Case 27-2005 — An 80-Year-Old Man with Fatigue, Unsteady Gait, and Confusion
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《新英格兰医药杂志》
Presentation of Case
Dr. Thanh Nguyen (Neurology): An 80-year-old man was admitted to the hospital in late summer because of difficulty walking, fatigue, confusion, and insomnia.
The patient had been in his usual state of health until approximately four weeks before admission, when he noticed severe fatigue, frequent yawning, and difficulty concentrating; insomnia, intermittent confusion, and unsteadiness of gait developed. During daily activities, he required multiple breaks that he had not needed previously.
Three weeks before admission, he saw his physician; the results of a physical examination and routine laboratory testing were normal. Computed tomographic (CT) scanning of the head and neck with angiographic examination showed diffuse cerebral volume loss with ventricular prominence and periventricular hypodensity, an old lacunar infarct in the left caudate head, and atherosclerotic calcification of the major intracranial vessels. An electrocardiogram showed a ventricular rate of 51 beats per minute and was otherwise normal. Ten days before admission, a transorbital Doppler study showed minimal disease of the left internal carotid artery and of the right carotid artery at the bifurcation.
Three weeks later, magnetic resonance imaging (MRI) of the brain before and after the administration of contrast material, performed at another facility, showed hyperintensity of the white matter and small lacunar infarcts in the right side of the thalamus, right pons, and left caudate. The results of magnetic resonance angiography were normal. Later that day, the patient saw his physician and reported progressively worsening insomnia, unsteadiness, and confusion. He could no longer swim, bicycle, or lift weights, and he had given up driving. He was admitted to this hospital.
The patient had no other symptoms. He had been bitten by a tick while visiting Cape Cod earlier that summer; he had traveled to France the previous year and to England nine years earlier. He had a history of hypertension, hyperlipidemia, and aortic stenosis; he had had rheumatic fever as a child. He had had a transient ischemic attack 20 years earlier, with no residual defect. He had chronic hearing loss and muscle changes and sensory loss in one leg from war injuries; a basal-cell carcinoma of the right inner canthus had been irradiated. He had had surgery for a right cataract with lens implantation.
The patient's father had died of cardiovascular disease at 80 years of age; he did not know the cause of his mother's death. One brother was alive with lymphoma; a sister had schizophrenia; another brother and sister were well. The patient was widowed and lived alone. His two sons were well. He was a semiretired businessman who had continued to be active in his field. He consumed one to two alcoholic beverages per day and had smoked cigarettes in the remote past. His medications were aspirin, atorvastatin, lisinopril, and a multivitamin.
The blood pressure was 147/81 mm Hg, the pulse 61 beats per minute, and the respiratory rate 18 breaths per minute; the temperature was 36.2°C and the oxygen saturation 98 percent. There was a systolic ejection murmur (grade 1 of 6) at the right upper sternal border. The patient had difficulty walking in a straight line. The remainder of the general physical examination was normal. A neurology consultant reported that the patient was alert and oriented and did not appear to be confused. An examination revealed a few beats of horizontal nystagmus with left and right far lateral gaze and fatiguing, decreased sensation to all stimuli on the right foot and calf, and mild ataxia on tandem gait; the Romberg test was positive.
The patient had severe difficulty sleeping that night, and the blood pressure increased to 166/77 mm Hg. Hydrochlorothiazide (25 mg) was administered and subsequently given daily. On the second day in the hospital, a neurologist noted that the patient appeared intermittently inattentive. He was unable to sleep that night. On the third day, a lumbar puncture revealed an opening pressure of 14 cm of water. The cerebrospinal fluid was clear, with a glucose level of 64 mg per deciliter (3.6 mmol per liter) and a protein level of 65 mg per deciliter. The cell count in the fourth tube was one red cell and one white cell per cubic millimeter, with 25 percent neutrophils, 50 percent lymphocytes, and 25 percent monocytes. A spun Gram's stain procedure was performed but there were no organisms; the culture had no growth. Cytologic examination of the cerebrospinal fluid, and tests for syphilis, herpes simplex virus DNA amplification, and Creutzfeldt–Jakob disease (14-3-3 protein) were negative.
MRI scanning of the brain showed volume loss, scattered white-matter changes and lacunar infarcts, and regions of reduced diffusion involving the cortex of the anterior frontal lobes, right parietal and temporal lobes, and the right caudate head. An electroencephalogram showed continuous focal slowing in the right hemisphere, mostly in the anterior region. No epileptiform activity was present. The patient was discharged on the third hospital day, with instructions to continue taking atorvastatin, lisinopril, hydrochlorothiazide, and lorazepam. Additional outpatient testing was scheduled.
Five days after discharge, the patient was evaluated in the outpatient neurology clinic at this hospital. Insomnia continued; he was taking lorazepam (1 mg) at 8 p.m. and 2 a.m. and feeling progressively more sleepy in the morning. Family members confirmed that he had worsening gait instability. On examination, there were signs of cognitive deterioration in his slow responses, errors in orientation as to year, recall that improved with prompting, and some naming difficulty. There was instability, as seen in the finger-to-nose test and his rapid alternating movements with the left hand. The gait was wide-based, and he was unable to perform tandem gait. Lorazepam was discontinued, and zolpidem was administered for insomnia.
During the next week, the patient's gait instability and confusion continued to worsen. The serum level of vitamin B12 was 416 pg per milliliter (307 pmol per liter) and the serum level of homocysteine was 8.9 μmol per liter. Tests for Lyme disease and for antibodies to the human immunodeficiency virus were negative, and a rapid plasma reagin test, a polymerase-chain-reaction assay for West Nile virus, and tests for antinuclear antibody and thyroid autoantibody were negative. The results of a test of thyroid function were normal. CT scanning of the chest, abdomen, and pelvis showed no cancer. Haloperidol (1 mg) and lorazepam (again) were administered for insomnia.
Thirteen days after discharge, the patient had increasing insomnia and restlessness, and an episode of total body jerking without loss of consciousness that lasted 30 seconds was witnessed. On examination, he was withdrawn but spoke readily when questioned. There were action tremors on the left side, asterixis, and ataxic tremor in the arms and legs. Haloperidol was discontinued, and quetiapine fumarate (50 mg) at night and oxcarbazepine (300 mg) daily were added. Two days later, the patient was readmitted to the hospital.
