Unforgettable in every way

An 86yearold Japanese man presented with altered mental status (AMS) for several weeks and recent dyspnea and anorexia. He had been unwell for several weeks for an unknown reason, when 10 days before the presentation, he developed dyspnea, anorexia, and general malaise. In the late morning of the presentation day, when the patient saw his primary doctor on schedule, the doctor found him lethargic and referred him for further evaluation and treatment. The patient lived home with his wife. Per the patient's family and homevisit care worker, the patient had a cognitive decline over the last several weeks, and he became to make frequent phone calls for help because he “does not know what to do.” The patient is an older gentleman and therefore is at high vascular risk. Agerelated cellular immunodeficiency and malignancy risks also need to be mentioned. This patient's main problem is AMS that progressed in several weeks and dyspnea that started sometime later. AMS in this patient is primarily of content dysfunction rather than arousal dysfunction. Hence, a widespread cortical involvement should be considered. Considering that dyspnea occurred in subacute AMS context involving diffuse cortical involvement, disorders with the respiratory control system stemming from central pathologies are concerned. I would list infectious or limbic encephalitis, CreutzfeldtJakob disease (CJD), and hypothalamicpituitaryadrenal (HPA) axis dysregulation, type A subacute aortic dissection affecting the anterior circulatory system with subsequent cardiac tamponade or aortic insufficiency, primary lung cancer with the anterior lobe metastasis, and ischemia on the anterior lobe of the brain. On the other hand, I also argue systemic pathologies affecting the cardiopulmonary system, the hematologic system, in search of the causes of dyspnea. These pathologies encompass metabolic disorders causing brain function and cardiac dysfunction (uremia, hypothyroidism, and syndrome of inappropriate antidiuresis (SIAD) based on intrathoracic pathology), toxic drug effect affecting both of central nervous and of cardiopulmonary vasculature, subacute infiltrative etiologies affecting multiple organs such as syphilis, HIV, lymphoma, or tuberculosis, indolent infective endocarditis (IE) with subsequent valvular destruction and systemic embolization, cardiac myxoma, and pulmonary tumor thromboembolic microangiopathy (PTTM). Meanwhile, since the patient is older, one may consider Hickam's dictum, an aphorism referring that a patient's clinical presentation is caused by more than one pathology: That is, AMS and dyspnea would be derived from different causes, respectively. Multiple medical conditions cause AMS with predominant content abnormality. Many of them are critical and require urgent diagnosis and intervention. Checking basic metabolic panel for abnormal blood glucose, uremia, and electrolyte abnormalities is the first test as it is quick and simple to pick up the critical and treatable condition. Other treatable causes of AMS include hypothyroidism, adrenal insufficiency, central causes such as encephalopathy, encephalitis, epilepsy, subdural hematomas, and depression, and insidious infectious diseases such as syphilis, tuberculosis, and HIV, and brain metastasis of the malignant neoplasm. All these conditions were already mentioned above. The differential diagnoses of dyspnea alone in this patient include heart failure of any cause, pneumonia, pneumonitis, pulmonary embolism (arterial or venous), pneumothorax, pleural effusion of any cause, anemia of any cause, thoracic problems, neuromuscular diseases (paraneoplastic neuromuscular syndrome, phrenic nerve paralysis, and brainstem infarction), psychiatric conditions causing


