please consider.....

Answer To Recent Case

Here are the answers to the recent case-- I am sorry if it is overly long to read but I hope it will cast some light on this difficult scenario.

Question 1: Please make a problem list soley from the history and physical examination findings.

Problem list

• Unsteadiness
  
• Slurred speech
  
• Periperal numbness (on history and physical)
  
• Diplopia
  
• Meningoencephalitis
  
• Seizures
  
• Medications- Phenobarbital / Phenytoin / Sodium Valproate / Flunitrazepam / Metoclopramide
  
• Fine tremor
  
• Coarse Facies
  
• Alopecia
  
• Cerebellar signs
  
• Absent reflexes

Question 2: What other specific question(s) would you like to learn from the history that might help you with this diagnosis?

The drug history is very important here and the drug doses and frequency should be investigated in addition to searching for hidden alcoholism.

The fact that the patient is happily married does not exclude her from being infected with a sexually transmitted infection by her partner and hence, a discussion with the partner might be in order especially if an unusual infectious aetiology were to be found e.g. neurosyphilis.

Moreover, the fact that the patient works in the 'fashion industry' is very non-specific. For example, she might make jewellery!! She might be using Lead!! Lead can cause cerebellar disease too ! Hence, a more in-depth questioning about her occupation would be in order here.

Question 3: What particular feature of the oral examination might give you a further clue regarding the cause of this problem.

Given the fact that the patient takes Phenytoin, one chronic side effect is gum (gingival) hypertrophy. This might give the clinician a clue regarding the cause of some of the symptoms and signs.

Question 4: What is the diagnosis?

The fact that the patient has severe cerebellar signs, peripheral neuropathy, a resting tremor, coarse facies, alopecia and gum hypertrophy, a diagnosis of acute on chronic phenytoin toxicity would be top of the list.

However, when one thinks of cerebellar dysfunction, one needs to consider various other causes such as:

Acquired

Drugs- Phenytoin, flunitrazepam (can cause drowsiness, slurred speech, tremor), Phenobarbital (known to cause ataxia), Na valproate (known to cause tremor, ataxia, speech disorder.

Salicylates, aminoglycosides, sedatives ( e.g. benzodiazepines), chemotherapy agents e.g. fluorouracil, cytarabine

Infection- Viral encephalitis, HIV, CJD, abscess

Trauma

Connective Tissue- SLE, Sjogren’s disease, Hashimoto’s thyroiditis, Auto-Ab associated Cerebellar Ataxia

Neoplastic- primary ( e.g. meningioma, haemangioblastoma) or secondary brain tumour (melanoma, lung, breast, thyroid etc), and Primary CNS Lymphoma. Cerebellar pontine angle tumour e.g. acoustic neuroma associated with neurofibromatosis type 2.

Paraneoplastic cerebellar dysfunction can occur with Breast Ca, Lung Ca (mainly SCC), Ovarian Ca, Uterine Ca and Cervical Ca.

Haematovascular- posterior circulation stroke (infarction or bleed), dissection.

Immune- Multiple sclerosis, Guillain-Barre Syndrome (Miller-Fisher variant)

Metabolic- Alcoholic cerebellar degeneration, Lead poisoning.

Granulomatous- sarcoidosis

Degenerative- olivopontocerebllar disease (may be part of a multi-system atrophy)

Congenital- Friederich’s ataxia- cerebellar degeneration, peripheral neuropathy, spinal degeneration, pes cavus, autosomal recessive, onset age 20; 1:50,000 prevalence (one of the several causes of absent reflexes but extensor plantar response). There are several other more rare congenital ataxias.

Question 5: Which one laboratory test would give you the diagnosis?

The primary lab test to be done is the serum phenytoin level. This correlates well with symptoms when there is toxicity.

Phenytoin is a well established drug used for various conditions including seizures and dysrhythmias (although the latter used less commonly these days). It can be given intravenously or orally.

Normal range for phenytoin in Japan is 10-20mg/L.

Above 20mg/L, nystagmus is common. Above 30mg/L, tremor, ataxia and slurred speech occur. When levels exceed 40mg/L, lethargy, confusion and unconsciousness occur. There have only been a handful of patient cases who have survived with levels >100mg/L.

Phenytoin is protein bound and hence, in patients with low albumin levels or renal failure, patients may experience toxicity at lower serum concentrations.