On examination, the patient was somnolent, at times with a blunted affect. The vital signs were normal. He was confused as to date and place; there was impairment in visual tracking, with slow saccades; a moderate action tremor was more pronounced on the left side. Myoclonus was present in the upper extremities. There were fasciculations of the legs, with increased tone. He had difficulty standing and had a wide-based, unsteady gait. There was ataxia on finger-to-nose testing of the left arm. The big toe was pointed up on the left foot and down on the right foot.
Oxcarbazepine and hydrochlorothiazide were discontinued, and haloperidol was again administered for insomnia. Toxicologic screening tests and tests conducted for the presence of a neoplastic syndrome, including assays for anti–MaTa 1 and 2 antibodies, CV 2 autoantibody, antineuronal nuclear and anti–Purkinje-cell antibodies, anti-RI, and paraneoplastic opsoclonus–myoclonus antibody, were negative. A timed urine collection for measurement of porphobilinogen and aminolevulinic acid showed no abnormalities.
On the third hospital day, treatment with rivastigmine was begun. Over the next two weeks, the patient became mute and more difficult to arouse, with persistent large amplitude tremor, startle myoclonus, and fasciculations of the legs. The temperature increased to 38.5°C. Medical therapy was discontinued, and comfort measures were instituted at the family's request. The patient died on the 23rd hospital day.
An autopsy was performed.
Differential Diagnosis
Dr. Richard T. Johnson: May we see the imaging studies?
Dr. R. Gilberto Gonzalez: A fluid-attenuated inversion recovery pulse-sequence MRI of the head performed during the patient's first admission showed parenchymal tissue loss with some widening of the sulci and the ventricles. There were multifocal signal abnormalities in the white matter, a nonspecific finding commonly seen in patients of this age. The diffusion-weighted images (Figure 1) showed multifocal areas of reduced diffusion involving the basal ganglia as well as the cortical mantle, throughout both hemispheres and the cerebral cortex.1,2,3
Figure 1. An Axial Diffusion-Weighted Magnetic Resonance Image.
There are multifocal cortical regions of abnormal diffusion (arrows).
Dr. Johnson: This 80-year-old man had enjoyed good health until the last three months of his life, when a relentlessly progressive disease of the central nervous system developed. His initial problems were fatigue, insomnia, unsteadiness of gait, and confusion. During the first month, there were no abnormal physical findings or laboratory test results, leaving a very broad differential diagnosis. Imaging studies suggested that his disorders of gait and cognition might have resulted from cerebrovascular disease. However, insomnia was unlikely to be related to cerebrovascular disease. One month into the illness, nystagmus and mild cerebellar ataxia developed; difficulty sleeping was a major problem, and mild hypertension was noted. MRI scanning showed reduced diffusion in frontal, right parietal, and temporal cortexes and in the right caudate nucleus. The electroencephalogram showed slowing in the right hemisphere. Six weeks into the illness, startle myoclonus and fasciculations in the legs were noted for the first time, narrowing the differential diagnosis.
The differential diagnosis of dementia and myoclonic jerking is limited, and Creutzfeldt–Jakob disease is the probable diagnosis. Mild myoclonus may occur in Alzheimer's disease, but the disease does not follow the rapid course seen with this patient. Some inflammatory diseases can have symptoms such as cognitive decline and myoclonus — notably neurosyphilis and subacute sclerosing panencephalitis — but the results of the cerebrospinal fluid examination rule out these disorders. Postanoxic encephalopathy and adult lipid-storage diseases may have symptoms that combine dementia and myoclonus, but neither of these diseases is consistent with the history or progression of this case. I have seen two patients in consultation for increasing confusion and myoclonus in whom a tentative diagnosis of Creutzfeldt–Jakob disease proved wrong; one had Hashimoto's encephalopathy (and eventually recovered with corticosteroid treatment), and the other had bismuth intoxication (with recovery after withdrawal from massive doses of Pepto-Bismol). In these two patients, however, myoclonus and seizures occurred at the onset of disease; in Creutzfeldt–Jakob disease, the myoclonus tends to develop late in the course of disease, as in this patient, and seizures are rare.
Myoclonus not associated with dementia occurs in several forms of epilepsy and in some movement disorders. It may be a comfort to readers to know that hypnic jerks and myoclonic jerks during sleep are normal; they may increase in frequency with age and preoccupy the worried well — particularly medical students and physicians who have been reading about prion diseases.
In this patient, the dissolution of cognitive function over a few months in association with cerebellar ataxia, myoclonus, and fasciculations indicates a diagnosis of transmissible spongiform encephalopathy or prion disease.4 Making the diagnosis of Creutzfeldt–Jakob disease can be difficult early in the course of disease, as in this case.5 About one third of patients present with behavioral and cognitive changes; about one third present with systemic symptoms such as fatigue, disordered sleep, and decreased appetite. The final third present with focal neurologic symptoms or signs that can obfuscate the diagnosis, such as the insidious onset of muscle wasting with fasciculations that suggests amyotrophic lateral sclerosis, or the abrupt onset of a focal neurologic deficit that suggests a stroke. The patient under discussion had features of each of these types of onset, with confusion, fatigue and sleep disruption, and cerebellar ataxia in the first month of illness. As time passed, the inexorable dementia and the development of myoclonic jerking, particularly startle myoclonus, clarified the diagnosis.
Several studies may support the diagnosis of Creutzfeldt–Jakob disease, but each has limited sensitivity or specificity. An electroencephalogram showing biphasic or triphasic synchronized sharp-wave complexes, MRI with hyperintense signals in the basal ganglia on T2-weighted images, and the presence of 14-3-3 protein, a normal brain protein, in the cerebrospinal fluid are all highly suggestive of Creutzfeldt–Jakob disease.6 None of these studies supported the diagnosis in this case; but often repetition of these tests later in the course of the disease will yield a positive result.
