A Case of Rapidly Progressive Dementia
Mr. D, a 51-year-old married male, accompanied by his wife and two teenage children, comes to the office of Dr. H, an internist and primary care physician. Mr. D has not seen a physician in over 10 years. Mrs. D describes a 3-month history of “strange behavior” by her husband, including getting up in the middle of the night and going to his office and eating meals at odd hours (eg, insisting it is dinnertime in the morning). He has been forgetful, calls his two children by a variety of different names, and last week was found banging on his neighbor’s door, insisting it was his house. Mr. D was able to perform his job as the manager of a grocery store, but in the past month his ability to write and fill out forms has deteriorated. Mrs. D reports that her husband always took pride in his appearance but now only wears t-shirts and sweatpants.
In the past week, the family has taken turns staying awake to prevent Mr. D from wandering out at night. His 16-year-old daughter and 18-year-old son are very devoted to their father. Mrs. D explains that her husband was always very involved with his children, but recently has acted as though they were strangers. She describes Mr. D staring at people as if he does not see them. The family has noted a few episodes when Mr. D was found looking “glassy eyed” but seemed to respond when they touched him. They tried to get Mr. D to see a physician several weeks ago, but he refused. The family was able to convince him to come after his son pretended to feel sick and needed to visit the doctor. Dr. H finds Mr. D to be alert, well nourished, and well developed. His physical examination is unremarkable; however, his gait appears wide-based, with a stooped posture. Mr. D appears rather perplexed when asked questions. During the evaluation, he displays a period of staring, with a prominent tremor noted in his left hand. After a few minutes, Mr. D appears drowsy and lays down on the examination table.
Dr. H consults a neurologist, who advises sending Mr. D to the hospital for an emergency computed tomography (CT) scan of the brain. Mr. D becomes combative in the emergency room. He is placed in restraints and given several doses of haloperidol 5 mg and lorazepam 2 mg by intramuscular injection. A head CT scan is performed, with the initial results reported as negative. Mr. D undergoes a lumbar puncture. An electrocephalogram (EEG) is performed, with significant abnormal findings. Phenytoin 1000 mg is given intravenously. He remains lethargic and confused, and is admitted to the neurology service for further evaluation of his change in mental status. A sample of spinal fluid is sent to a reference laboratory to test for neuronal proteins. His wife is counseled regarding brain biopsy as a diagnostic procedure. A great deal of tension develops between Mr. D’s son, who tries to take his father for walks, and the hospital staff, who are instructed to keep him in bed. The family appears overwhelmed and asks if Mr. D can be discharged home.
Creutzfeldt-Jakob disease (CJD) is the most common form of a group of rapidly progressive dementias caused by proteins known as prions. The disease was first described in Austria in 1920 and 1921 by the two physicians for whom the disease is now named. They identified the characteristic clinical features of the disease, including dementia, myoclonus, and seizures, with death occurring within 6 months of onset.1 Prions aggregate in the central nervous system (CNS) tissues, producing fibrillary particles in the brain tissue that result in characteristic spongiform changes associated with neuronal death. Prions have also been found in the membranes of platelets and white blood cells, leading to the search for a blood test for CJD.1,2
Creutzfeldt-Jakob disease typically presents with memory loss, difficulties with speech and language, disorientation, and confusion.2 Motor symptoms may be variable in onset, with disturbances of gait and balance that progress to lack of muscle coordination, poor balance, and ataxia, and tremor that progresses to myoclonus. Vision impairment due to cortical degeneration develops in a subgroup of patients. Lack of recognition, apraxia, and disinhibition due to frontal lobe degeneration occur as the disease progresses. Seizures are common, and EEG abnormalities are present in more than half of those affected.1,2 Psychiatric symptoms, including insomnia, anxiety, depression, and psychosis, often occur, sometimes prior to onset of the dementia.3 Creutzfeldt-Jakob disease is one of the potentially transmissible spongiform encephalopathies (TSEs) associated with rapidly progressive and typically early-onset dementia (Table).1,2,4
The onset of CJD is usually between the ages of 40 and 60 years, with males affected as frequently as females.1,2 The evaluation of any early-onset or rapidly progressive dementia must include a thorough history, medication review, and physical examination. In addition, a lumbar puncture, an EEG, and a magnetic resonance imaging (MRI) scan of the brain are recommended. The spinal fluid should be evaluated for the presence of the neuronal protein 14-3-3 and tau, both of which are common in CJD but not conclusively diagnostic. The presence of protein 13-4-4 and the relative absence of amyloid have been shown to increase the accuracy of the diagnosis of CJD.5 An EEG typically reveals symmetrical spike and wave patterns in the frontal lobes, but occurs in only half of those affected.1,2 Diffusion weighted imaging (DWI) MRI is a relatively new imaging technique that is more sensitive to spongiform changes in the brain, and may identify abnormalities in the frontal lobes, putamen, caudate, and thalamus.6 Other sensitive MRI techniques include fluid-attenuated-inversion-recovery (FLAIR) MRI, and apparent diffusion coefficient (ADC) mapping MRI.