Phenytoin exhibits dose-dependent elimination kinetics, and toxicity can occur easily in patients on chronic therapy especially when there are drug interactions or slight alterations of daily dose. As the phenytoin level reaches therapeutic range, the liver elimination of the drug becomes saturated and therefore becomes Zero-Order in Kinetics. Hence, the half-life increases as serum levels rise e.g. T1/2 = 26 hours at 10mg/L, 40 hours at 20mg/L and 60 hours at 40mg/L respectively.

There is no specific antidote available for treatment of phenytoin toxicity whether iatrogenic or intentional and treatment is supportive e.g. charcoal for elimination (if orally administered) and maintaining airway, breathing and circulation.

In this case, the patient was also taking several other drugs and hence, drug-drug interactions must be considered here and include:

Phenytoin-Valproic Acid interaction- valproate displaces phenytoin from protein binding causing toxicity

Phenobarbital - Valproate Interaction- valproate reduced metabolism of Phenobarbital and can result in toxicity. One case report of decreased valproate effect through increased metabolism.

Phenobarbital – Flunitrazepam interaction- decreased effect of benzodiazepine through increased metabolism induced by phenobarbital. Increased risk of respiratory failure with combination of benzodiazepine plus phenobarbital (one case report 1986).

Benzodiazepine – Phenytoin interaction - decreased effect of benzodiazepine through increased degradation via liver enzyme induction. Possible toxicity when phenytoin and benzodiazepine combined although mechanism not established.

Benzodizepine – Valproate interaction – possible benzodiazepine toxicity by displaced protein binding by valproate and also possible decreased detoxification by the liver (glucuronidation).

Hence, there are several potential drug interactions at work in this patient. Other drugs being used to control the seizures may result in phenytoin toxicity, and toxicity or reduced activity of other drugs.

I have no doubt that drug-drug interactions contributed to the acute on chronic toxicity. However, another part of the history found out later was that the patient had poor daily compliance and she took sometimes more medication than prescribed in order to make up for lost doses.

The usual daily dose is up to 300mg of phenytoin and only several cases has there been doses up to 500mg/day. This patient was apparently taking doses far in excess of the recommended daily dose.

Other clues to the diagnosis of phenytoin chronic administration were the mild leucopenia and thrombocytopaenia which are also well described. The CT and MRI scan of the cerebellum were both entirely normal.

Case Response From Dr Masami Matumura from Kanazawa Medical University. As usual, Dr Matsumura provided an excellent breakdown of the case, and is as follows;

Question 1:Please make a problem list soley from the history and physical examination findings.

#1 Ataxia

She showed unsteadiness when walking, gait- wide based, staggering in nature, heel to toe test positive, heel to shin test positive R>L, finger to nose test positive bilaterally, dysdiadochokinesis positive bilaterally, nystagmus, slurred speech, and fine resting tremor.

#2 Polyneuropathy

She had numbness of her arms and legs, mildly reduced light touch, and no reflexes.

#3 Diplopia

#4 Pinky-red cheeks

#5 Coarse skin

#6 Alopecia.

#7 Viral meningoencephalitis

#8 Post-meningitis seizures treated with medication

Interestingly, she has two neuro-anatomical disorders, ataxia and polyneuropathy.

I have to pick up all possibilities in this case.

Differential diagnosis:

• Vascular: Cerebellar infarction, Subdural hematoma
  
• Infection: Cerebellar abscess, HIV, Acute viral cerebellitis, Lyme disease, Syphilis, Lepromatous leprosy,
  
• Neoplastic: Paraneoplastic syndrome, Cerebellar glioma, Cerebellar metastasis
  
• Collagen (autoimmune): Systemic lupus erythematosus, Sarcoidosis, Sjogren’s syndrome, Dermatomyositis, Primary biliary cirrhosis, Guillain-Barre syndrome, Post infection syndrome
  
• Toxic/Metabolic: Phenobarbital, Sodium valproate, Metoclopramide, Lead, Aluminum, Hypothyroidism, Vitamin B12 neuropathy, Diabetes
  
• Trauma/Degenerative: Spinocerebellar atrophy
  
• Iatrogenic: Phenobarbital, Sodium valproate, Metoclopramide
  
• Idiopathic: Amyloidosis, Multiple sclerosis
  
• Congenital: Fabry’s disease, Friedreich’s ataxia, Porphyria

She could not describe onset of symptoms. I assume these conditions were acute course or subacute course. If it was true, infection, neoplastic, collagen, toxic, and metabolic causes must be considered.

Question 2: What other specific question(s) would you like to learn from the history that might help you with this diagnosis?