Sporadic Creutzfeldt–Jakob disease has a worldwide incidence of 1 per 1 million population per year; there is no temporal or geographic clustering, no occupational risks, and a paucity of conjugal cases. Most observers now believe that a random protein misfolding or a somatic mutation in the gene coding for the prion protein leads to the disease.7 The disease is transmissible both in the laboratory and in the clinical setting — by corneal transplantation, dural grafts, injection of human growth hormone extracted from human pituitary glands, and improperly cleaned surgical instruments.8
In about 10 percent of cases, a mutation in the prion protein gene (PRNP) causes the disease; a dominant pattern of transmission is seen in the families of patients with such mutations, and different sites of mutations and polymorphisms lead to somewhat different phenotypes (Table 1). Two inheritable forms have distinctive syndromes: Gerstmann–Str?ussler–Scheinker disease, which is characterized by an onset of cerebellar ataxia, and fatal familial insomnia, which is characterized by progressive insomnia, dysautonomia, and dementia.9 This patient had both cerebellar ataxia and insomnia and did not know the cause of his mother's death. In typical cases of fatal familial insomnia, the patients are relatively young (between 36 and 62 years of age) and have a protracted course (8 to 72 months)10; the patient we are discussing was 80 years of age and died in less than 3 months. Autonomic dysfunction is prominent in fatal familial insomnia with hypertension, evening pyrexia, excessive perspiration, lacrimation, and salivation; this patient had bradycardia, transient hypertension, and fever, but autonomic dysfunction was not prominent.
Table 1. Classification of Creutzfeldt–Jakob Disease.
A few cases of sporadic fatal insomnia have been described.11 However, many patients with sporadic Creutzfeldt–Jakob disease have sleep disorders, particularly insomnia. The diagnosis has been based in part on polysomnography12 and in part on autopsy; the findings include the localization of neuron loss to the thalamus, particularly the anterior ventral and mediodorsal nuclei, and the olivary nuclei,13 similar to findings in the familial cases. Could this case qualify for a diagnosis of sporadic fatal insomnia? I would say no, unless we find out that the histopathological changes mimic those of familial fatal insomnia.
Another teaser is in the history: the patient had visited England during the period when exposure to bovine spongiform encephalopathy was maximal, but he is not reported to have received blood transfusions there. The variant form of Creutzfeldt–Jakob disease (vCJD) related to bovine spongiform encephalopathy has been seen in England since 1994, but patients have generally been young (mean age at onset, 29 years), have presented with dysesthesias and personality changes, with later evolution of cerebellar ataxia and dementia, and have had long survival (mean, 15 months).14 Unlike sporadic Creutzfeldt–Jakob disease, which does not appear transmissible through transfusion of blood products, the variant form does appear to be transmitted by transfusion, accounting for variant disease in an elderly man.15
In summary, I think this man had Creutzfeldt–Jakob disease. The late age at onset, the prominence of insomnia, and the fulminant course make this an atypical story, but I suspect we will find the characteristic spongiform pathological features of sporadic Creutzfeldt–Jakob disease.
I would like to add a historical footnote here: the first case of Creutzfeldt–Jakob disease presented in these Case Records was in 1961.16 As a fellow in neuropathology under Dr. Edward P. Richardson, Jr., I presented the pathological discussion. We, like many of our contemporaries, commented only on the neuronal loss and gliosis and disregarded the spongiform changes, which we dismissed as postmortem artifacts. Ironically, we overlooked the feature that has become the hallmark of this and other related diseases.
A Physician: Would you ever need to perform a biopsy, or is the clinical diagnosis sufficient?
Dr. Johnson: We perform biopsies on about 1 of 10 patients with symptoms suggestive of Creutzfeldt–Jakob disease. This diagnosis almost invariably starts as a mystery but within a few months becomes obvious. During that early period, biopsies may be indicated because of management considerations or social circumstances. Small cortical biopsies are quite easy and safe. However, because of fear of contracting the disease, the problem can be convincing the neurosurgeons to perform the biopsy and the pathologists to process it.
Dr. Nancy Lee Harris (Pathology): Dr. Ronan and Dr. Venna, could you tell us what your thoughts were as you cared for this patient?
Dr. Laurence J. Ronan (Internal Medicine): This was a remarkably high-functioning person, whom I had known for many years. His chief complaint to me was, "I lost my train of thought in a board meeting." I was thinking that at 80 years old, this was not surprising. But he grabbed me from behind and said, "You may think that's okay, but when I lose my train of thought, I lose millions of dollars. You find out what's wrong." Five weeks later he was in diapers, and very shortly thereafter he died. It was startling to watch him lose function daily. Initially, the diagnosis was not easy, but the neurologic team made the diagnosis very quickly.
Dr. Nagagopal Venna (Neurology): When I first examined the patient, neurologic symptoms were prominent, but the abnormalities on examination were slight and subtle. The clinical syndrome suggested an evolving subacute encephalopathy with a broad differential diagnosis. Dr. Ronan astutely suggested prion disease even at this stage, because of the patient's dramatic decline from his previous high level of functioning.
When I examined the patient a second time, his neurologic state had deteriorated markedly. This relentless course, combined with the results of the cerebrospinal fluid examination that did not reveal inflammation, made prion disease likely. We focused the investigation on three groups of diseases that mimic prion encephalopathy, especially those that are treatable: cerebral infections (Lyme disease, neurosyphilis, indolent herpes simplex encephalitis, and fungal meningoencephalitis), immune-mediated encephalopathies (paraneoplastic and nonparaneoplastic limbic encephalitis and Hashimoto's encephalitis), all of which are at least partially responsive to corticosteroids or intravenous immunoglobulin therapy, and metabolic and toxic causes, including bismuth and lithium intoxications, which can induce clinical syndromes with an uncanny resemblance to Creutzfeldt–Jakob disease.
In the final stage of the illness, the new neurologic deficits that appeared and accumulated almost daily, combined with the negative results of the other laboratory tests, made the diagnosis of prion disease inescapable. The case illustrated the value of the characteristic serial changes in the clinical picture that occur over a period of weeks in the diagnosis of prion disease, although making the diagnosis can be difficult at a single point in time.
Clinical Diagnosis
Creutzfeldt–Jakob disease.
Dr. Richard T. Johnson's Diagnosis
Creutzfeldt–Jakob disease.
