By Eduardo Garcia, MD

Memory the warder of the brain—William Shakespeare

The other day we were asked to see a gentleman in his late 50’s for altered mental status. Bread and butter Neurology, I told my students. As we dove into the patient’s medical records we found, well… nothing! The patient was one of those healthy individuals who had not seen a doctor in 20 years! Without the usual navigational tools—like past medical history, prior medications, allergies, previous lab work, and imaging—I felt as though we were flying into a storm with no instruments. In the practice of 21st-century medicine, data is king. Data allows physicians to prepare Mental Predictive Models* that help narrow the differential diagnosis before setting eyes on the patient. Thankfully, we could still ascertain a trove of information using the time-honored history and physical exam.

When we entered the patient’s room we found a pleasant middle-aged man who greeted us with a big smile. His wife sat on a chair across his bed. I introduced myself and my team and asked what brought him to the hospital. Without wasting time, his wife explained how she had noticed some alarming changes in her husband’s behavior over the preceding weeks. He had become more irritable. She also noticed he had problems expressing himself, coming up with words, articulating his thoughts, and recalling recent events. She was also concerned about his driving which had become aggressive and erratic. Lastly, she remarked on how her husband had become uncharacteristically disorganized. His office, which had always been spotless and organized, had become a mess in a few weeks. To the extent that he could no longer keep up with bills and orders.

As the interview unfolded, I could not help but notice how the patient sat on his bed contemplating the exchange between his wife and the author, much like a spectator in a tennis match. I turned to the patient and asked if he had anything else to add—he didn’t. “Any headaches, fevers, chills, weight loss, or neck stiffness? I asked. “No doctor” he replied parsimoniously. He also denied any tick or insect bites, rashes, recent foreign travel, new medications, or abusing alcohol, or other substances. His wife denied any abnormal movements, staring spells, or weakness. His toxicology screen, routine labs, and head CT on admission had all been reported as normal.

On examination, our patient was a medium build middle-aged Caucasian male. He was shaven and coiffed. His comportment was normal, albeit somewhat withdrawn. He otherwise had good eye contact and followed commands appropriately. He knew who the US president was. He knew he was in a hospital, but could name the hospital, or the city where it is located. He knew the year, but could not tell me the date, or the day of the week. He could only retain 1 of the 3 words I gave him to memorize. He could not name the months of the year backward and had effortful and at times garbled speech. His strength was otherwise normal and symmetric, sensation was intact, as were his reflexes. His gait was normal.

When evaluating a patient I tell my students to keep seven guiding principles in mind: 1. Do your homework, and comb through the records for clues that may help solve the problem. 2. Listen to what the patient (or family) has to say, you can learn a wealth of information about the circumstances that led to the patient’s admissions, symptoms, educational background, and psychosocial situation, all just by listening! 3. Do a thorough exam, do not cut corners. 4. Localize the lesion, meaning, try to ascertain if the lesion involves the peripheral nervous system (nerves, plexus, or nerve root), central nervous system (spinal cord, brain stem, or brain), or both. Don’t forget supratentorial or functional disorders. 5. Remember Occam’s razor, that is, common things are common—if you hear hoofbeats outside your window, think of horses, not zebras! But don’t forget Hickam’s dictum, the principle in medicine that suggests that “patients can have as many diseases as they damn well please.” Once common things have been ruled out (including atypical presentations of common illnesses) you can go on your safari expedition. 6 . Think of the thing(s) you can not afford to miss and rule them out. Lastly, 7. Give the patient the benefit of the doubt, in other words, don’t judge a book by its cover.

As I finished examining the patient I knew we were dealing with a process involving the central nervous system. It also became clear that his presentation was atypical, it could still be a horse, but it looked more like a zebra—so much for bread and butter! It appeared we were dealing with a rapidly progressive neurological process. A process involving several cognitive domains including, working and episodic memory, attention, executive function, and language. The areas of the brain subservient to such domains included a large swath of valuable real estate including, the prefrontal cortex, thalamus, temporal, and parietal lobes.