| INTRODUC TI ON
An 86-year-old Japanese man presented with altered mental status (AMS) for several weeks and recent dyspnea and anorexia. He had been unwell for several weeks for an unknown reason, when 10 days before the presentation, he developed dyspnea, anorexia, and general malaise. In the late morning of the presentation day, when the patient saw his primary doctor on schedule, the doctor found him lethargic and referred him for further evaluation and treatment. The patient lived home with his wife. Per the patient's family and homevisit care worker, the patient had a cognitive decline over the last several weeks, and he became to make frequent phone calls for help because he "does not know what to do." The patient is an older gentleman and therefore is at high vascular risk. Age-related cellular immunodeficiency and malignancy risks also need to be mentioned. This patient's main problem is AMS that progressed in several weeks and dyspnea that started sometime later. AMS in this patient is primarily of content dysfunction rather than arousal dysfunction. Hence, a widespread cortical involvement should be considered.
Considering that dyspnea occurred in subacute AMS context involving diffuse cortical involvement, disorders with the respiratory  insidious infectious diseases such as syphilis, tuberculosis, and HIV, and brain metastasis of the malignant neoplasm. All these conditions were already mentioned above.
The differential diagnoses of dyspnea alone in this patient include heart failure of any cause, pneumonia, pneumonitis, pulmonary embolism (arterial or venous), pneumothorax, pleural effusion of any cause, anemia of any cause, thoracic problems, neuromuscular diseases (paraneoplastic neuromuscular syndrome, phrenic nerve paralysis, and brainstem infarction), psychiatric conditions causing dyspnea (anxiety and panic disorders), or the compensation of metabolic acidosis.
The patient's past medical history included chronic obstructive pulmonary disease (COPD) with an episode of acute exacerbation 9 months before, pulmonary tuberculosis, chronic hepatitis C, hypertension, constipation, and insomnia. He had not had any history of pet or animal contact. He had not been exposed to any inhalant antigen as far as the family knew. He did not undertake home oxygen therapy because he did not show hypoxemia when taking a rest. He spent most of his day sitting on his chair or lying down on his bed and seldom went out or walked up and downstairs. His regular medication included tiotropium (2.5 µg/puff) 2 puff/d, slow-release theophylline 400 mg/d, carbocisteine 1000 mg/d, verapamil 120 mg/d, magnesium oxide 660 mg/d, and zolpidem 10 mg/d. He seldom drank alcohol. He quitted smoking several days before.
The patient had COPD, usually because of smoking. Smoking is a significant risk factor for vascular diseases and malignant neoplasms, raising the possibility of these patients' pathologies. It is interesting to note that he quitted smoking several days before. I would like to know what made the patient quit smoking. If he could not smoke because of his cognitive impairment or dyspnea, the patient's condition may indicate a severe condition. Malignancy-related conditions and tuberculosis are of great concern. Paraneoplastic syndrome, lymphomas, lung or brain tumors, and PTTM should be ruled out.
His tuberculosis history raises concerns about the reactivation of tuberculosis in the context of immunosuppression, causing dyspnea (pulmonary tuberculosis) and cognitive impairment (tuberculosis meningoencephalitis). In such an immobile patient with vascular risks, pulmonary embolism should be considered until proven otherwise.
The patient also had a recent episode of acute COPD exacerbation. This medical history increased the possibility that the patient developed COPD exacerbation again. Triggers of COPD exacerbation include pneumonia and other infections, heart failure with or without acute coronary syndrome, pulmonary embolism, asthma, smoking, environmental factors, and drug nonadherence. However, there was no clinical information so far indicating preceding pneumonia, heart failure, pulmonary embolism, asthma, or substance inhalation before the development of dyspnea. Patients with COPD are vulnerable to hypercapnic narcosis resulting in a stupor, but it usually occurs in patients on oxygen therapy. Considering the patient's age and progressive cognitive decline, medication noncompliance may have been possible. If he recently forgot to inhale the powders or take medicines for COPD, he might develop dyspnea.
If the patient failed to take verapamil for hypertension because of the cognitive decline, this might develop dyspnea from hypertensive heart failure. The patient may also be at risk of medication overuse because of cognitive decline. He was on theophylline, which is notorious for its potential toxicity. Theophylline poisoning in cognitively impaired older people is well known and common. It is also known that quitting smoking may elevate the theophylline concentration, sometimes leading to intoxication. The poisoning symptoms become severe and prolonged, especially with a single large dose or use of extended-release agents. Adverse symptoms are diverse, affecting cardiac, pulmonary, metabolic, hematopoietic, and neuropsychiatric systems. Magnesium oxide may cause AMS due to hypermagnesemia, especially when a patient has chronic kidney disease. Zolpidem may also cause hypersomnolence. If the cognitive decline itself was due to medication poisoning, it is essential to check the prescription history. Besides, detailed history of the patient's current volume status is also necessary because medication intoxication is caused by Heart sounds were normal without murmurs, rubs, and gallops. His abdomen was flat and soft, and there was no hepatosplenomegaly.
His legs were not swollen without clubbing and cyanosis. The patient did not obey simple commands because of AMS. Pupillary light reflex was normal. Deep tendon reflexes were normal. Pathological reflexes, including Babinski's reflex, Hoffmann's sign, and Trömner's reflex, were not seen. There was no asterixis. Any apparent paralysis was not seen. There was no rigidity, coarse tremor, dystonia, or myoclonus.
On examination, the patient also had problems with arousal in addition to the problem of the contents. However, the differential listed so far does not change significantly at this moment. The patient's oxygen saturation seemed not too low despite his COPD.
Tachypnea was the most prominent finding among his vital signs.
The combination of seemingly normal oxygen saturation and tachypnea yields some clinical hypotheses. First, the patient may develop respiratory failure, and increasing respiratory rates may conceal Verapamil noncompliance is less likely because of his normal blood pressure.
Laboratory data (Table 1)   His blood gas analysis unexpectedly showed metabolic alkalosis as the main component, probably from hypokalemia. There was concomitant respiratory alkalosis, which was probably due to tachypnea. The information I would need to know at this point includes history information suggesting psychiatric disorders, and history of medication compliance. I would suggest to add blood tests for thyroid function, cortisol, corticotropin, theophylline level, and blood culture. If these investigations do not reveal the cause, lumbar puncture and contrast-enhanced magnetic resonance imaging were performed for detecting intracranial lesions that cannot be detected by noncontrast head CT. Besides, a whole-body contrast-enhanced CT with or without 18F-fluorodeoxyglucose positron emission tomography for neoplastic lesions or intravascular lesions may be considered.
Based on his symptoms, data, and a history of taking theophylline, he was tentatively diagnosed with theophylline intoxication.
Two sets of blood cultures were obtained to rule out bacteremia.
The patient did not develop seizures or significant electrocardiography changes, and administration of activated charcoal or hemodialysis was not performed. Fluid repletion with potassium was initiated, and theophylline intake was discontinued. The patient was admitted for further evaluation and treatment. Additional diagnostic tests were planned to perform if the patient's AMS did not improve even on the next day. On day 29, the patient was discharged to the nursing home, where nursing staff helped him inhale a long-acting beta-agonist plus longacting muscarinic antagonist.
The chronology of this case is as follows. Several weeks before, chronic mild intoxication caused cognitive decline and feeling unwell. Ten days before, dyspnea and anorexia were developed and the patient quitted smoking, which unfortunately increased theophylline concentration to over 40 µg/mL. In the subsequent few days, acute exacerbation on chronic intoxication occurred and AMS was developed. This time course is also supported by the findings of hypokalemia, hyperglycemia, and respiratory alkalosis, which were more typical in acute theophylline poisoning rather than chronic.