Pathological Discussion
Dr. Matthew P. Frosch: The brain was normal in weight, with no signs of atrophy, and there was a 1.5-cm lacunar infarct in the left caudate. Tissue samples were frozen at –80°C; all tissue blocks were processed through formic acid to eliminate infective prions from tissue sections while still allowing for histologic diagnosis.17
The cerebral cortex showed widespread but patchy spongiform changes (Figure 2A), most prominent in the deep cortical layers; the vacuoles arose within neuronal cell bodies and dendrites (Figure 2A, inset). Spongiform changes were diffusely present in the striatum (Figure 2B) and in the cerebellar cortex (Figure 2C). These features are diagnostic of prion disease (transmissible spongiform encephalopathy and Creutzfeldt–Jakob disease). The hallmarks of fatal familial insomnia and fatal sporadic insomnia — severe neuronal loss and gliosis in the thalamus and the inferior olivary nucleus — were absent, excluding these two entities.11,12,18 A reexamination of the 1961 case with which Dr. Johnson made his debut in this forum revealed that the cerebral cortex did show mild spongiform changes (Figure 1 of Supplementary Appendix, available with the full text of this article at www.nejm.org).
Figure 2. Photomicrographs of the Brain.
The cerebral cortex (Panel A) has widespread spongiform changes. Neuronal cell bodies (Panel A, inset) contain vacuoles. The striatum (Panel B) has prominent spongiform changes involving the gray matter, with sparing of the white-matter bundles; the contrast between the intact white matter and the spongiotic gray matter increases a pathologist's confidence when making the diagnosis on the basis of a stereotactic biopsy that these vacuoles do not represent artifact. The cerebellum (Panel C) has prominent spongiform changes involving the molecular layer. Immunostaining of the cerebellum for PrP (Panel D) shows granular staining in the molecular and granular-cell layers. A section of cerebral cortex from a case of variant Creutzfeldt–Jakob disease (vCJD) (Panel E) shows more localized spongiform changes than those seen in classic Creutzfeldt–Jakob disease. A plaque of PrP-amyloid (Panel E, inset) is located in the center of an area of spongiform change. Immunostaining of vCJD for PrP (Panel F and inset) shows localization of the staining to the amyloid plaque. (Panel A, Panel B, and Panel C are stained with Luxol fast blue hematoxylin and eosin, Panel E and inset with hematoxylin and eosin, and Panel D and Panel F and inset with immunoperoxidase stain for PrP, courtesy of Dr. Pierluigi Gambetti, National Prion Disease Pathology Surveillance Center.)
Samples of brain tissue were sent to the National Prion Disease Pathology Surveillance Center, directed by Dr. Pierluigi Gambetti (www.cjdsurveillance.com/), as is done for all suspected cases of prion disease in our institution. The immunohistochemical and biochemical studies performed there that support the histologic diagnosis are based on the differences between the normal cellular form of the prion protein (PrPC) and the pathologic form of the protein (PrPSc). The fixed tissue was treated to eliminate PrPC and stained with use of immunohistochemistry for PrP; positive immunoreactivity was observed in cerebellum (Figure 2D) and cerebral cortex, indicating the presence of PrPSc and thus confirming the diagnosis of Creutzfeldt–Jakob disease.
Because of this patient's history of travel to England, the question of whether or not his condition represented vCJD could theoretically arise.19 Neuropathologically, vCJD cases differ from the classic type of Creutzfeldt–Jakob disease in the finding of florid plaques20 (Figure 2E), which have a dense core and a surrounding rim of delicate fibrils, both of which contain PrPSc (Figure 2F). The plaques are numerous in the cerebral cortex, tend to cluster, and often form the centers of localized areas of prominent spongiform change — quite different from the findings in this case.
In order to characterize further the type of prion disease, Western blotting for the presence of PrP was performed. Although PrPC is completely digested by proteinase K, PrPSc is partially resistant, with cleavage occurring at either of two positions — roughly 82 or 97 amino acids from the N-terminal (Figure 3) — depending on the conformation of the PrPSc molecules. Western blotting of brain homogenates from this patient revealed type 1 PrPSc (Figure 4). Standard forms of Creutzfeldt–Jakob disease can also be associated with type 2 PrPSc, with a shorter protein backbone. In vCJD, the type 2 PrPSc is found with an overabundance of diglycosylated forms.
Figure 3. The Structure of the Prion Protein (PrPC).
After synthesis of the protein, maturation involves removal of the signal peptide sequence at the N-terminal as well as removal of the C-terminal for attachment of the glycosylphosphatidylinositol (GPI) anchor (black). Also indicated in this model is the region of octapeptide repeats (blue) and the alpha-helical domains (red). The residues involved in the intramolecular disulfide bridge (S–S) are shown, as well as the two locations for N-glycosylation (N). The polymorphic codon 129, which may be either methionine (M) or valine (V), is indicated. When PrP takes up the pathologic conformation (PrPSc), the alpha-helical domains change conformation and the protein acquires the property of partial resistance to digestion with proteinase K. The two arrows indicate the approximate points at which the proteinase K clips the molecule (type 1 PrPSc is associated with the cleavage site and a larger fragment).
Figure 4. Western Blotting of Tissue Homogenates for PrP.
Tissue from the patient and controls is shown as follows: lane 1, occipital cortex; lane 2, reference case, type 1 PrPSc; lane 3, reference case, type 2 PrPSc; lanes 4,5, and frontal cortex; lanes 7 and 8, cerebellum. Lanes 1, 2, 3, 5, 6, and 8 were digested with proteinase K before loading onto the gel. The higher molecular weight bands reflect the presence of mono- and di- N–linked glycosylation of PrP. The PrPSc in these homogenates has more glycosylated than diglycosylated forms. These data provide additional support for the diagnosis of prion disease.