Several mental representations played out in my mind. We still had to rule out stroke in keeping with our second heuristic**. To be sure, there was an element of aphasia in his exam. However, the subacute and progressive nature of his illness, along with his cognitive decline, and nonfocal exam, argued for a rapidly progressive dementia. The differential diagnosis of which includes, autoimmune encephalitides, paraneoplastic syndromes, and the most dreaded, prion disease. I recommended a brain MRI and lumbar puncture and started him on aspirin and atorvastatin in the off chance he had a stroke.

The human brain with its 100 billion neurons and more than 100 trillion synapses, or connections may be regarded as the mother of all complex systems. To put this in perspective, it is said that the number of synapses or connections in the human brain may exceed the number of stars in the observable universe! So what exactly is a complex system? A complex system consists of interacting components that exhibit emergent properties such as patterns or behaviors seen in an ant colony, a flock of birds, or consciousness. The components within the system are highly interconnected in both direct and indirect ways which can lead to feedback loops. The relationship between the components in the system is nonlinear, and the Complex loops can adapt to changing conditions, which may contribute to the system’s ability to self-organize¹.

Chaos theory, a branch of mathematics that deals with the behavior of complex and nonlinear systems, states that a small change in the initial condition may lead to different and difficult-to-predict outcomes. Think, The butterfly effect—a metaphor coined by meteorologist Edward Norton Lorenz, who illustrated how the flapping of a butterfly’s wings in Brazil could ultimately lead to a tornado in Texas².

Between order and chaos lies a dynamic state that facilitates information processing and adaptability, this Goldilocks state is referred to as “The Edge of Chaos.³“ The healthy human brain operates in such optimal complexity state. However, too much order, and the system malfunctions, too much chaos, and the system may run amok. An epileptic seizure is a perfect example of too much order, where networks of neurons fire simultaneously thus lowering the system’s entropy, or randomness. On the other hand, dementias increase the system’s entropy due to the breakdown in the brain’s organized structures and systems from misfolding proteins which disrupt the brain’s normal function.

The following morning I received an alert in my inbox, our patient’s brain MRI showed significant abnormalities in the basal ganglia—a cluster of neurons located deep within each brain hemisphere—, and cerebral cortex—the outer layer of the brain—concerning for Creutzfeldt Jacob Disease. Creutzfeldt-Jacob Disease, or CJD, is a fatal neurodegenerative disorder caused by abnormal proteins called prions⁴. Prions can trigger the misfolding of normal brain proteins which can spread like wildfire. This results in the accumulation of amyloid plaques that lead to cognitive decline, personality changes, rigidity, muscle twitches called myoclonus, and seizures. Most patients succumb within a year.

Our patient underwent a lumbar puncture before discharge and the cerebrospinal fluid was sent for analysis. We ordered the standard lab tests, as well as, autoimmune encephalitis panel, Protein 14-3-3, and Real-time quacking-induced conversion or RT-QuIC, a sensitive test that detects prion proteins. I never saw our patient again, as we referred him to a memory disorders clinic at an academic medical center downtown. However, a few weeks later I learned his Rt-QuIC had come back positive.

*Mental Predictive models are cognitive processes through which individuals create mental representations of future scenarios, events, or outcomes.

**Heuristic is a mental shortcut that helps one make decisions quickly and efficiently.

Reference:

1. Ladyman, J. Lambert, J. Weisener, K. What is a Complex System? European Journal for Philosophy and Science, June 2013.
2. Lorenz, EN. Deterministic Nonperiodic Flow, J. of Atmosph Sci, Vol 20, 130-141, 1963
3. Kitzbichler, ML, Smith, ML, Bullmore, ET Broadband Criticality of Human Brain Network Synchronization PLOS Computational Biology 2009.
4. Appleby, BS, Cohen, ML, Creutzfeld-Jakob disease Up to Date