I would ask her whether she has episodes of skin rash after sun exposure or not. And I would ask her change of voice and feeling cold or not.

Question 3: What particular feature of the oral examination might give you a further clue regarding the cause of this problem?

I seek oral ulcers!

Question 4: What is the diagnosis?

Systemic lupus erythematosus (SLE) is highly suspected in this case. She had two neuro-anatomical disorders, pinky-red cheeks, coarse skin, and alopecia.

Second candidate is autoimmune thyroiditis. She is Japanese woman.

Interestingly, both SLE and Hashimoto’s thyroiditis can be associated in several cases.

I can’t explain the cause of diplopia. Opthalmopathy is not described.

Metoclopramide is often prescribed in many patients. This drug can cause extrapyramidal sign. Tremor might be caused by metoclopramide in this case.

Question 5: Which one laboratory test would give you the diagnosis?

Serum antinuclear antibodies.

If it is possible, I would order CBC, FT4, and TSH.

Comments from B:

Dr Matusmura raises some very interesting points with his case interpretation. SLE is still a possibility. However, the pink cheeks on this patient did not involve the bridge of her nose, which the classical ‘Butterfly Rash’ of SLE does. Moreover, skin rashes are known to be a manifestation of phenytoin administration as well.

Alopecia is indeed a feature of SLE although it is not a pathognomic feature and can be found in phenytoin toxicity too—as can hirsuitism!

However, interestingly, phenytoin has been associated with inducing SLE in several patients although this tends to be a discoid-type rather than systemic.

Lastly, when the phenytoin dose was decreased, the symptoms began to resolve, and if this were purely SLE, one might not expect such a rapid improvement.

In order to diagnose SLE, the must be several criteria met and they include the following:

1) Malar rash

2) Discoid rash

3) Photosensitivity

4) Oral ulcers

5) Arthritis

6) Serositis- pleurisy or pericarditis

7) Renal disorder- persistent proteinuria >0.5g/24h or cellular casts

8) Neurological Disorder- seizures or psychosis (having excluded other causes first)

9) Haematologic disorders

• Haemolytic anaemia or
  
• Leucopaenia <4.0x109/litre>
  
• Lymphopaenia <1.5x109/l>
  
• Thrombocytopaenia
  

10) Immunological disorders-

• Raised anti-DNA antibodies
  
• Anti-Sm antibody
  
• Positive anti-phospholipid antibodies
  

11) Raised titre of Anti-nuclear antibody

SLE can be diagnosed if 4 or more of the above criteria are met either simultaneously or serially over time.

(1982 revised criteria of the American Rheumatologu Association [now American College of Rheumatology] for the diagnosis of SLE)

From the above criteria, at most, the patient may have only had two criteria for suspecting SLE, those being the haematological disorders and the possible Malar rash. Cerebellar dysfunction although well recongised in SLE is not one of the diagnostic criteria. Unfortunately, antibodies for SLE were not performed in this patient.

Hence, it is still possible that phenytoin may have induced some features of SLE, and checking autoantibodies would be certainly worthwhile.

Finally, the haematological disorders in phenytoin toxicity are related to depleted folic acid and hence, checking this blood level and giving replenishment would be one way to correct the problem.

I think this paper from 25 years ago sums up what needs to be said:

1: Acta Neurol Scand Suppl. 1983;97:49-67.


Side effects of phenobarbital and phenytoin during long-term treatment of epilepsy.

Iivanainen M, Savolainen H.

Phenobarbital and phenytoin have good antiepileptic effect, but clinically significant untoward effects occur during their long-term use. Phenobarbital may cause hyperactivity, behavioral problems, sedation, and even dementia; these effects are dose related to some extent. Side effects of phenytoin include sedation, a cerebellar syndrome, phenytoin encephalopathy, psychosis, locomotor dysfunction, hyperkinesia, megaloblastic anemia, decreased serum folate level, decreased bone mineral content, liver disease, IgA deficiency, gingival hyperplasia, and a lupus-like hypersensitivity syndrome. Especially susceptible to the neurotoxic effects of phenytoin are epileptic children with severe brain damage who are on multiple drugs. In those children, balance disturbance may develop and be followed by gradual loss of locomotion. Among 131 mentally retarded epileptic patients, phenytoin intoxication occurred in 73 (56%), of whom 18 experienced persistent loss of locomotion. There is experimental evidence that the toxic action of phenytoin lies at the cellular level, predominantly in the cerebellum. Many experts avoid the long-term use of phenytoin because of its insidious and potentially dangerous side effects.