This autopsy was limited to the brain; therefore other tissues could not be examined for the presence of PrPSc. In cases of vCJD, but not other forms of prion disease, the accumulation of PrPSc in lymphoid tissue has been observed,21 possibly before the development of neurologic disease.22
Sequencing of the PRNP gene showed no mutations, ruling out the diagnosis of familial Creutzfeldt–Jakob disease; the patient was homozygous at codon 129 for methionine, which is the genotype that is associated with an increased risk of sporadic Creutzfeldt–Jakob disease and has also been observed in all cases of vCJD to date. Six different combinations of the codon 129 polymorphisms and the molecular types of PrPSc have been described in cases of sporadic Creutzfeldt–Jakob disease, with some correlations with clinical and neuropathological patterns of disease.23,24 The final neuropathological and molecular diagnosis in this case is prion disease (sporadic Creutzfeldt–Jakob disease with MM1 ) PrPSc. This is the most common type, with the typical symptoms of Creutzfeldt–Jakob disease and distribution of pathological findings.
To date, all of the cases of both classic and variant Creutzfeldt–Jakob disease have been in patients who were homozygous for methionine at codon 12925; whether this implies an absolute protection for persons with other genotypes at this site or simply a difference in incubation time remains to be seen.26
Dr. Lloyd Axelrod (Internal Medicine): What is the neuropathological basis for the fasciculations in this patient?
Dr. Frosch: Spongiform changes may be seen in the spinal cord gray matter, with neuronal loss from the anterior horns; however, the spinal cord was not examined in this case.
Anatomical Diagnosis
Prion disease (sporadic Creutzfeldt–Jakob disease with MM1) PrPSc.
Dr. Johnson reports having served on the Cephalon Medical advisory board and having equity ownership in Cephalon; he reports serving as a consultant for Millennium.
Source Information
From the Department of Neurology, Microbiology, and Neuroscience, Johns Hopkins University School of Medicine and Bloomberg School of Public Health, Baltimore (R.T.J.); the Departments of Radiology (R.G.G.) and Pathology (M.P.F.), Massachusetts General Hospital, Boston; and the Departments of Radiology (R.G.G.) and Pathology (M.P.F.), Harvard Medical School, Boston.
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Dr. Thanh Nguyen (Neurology): An 80-year-old man was admitted to the hospital in late summer because of difficulty walking, fatigue, confusion, and insomnia.
The patient had been in his usual state of health until approximately four weeks before admission, when he noticed severe fatigue, frequent yawning, and difficulty concentrating; insomnia, intermittent confusion, and unsteadiness of gait developed. During daily activities, he required multiple breaks that he had not needed previously.
Three weeks before admission, he saw his physician; the results of a physical examination and routine laboratory testing were normal. Computed tomographic (CT) scanning of the head and neck with angiographic examination showed diffuse cerebral volume loss with ventricular prominence and periventricular hypodensity, an old lacunar infarct in the left caudate head, and atherosclerotic calcification of the major intracranial vessels. An electrocardiogram showed a ventricular rate of 51 beats per minute and was otherwise normal. Ten days before admission, a transorbital Doppler study showed minimal disease of the left internal carotid artery and of the right carotid artery at the bifurcation.
Three weeks later, magnetic resonance imaging (MRI) of the brain before and after the administration of contrast material, performed at another facility, showed hyperintensity of the white matter and small lacunar infarcts in the right side of the thalamus, right pons, and left caudate. The results of magnetic resonance angiography were normal. Later that day, the patient saw his physician and reported progressively worsening insomnia, unsteadiness, and confusion. He could no longer swim, bicycle, or lift weights, and he had given up driving. He was admitted to this hospital.
The patient had no other symptoms. He had been bitten by a tick while visiting Cape Cod earlier that summer; he had traveled to France the previous year and to England nine years earlier. He had a history of hypertension, hyperlipidemia, and aortic stenosis; he had had rheumatic fever as a child. He had had a transient ischemic attack 20 years earlier, with no residual defect. He had chronic hearing loss and muscle changes and sensory loss in one leg from war injuries; a basal-cell carcinoma of the right inner canthus had been irradiated. He had had surgery for a right cataract with lens implantation.
The patient's father had died of cardiovascular disease at 80 years of age; he did not know the cause of his mother's death. One brother was alive with lymphoma; a sister had schizophrenia; another brother and sister were well. The patient was widowed and lived alone. His two sons were well. He was a semiretired businessman who had continued to be active in his field. He consumed one to two alcoholic beverages per day and had smoked cigarettes in the remote past. His medications were aspirin, atorvastatin, lisinopril, and a multivitamin.
The blood pressure was 147/81 mm Hg, the pulse 61 beats per minute, and the respiratory rate 18 breaths per minute; the temperature was 36.2°C and the oxygen saturation 98 percent. There was a systolic ejection murmur (grade 1 of 6) at the right upper sternal border. The patient had difficulty walking in a straight line. The remainder of the general physical examination was normal. A neurology consultant reported that the patient was alert and oriented and did not appear to be confused. An examination revealed a few beats of horizontal nystagmus with left and right far lateral gaze and fatiguing, decreased sensation to all stimuli on the right foot and calf, and mild ataxia on tandem gait; the Romberg test was positive.
The patient had severe difficulty sleeping that night, and the blood pressure increased to 166/77 mm Hg. Hydrochlorothiazide (25 mg) was administered and subsequently given daily. On the second day in the hospital, a neurologist noted that the patient appeared intermittently inattentive. He was unable to sleep that night. On the third day, a lumbar puncture revealed an opening pressure of 14 cm of water. The cerebrospinal fluid was clear, with a glucose level of 64 mg per deciliter (3.6 mmol per liter) and a protein level of 65 mg per deciliter. The cell count in the fourth tube was one red cell and one white cell per cubic millimeter, with 25 percent neutrophils, 50 percent lymphocytes, and 25 percent monocytes. A spun Gram's stain procedure was performed but there were no organisms; the culture had no growth. Cytologic examination of the cerebrospinal fluid, and tests for syphilis, herpes simplex virus DNA amplification, and Creutzfeldt–Jakob disease (14-3-3 protein) were negative.
MRI scanning of the brain showed volume loss, scattered white-matter changes and lacunar infarcts, and regions of reduced diffusion involving the cortex of the anterior frontal lobes, right parietal and temporal lobes, and the right caudate head. An electroencephalogram showed continuous focal slowing in the right hemisphere, mostly in the anterior region. No epileptiform activity was present. The patient was discharged on the third hospital day, with instructions to continue taking atorvastatin, lisinopril, hydrochlorothiazide, and lorazepam. Additional outpatient testing was scheduled.