Traditional MRI and CT scan results of patients with CJD are typically normal.1,2 In cases where the results lead to no conclusive diagnosis but symptoms persist, brain biopsy may be needed to identify the syndrome. The potential risks, as well as the possibility that the brain tissue taken for biopsy may not yield a definitive diagnosis, should be discussed with the patient and his or her significant others. The spongiform encephalopathies have received a great deal of public attention, due to variant types associated with the ingestion of affected beef in the United Kingdom. In the period from mid-1980 through 2000, exposure to prion-associated bovine spongiform encephalopathy led to more than 150 reported cases of variant CJD.7 Prions have been associated with transmitted cases of CJD from infected corneal tissue, dura mater grafts, and purified human growth hormone, which has been associated with more than 75% of iatrogenic cases. These cases may have a long incubation period, with a clinical presentation of longer duration and more variable symptoms. This has led to use of the term variant CJD for this form of the disease.1,7
The prions that are associated with CJD and other spongiform encephalopathies are not destroyed by ultraviolet light, irradiation, formaldehyde, or nucleases. There have been a few unfortunate cases associated with transmission linked to the use of steel surgical instruments used for the placement of depth electrodes in the brain for continuous EEG monitoring. Despite standard cleaning, sterilization, and storage in formaldehyde, two patients under the age of 25 years developed CJD after being exposed to electrodes that were initially used to evaluate a patient with CJD.2 The most common form of CJD is sporadic, the result of a spontaneous mutation, with no specific pattern to its occurrence. In the United States, about 250 cases of CJD are diagnosed each year. Many local and state health departments now require the reporting of each case in order to track any possible patterns. Creutzfeldt-Jakob disease occurs in a familial form in about 10% of all cases. The disease appears to have an autosomal dominant pattern of inheritance. Genetic counseling is recommended when there is a history of early-onset or rapidly progressive dementia in the family, or if other relatives have similar symptoms.1,2,5
Other rare genetic prion diseases include Gerstmann-Straussler-Scheinker syndrome and fatal familial insomnia. Medications including quinacrine and chlorpromazine have been used on an anecdotal basis to attempt to slow disease progression, based on in vitro testing of these drugs with infected tissue.4 Unfortunately, no positive outcome has been noted among patients treated with these agents. Due to the rapidly progressive nature of the illness, with life expectancy in the range of 4-18 months from the time of diagnosis, palliative care and referral to hospice services is usually indicated. Symptomatic relief of pain, muscle spasms, anxiety, and psychotic symptoms is helpful.4 Family support services are vital. Because of the relatively young age of onset of this progressive dementia, psychosocial, financial, and legal counseling is often needed. Information for patients and families is available from the Creutzfeldt-Jakob Disease Foundation, Inc., at www.cjdfoundation.org and the National Organization for Rare Disorders at www.rarediseases.org.
OUTCOME OF THE CASE PATIENT
The patient was found to have high concentrations of protein 14-3-3 present in his cerebrospinal fluid, and his EEG revealed very characteristic spike and slow-wave activity. Mr. D has no family history of dementia; in fact, both of his parents and his three older brothers are alive and in relatively good health. The remainder of his medical evaluation yielded no treatable or reversible cause of the progressive mental and motor decline. The patient’s family was informed of the likely diagnosis of CJD, and offered the option of a brain biopsy for confirmation. Mr. D was very agitated in the hospital, and received many doses of haloperidol. He developed a more prominent tremor and muscle rigidity. Mrs. D felt that he was getting worse in the hospital, and chose to take him home. Dr. H referred the patient to a hospice program. His parents and brothers visited frequently to help with care and to support the family. Mr. D progressively declined over the next 6 months, becoming bedridden with poor oral intake. He was transferred to the hospice inpatient unit after the family decided not to implement any artificial feeding. The patient died 9 months following the initial onset of his symptoms. Brain autopsy revealed a diagnosis of Creutzfeldt-Jakob disease, sporadic type. Mr. D’s widow and children continued in counseling to deal with issues of grief and bereavement. The patient’s son had a difficult time, and postponed entering college after his father’s death. He was referred to a genetic counselor due to his overwhelming fears that he would develop the same disease as his father. With education and counseling, he became less anxious and decided to begin school part-time while training as an emergency medical technician. The author reports no relevant financial relationships.