Thank you very much Dr Matsumura.

Another response was from Professor Lefor of Jichi Medical University who made an excellent attempt to answer this very difficult case. Professor Lefor’s way of working up this case is also very thorough and indeed, the diagnosis for this case does fall into that ‘other’ group. His reponse is below:

1.My problem list includes:

a. Unsteady gait

b. Diplopia x2y

c. Sensory changes

d. Slurred speech

e. Hx seizures in the distant past, on meds

f. PE showed no bruits, nystagmus, slurred speech, tremor, decr sensation and wide gait

2. What other questions?

I would want to know more about the time course of onset of these various symptoms.

3. Oral Exam: I am not sure what to look for

4. What is the diagnosis?

This is a tough case. There is a wide variety of disparate neurologic findings here. It is difficult to put it all together. The major etiologies would include vascular, infectious, tumor, and other. I doubt it is vascular given her age, physical findings and onset. Infectious is possible, but the time course does not support this. Tumor is certainly possible, but the wide variety of symptoms makes it hard to assign to a mass lesion. My number one is in “Other” category, and I believe that this is most consistent with some global neurologic disorder such as Multiple sclerosis which affects a wide area of the CNS as a de-myelinating disease. She is a little bit old for the usual patient (in the USA the onset is rarely over age 40), but this disease, or some other de-myelinating condition seems most probable given the wide range of structures affected as evidenced by her symptoms.

5. What is the one test: For MS, there is no one absolute test, but MRI is quite good and is the one test I would get. MRI would also rule out a brain tumor, which is also a possible dx, and must be fully ruled out quickly to avoid “missing it”.

Thanks for letting me participate

Alan Lefor

Comment from Dr B： Professor Lefor’s consideration of MS is very thought provoking especially as diplopia can be a symptom of MS. Moreover, the onset of cerebellar dysfunction can also occur in MS and neurological deficits occuring in various places over time is one feature of this disorder. Indeed, exacerbations of MS with acute deterioration can occur although this is usually related to an underlying infection which there is no history of in this case. Moreover, the generalised loss of peripheral tendon reflexes is not a usual presentation of MS. However, with an acute deterioration, one might expect the loss of reflexes e.g. in a single limb, and for them to return in time and become hyper-reflexic signifying a previous upper motor neurone lesion.

However, the pinky cheeks, coarse face, alopecia etc do not fit with MS or with a tumour and hence, a metabolic or autoimmune condition would be considerably higher up on the list. However, things such as tumours and MS should always be ruled out in such conditions as has been described above.

Thank you very much Prof Lefor.

Learning Points From This Case

If a detailed history is taken, if it is a common disorder, the cause will usually become obvious quickly.

Taking a thorough drug history, drug doses and frequency is very important. One must not just re-prescribe the drugs just because that is what the previous physician did or that is what the patient says they are taking. You must check the correct doses if you do not already know.

In this case, the drug doses and frequencies were purposely omitted in order to draw your attention to the fact that they were missing. They should never be over-looked or omitted from the history and young physicians should always be asking about drugs the patient takes. Drug doses and frequencies must be checked to avoid toxicity. This case demonstrates this example very clearly.

Checking drug-drug interactions is also essential. I would suggest obtaining a handbook on drugs that deals with this or perhaps one for PDA e.g. Epocrates (epocrates.com [free]) or the Handbook of Adverse Drug Interactions (skyscape.com).

Generally, as physicians we all have to know an awful lot about drugs but it is something that can cure or curse a patient but we must know when that happens. The only way is learn throughly about drugs and especially about commonly used ones in daily practise. One textbook that I used as a student was Rang & Dale's Pharmacology with an updated edition just last year. You can never know too much about a drug.

Common Things Are Common and 'When You Hear Hoofbeats, Don’t Expect To See A Zebra'~~(Theodore E. Woodward M.D) are very important ideas. Obviously, things such as drugs, alcohol, stroke and infection are high up on any list for cerebellar diseases. These should be excluded initially and if ruled out, investigation for other causes such as MS, SLE and even Friederich’s ataxia which lie somewhere further down the investigative road.

Usually, if you prioritise your differential diagnosis according to the history and physical plus specific lab and radiological tests, the answer will soon become apparent.

But remember this, the answer usually lies somewhere within the history but you have to elicit the right answers to find it.

Please consider and have a good week!

Finally, thank you to Dr T and his team for showing me such a great case.