Five days after discharge, the patient was evaluated in the outpatient neurology clinic at this hospital. Insomnia continued; he was taking lorazepam (1 mg) at 8 p.m. and 2 a.m. and feeling progressively more sleepy in the morning. Family members confirmed that he had worsening gait instability. On examination, there were signs of cognitive deterioration in his slow responses, errors in orientation as to year, recall that improved with prompting, and some naming difficulty. There was instability, as seen in the finger-to-nose test and his rapid alternating movements with the left hand. The gait was wide-based, and he was unable to perform tandem gait. Lorazepam was discontinued, and zolpidem was administered for insomnia.
During the next week, the patient's gait instability and confusion continued to worsen. The serum level of vitamin B12 was 416 pg per milliliter (307 pmol per liter) and the serum level of homocysteine was 8.9 μmol per liter. Tests for Lyme disease and for antibodies to the human immunodeficiency virus were negative, and a rapid plasma reagin test, a polymerase-chain-reaction assay for West Nile virus, and tests for antinuclear antibody and thyroid autoantibody were negative. The results of a test of thyroid function were normal. CT scanning of the chest, abdomen, and pelvis showed no cancer. Haloperidol (1 mg) and lorazepam (again) were administered for insomnia.
Thirteen days after discharge, the patient had increasing insomnia and restlessness, and an episode of total body jerking without loss of consciousness that lasted 30 seconds was witnessed. On examination, he was withdrawn but spoke readily when questioned. There were action tremors on the left side, asterixis, and ataxic tremor in the arms and legs. Haloperidol was discontinued, and quetiapine fumarate (50 mg) at night and oxcarbazepine (300 mg) daily were added. Two days later, the patient was readmitted to the hospital.
On examination, the patient was somnolent, at times with a blunted affect. The vital signs were normal. He was confused as to date and place; there was impairment in visual tracking, with slow saccades; a moderate action tremor was more pronounced on the left side. Myoclonus was present in the upper extremities. There were fasciculations of the legs, with increased tone. He had difficulty standing and had a wide-based, unsteady gait. There was ataxia on finger-to-nose testing of the left arm. The big toe was pointed up on the left foot and down on the right foot.
Oxcarbazepine and hydrochlorothiazide were discontinued, and haloperidol was again administered for insomnia. Toxicologic screening tests and tests conducted for the presence of a neoplastic syndrome, including assays for anti–MaTa 1 and 2 antibodies, CV 2 autoantibody, antineuronal nuclear and anti–Purkinje-cell antibodies, anti-RI, and paraneoplastic opsoclonus–myoclonus antibody, were negative. A timed urine collection for measurement of porphobilinogen and aminolevulinic acid showed no abnormalities.
On the third hospital day, treatment with rivastigmine was begun. Over the next two weeks, the patient became mute and more difficult to arouse, with persistent large amplitude tremor, startle myoclonus, and fasciculations of the legs. The temperature increased to 38.5°C. Medical therapy was discontinued, and comfort measures were instituted at the family's request. The patient died on the 23rd hospital day.
An autopsy was performed.
Differential Diagnosis
Dr. Richard T. Johnson: May we see the imaging studies?
Dr. R. Gilberto Gonzalez: A fluid-attenuated inversion recovery pulse-sequence MRI of the head performed during the patient's first admission showed parenchymal tissue loss with some widening of the sulci and the ventricles. There were multifocal signal abnormalities in the white matter, a nonspecific finding commonly seen in patients of this age. The diffusion-weighted images (Figure 1) showed multifocal areas of reduced diffusion involving the basal ganglia as well as the cortical mantle, throughout both hemispheres and the cerebral cortex.1,2,3
Figure 1. An Axial Diffusion-Weighted Magnetic Resonance Image.
There are multifocal cortical regions of abnormal diffusion (arrows).
Dr. Johnson: This 80-year-old man had enjoyed good health until the last three months of his life, when a relentlessly progressive disease of the central nervous system developed. His initial problems were fatigue, insomnia, unsteadiness of gait, and confusion. During the first month, there were no abnormal physical findings or laboratory test results, leaving a very broad differential diagnosis. Imaging studies suggested that his disorders of gait and cognition might have resulted from cerebrovascular disease. However, insomnia was unlikely to be related to cerebrovascular disease. One month into the illness, nystagmus and mild cerebellar ataxia developed; difficulty sleeping was a major problem, and mild hypertension was noted. MRI scanning showed reduced diffusion in frontal, right parietal, and temporal cortexes and in the right caudate nucleus. The electroencephalogram showed slowing in the right hemisphere. Six weeks into the illness, startle myoclonus and fasciculations in the legs were noted for the first time, narrowing the differential diagnosis.
The differential diagnosis of dementia and myoclonic jerking is limited, and Creutzfeldt–Jakob disease is the probable diagnosis. Mild myoclonus may occur in Alzheimer's disease, but the disease does not follow the rapid course seen with this patient. Some inflammatory diseases can have symptoms such as cognitive decline and myoclonus — notably neurosyphilis and subacute sclerosing panencephalitis — but the results of the cerebrospinal fluid examination rule out these disorders. Postanoxic encephalopathy and adult lipid-storage diseases may have symptoms that combine dementia and myoclonus, but neither of these diseases is consistent with the history or progression of this case. I have seen two patients in consultation for increasing confusion and myoclonus in whom a tentative diagnosis of Creutzfeldt–Jakob disease proved wrong; one had Hashimoto's encephalopathy (and eventually recovered with corticosteroid treatment), and the other had bismuth intoxication (with recovery after withdrawal from massive doses of Pepto-Bismol). In these two patients, however, myoclonus and seizures occurred at the onset of disease; in Creutzfeldt–Jakob disease, the myoclonus tends to develop late in the course of disease, as in this patient, and seizures are rare.
Myoclonus not associated with dementia occurs in several forms of epilepsy and in some movement disorders. It may be a comfort to readers to know that hypnic jerks and myoclonic jerks during sleep are normal; they may increase in frequency with age and preoccupy the worried well — particularly medical students and physicians who have been reading about prion diseases.