| D ISCUSS I ON
This case illustrates an older patient with AMS, tachypnea without hypoxemia, hypokalemia, and hyperglycemia. These findings turned | 201 MIZUMOTO and SHIMIZU out to be a manifestation of theophylline intoxication. The patient's cognitive decline was improved after stopping theophylline intake.
In most of the healthcare facilities, it takes several times to turn out serum theophylline concentration. Suspecting theophylline intoxication based on history taking and nonspecific systemic abnormalities is therefore important.
Dyspnea is "the result of a complex interaction of physiological, psychosocial, social, and environmental factors." 1 In this case, dyspnea was probably caused by multiple factors, including tachypnea due to theophylline intoxication, AMS, and other psychological disturbance due to intoxication, baseline COPD condition, and growing anxiety of the patient and his wife.
Theophylline was formerly used for asthma and COPD because it antagonizes adenosine receptors and functions as a bronchodilator. Its various side effects lie in the wide distribution of adenosine receptors throughout the body. 2 Besides, theophylline also activates catecholamine release indirectly. 2 Because of its side effects and a broad acceptance of inhaled beta-agonist and muscarinic antagonist, theophylline now plays a minimal role in treating asthma 3 or COPD. 4 However, theophylline is still widely used to treat asthma and COPD, especially in developing countries. 5 Japan is another country in which theophylline is widely prescribed. One study revealed that about 15% of patients with asthma were prescribed theophylline. 6 The therapeutic concentration of theophylline for asthma or COPD ranges from 10 to 20 µg/mL. Unfortunately, theophylline has a very narrow therapeutic ratio, and poisoning symptoms or signs criteria is one of the various strategies for preventing adverse drug reactions, and these criteria may be useful in improving clinical outcomes in multimorbid older people. 9 STOPP/START criteria say that theophylline as monotherapy for COPD should not be prescribed. 10 If the patient had received a medication review, this adverse drug reaction might have been prevented.
In summary, this case conveys three important messages. First, physicians should always suspect adverse drug reactions when seeing older patients taking multiple medications, taking any potentially inappropriate medication, or manifesting multiple-organ dysfunction. Physicians should be aware that two "reviews" are important to correct diagnoses, especially seeing older patients: review of systems and review of prescription. Second, as theophylline intoxication syndrome manifests diverse symptoms, patients taking theophylline with any complaints should be at least once suspected of developing the intoxication. In particular, tachypnea without hypoxemia and slight AMS may be easily overlooked unless physicians do not keep theophylline toxidrome in mind. Detailed history information is also important because smoking cessation may lead to theophylline poisoning. Third, theophylline should not be used in frail older patients. Theophylline is now not strongly recommended for patients with asthma or COPD. Physicians who prescribe theophylline for some inevitable reasons should monitor the concentration regularly and pay close attention to drug interaction including tobacco.

ACK N OWLED G EM ENTS
The authors thank Dr. Michiko Kawasaki for her thoughtful advice about clinical course and management.

CO N FLI C T O F I NTE R E S T
The authors have stated explicitly that there are no conflicts of interest in connection with this article.