In this patient, the dissolution of cognitive function over a few months in association with cerebellar ataxia, myoclonus, and fasciculations indicates a diagnosis of transmissible spongiform encephalopathy or prion disease.4 Making the diagnosis of Creutzfeldt–Jakob disease can be difficult early in the course of disease, as in this case.5 About one third of patients present with behavioral and cognitive changes; about one third present with systemic symptoms such as fatigue, disordered sleep, and decreased appetite. The final third present with focal neurologic symptoms or signs that can obfuscate the diagnosis, such as the insidious onset of muscle wasting with fasciculations that suggests amyotrophic lateral sclerosis, or the abrupt onset of a focal neurologic deficit that suggests a stroke. The patient under discussion had features of each of these types of onset, with confusion, fatigue and sleep disruption, and cerebellar ataxia in the first month of illness. As time passed, the inexorable dementia and the development of myoclonic jerking, particularly startle myoclonus, clarified the diagnosis.
Several studies may support the diagnosis of Creutzfeldt–Jakob disease, but each has limited sensitivity or specificity. An electroencephalogram showing biphasic or triphasic synchronized sharp-wave complexes, MRI with hyperintense signals in the basal ganglia on T2-weighted images, and the presence of 14-3-3 protein, a normal brain protein, in the cerebrospinal fluid are all highly suggestive of Creutzfeldt–Jakob disease.6 None of these studies supported the diagnosis in this case; but often repetition of these tests later in the course of the disease will yield a positive result.
Sporadic Creutzfeldt–Jakob disease has a worldwide incidence of 1 per 1 million population per year; there is no temporal or geographic clustering, no occupational risks, and a paucity of conjugal cases. Most observers now believe that a random protein misfolding or a somatic mutation in the gene coding for the prion protein leads to the disease.7 The disease is transmissible both in the laboratory and in the clinical setting — by corneal transplantation, dural grafts, injection of human growth hormone extracted from human pituitary glands, and improperly cleaned surgical instruments.8
In about 10 percent of cases, a mutation in the prion protein gene (PRNP) causes the disease; a dominant pattern of transmission is seen in the families of patients with such mutations, and different sites of mutations and polymorphisms lead to somewhat different phenotypes (Table 1). Two inheritable forms have distinctive syndromes: Gerstmann–Str?ussler–Scheinker disease, which is characterized by an onset of cerebellar ataxia, and fatal familial insomnia, which is characterized by progressive insomnia, dysautonomia, and dementia.9 This patient had both cerebellar ataxia and insomnia and did not know the cause of his mother's death. In typical cases of fatal familial insomnia, the patients are relatively young (between 36 and 62 years of age) and have a protracted course (8 to 72 months)10; the patient we are discussing was 80 years of age and died in less than 3 months. Autonomic dysfunction is prominent in fatal familial insomnia with hypertension, evening pyrexia, excessive perspiration, lacrimation, and salivation; this patient had bradycardia, transient hypertension, and fever, but autonomic dysfunction was not prominent.
Table 1. Classification of Creutzfeldt–Jakob Disease.
A few cases of sporadic fatal insomnia have been described.11 However, many patients with sporadic Creutzfeldt–Jakob disease have sleep disorders, particularly insomnia. The diagnosis has been based in part on polysomnography12 and in part on autopsy; the findings include the localization of neuron loss to the thalamus, particularly the anterior ventral and mediodorsal nuclei, and the olivary nuclei,13 similar to findings in the familial cases. Could this case qualify for a diagnosis of sporadic fatal insomnia? I would say no, unless we find out that the histopathological changes mimic those of familial fatal insomnia.
Another teaser is in the history: the patient had visited England during the period when exposure to bovine spongiform encephalopathy was maximal, but he is not reported to have received blood transfusions there. The variant form of Creutzfeldt–Jakob disease (vCJD) related to bovine spongiform encephalopathy has been seen in England since 1994, but patients have generally been young (mean age at onset, 29 years), have presented with dysesthesias and personality changes, with later evolution of cerebellar ataxia and dementia, and have had long survival (mean, 15 months).14 Unlike sporadic Creutzfeldt–Jakob disease, which does not appear transmissible through transfusion of blood products, the variant form does appear to be transmitted by transfusion, accounting for variant disease in an elderly man.15
In summary, I think this man had Creutzfeldt–Jakob disease. The late age at onset, the prominence of insomnia, and the fulminant course make this an atypical story, but I suspect we will find the characteristic spongiform pathological features of sporadic Creutzfeldt–Jakob disease.
I would like to add a historical footnote here: the first case of Creutzfeldt–Jakob disease presented in these Case Records was in 1961.16 As a fellow in neuropathology under Dr. Edward P. Richardson, Jr., I presented the pathological discussion. We, like many of our contemporaries, commented only on the neuronal loss and gliosis and disregarded the spongiform changes, which we dismissed as postmortem artifacts. Ironically, we overlooked the feature that has become the hallmark of this and other related diseases.
A Physician: Would you ever need to perform a biopsy, or is the clinical diagnosis sufficient?
Dr. Johnson: We perform biopsies on about 1 of 10 patients with symptoms suggestive of Creutzfeldt–Jakob disease. This diagnosis almost invariably starts as a mystery but within a few months becomes obvious. During that early period, biopsies may be indicated because of management considerations or social circumstances. Small cortical biopsies are quite easy and safe. However, because of fear of contracting the disease, the problem can be convincing the neurosurgeons to perform the biopsy and the pathologists to process it.
Dr. Nancy Lee Harris (Pathology): Dr. Ronan and Dr. Venna, could you tell us what your thoughts were as you cared for this patient?
Dr. Laurence J. Ronan (Internal Medicine): This was a remarkably high-functioning person, whom I had known for many years. His chief complaint to me was, "I lost my train of thought in a board meeting." I was thinking that at 80 years old, this was not surprising. But he grabbed me from behind and said, "You may think that's okay, but when I lose my train of thought, I lose millions of dollars. You find out what's wrong." Five weeks later he was in diapers, and very shortly thereafter he died. It was startling to watch him lose function daily. Initially, the diagnosis was not easy, but the neurologic team made the diagnosis very quickly.
Dr. Nagagopal Venna (Neurology): When I first examined the patient, neurologic symptoms were prominent, but the abnormalities on examination were slight and subtle. The clinical syndrome suggested an evolving subacute encephalopathy with a broad differential diagnosis. Dr. Ronan astutely suggested prion disease even at this stage, because of the patient's dramatic decline from his previous high level of functioning.
When I examined the patient a second time, his neurologic state had deteriorated markedly. This relentless course, combined with the results of the cerebrospinal fluid examination that did not reveal inflammation, made prion disease likely. We focused the investigation on three groups of diseases that mimic prion encephalopathy, especially those that are treatable: cerebral infections (Lyme disease, neurosyphilis, indolent herpes simplex encephalitis, and fungal meningoencephalitis), immune-mediated encephalopathies (paraneoplastic and nonparaneoplastic limbic encephalitis and Hashimoto's encephalitis), all of which are at least partially responsive to corticosteroids or intravenous immunoglobulin therapy, and metabolic and toxic causes, including bismuth and lithium intoxications, which can induce clinical syndromes with an uncanny resemblance to Creutzfeldt–Jakob disease.
In the final stage of the illness, the new neurologic deficits that appeared and accumulated almost daily, combined with the negative results of the other laboratory tests, made the diagnosis of prion disease inescapable. The case illustrated the value of the characteristic serial changes in the clinical picture that occur over a period of weeks in the diagnosis of prion disease, although making the diagnosis can be difficult at a single point in time.
Clinical Diagnosis
Creutzfeldt–Jakob disease.
Dr. Richard T. Johnson's Diagnosis
Creutzfeldt–Jakob disease.
Pathological Discussion
Dr. Matthew P. Frosch: The brain was normal in weight, with no signs of atrophy, and there was a 1.5-cm lacunar infarct in the left caudate. Tissue samples were frozen at –80°C; all tissue blocks were processed through formic acid to eliminate infective prions from tissue sections while still allowing for histologic diagnosis.17
The cerebral cortex showed widespread but patchy spongiform changes (Figure 2A), most prominent in the deep cortical layers; the vacuoles arose within neuronal cell bodies and dendrites (Figure 2A, inset). Spongiform changes were diffusely present in the striatum (Figure 2B) and in the cerebellar cortex (Figure 2C). These features are diagnostic of prion disease (transmissible spongiform encephalopathy and Creutzfeldt–Jakob disease). The hallmarks of fatal familial insomnia and fatal sporadic insomnia — severe neuronal loss and gliosis in the thalamus and the inferior olivary nucleus — were absent, excluding these two entities.11,12,18 A reexamination of the 1961 case with which Dr. Johnson made his debut in this forum revealed that the cerebral cortex did show mild spongiform changes (Figure 1 of Supplementary Appendix, available with the full text of this article at www.nejm.org).
Figure 2. Photomicrographs of the Brain.
The cerebral cortex (Panel A) has widespread spongiform changes. Neuronal cell bodies (Panel A, inset) contain vacuoles. The striatum (Panel B) has prominent spongiform changes involving the gray matter, with sparing of the white-matter bundles; the contrast between the intact white matter and the spongiotic gray matter increases a pathologist's confidence when making the diagnosis on the basis of a stereotactic biopsy that these vacuoles do not represent artifact. The cerebellum (Panel C) has prominent spongiform changes involving the molecular layer. Immunostaining of the cerebellum for PrP (Panel D) shows granular staining in the molecular and granular-cell layers. A section of cerebral cortex from a case of variant Creutzfeldt–Jakob disease (vCJD) (Panel E) shows more localized spongiform changes than those seen in classic Creutzfeldt–Jakob disease. A plaque of PrP-amyloid (Panel E, inset) is located in the center of an area of spongiform change. Immunostaining of vCJD for PrP (Panel F and inset) shows localization of the staining to the amyloid plaque. (Panel A, Panel B, and Panel C are stained with Luxol fast blue hematoxylin and eosin, Panel E and inset with hematoxylin and eosin, and Panel D and Panel F and inset with immunoperoxidase stain for PrP, courtesy of Dr. Pierluigi Gambetti, National Prion Disease Pathology Surveillance Center.)
Samples of brain tissue were sent to the National Prion Disease Pathology Surveillance Center, directed by Dr. Pierluigi Gambetti (www.cjdsurveillance.com/), as is done for all suspected cases of prion disease in our institution. The immunohistochemical and biochemical studies performed there that support the histologic diagnosis are based on the differences between the normal cellular form of the prion protein (PrPC) and the pathologic form of the protein (PrPSc). The fixed tissue was treated to eliminate PrPC and stained with use of immunohistochemistry for PrP; positive immunoreactivity was observed in cerebellum (Figure 2D) and cerebral cortex, indicating the presence of PrPSc and thus confirming the diagnosis of Creutzfeldt–Jakob disease.
Because of this patient's history of travel to England, the question of whether or not his condition represented vCJD could theoretically arise.19 Neuropathologically, vCJD cases differ from the classic type of Creutzfeldt–Jakob disease in the finding of florid plaques20 (Figure 2E), which have a dense core and a surrounding rim of delicate fibrils, both of which contain PrPSc (Figure 2F). The plaques are numerous in the cerebral cortex, tend to cluster, and often form the centers of localized areas of prominent spongiform change — quite different from the findings in this case.
In order to characterize further the type of prion disease, Western blotting for the presence of PrP was performed. Although PrPC is completely digested by proteinase K, PrPSc is partially resistant, with cleavage occurring at either of two positions — roughly 82 or 97 amino acids from the N-terminal (Figure 3) — depending on the conformation of the PrPSc molecules. Western blotting of brain homogenates from this patient revealed type 1 PrPSc (Figure 4). Standard forms of Creutzfeldt–Jakob disease can also be associated with type 2 PrPSc, with a shorter protein backbone. In vCJD, the type 2 PrPSc is found with an overabundance of diglycosylated forms.
Figure 3. The Structure of the Prion Protein (PrPC).
After synthesis of the protein, maturation involves removal of the signal peptide sequence at the N-terminal as well as removal of the C-terminal for attachment of the glycosylphosphatidylinositol (GPI) anchor (black). Also indicated in this model is the region of octapeptide repeats (blue) and the alpha-helical domains (red). The residues involved in the intramolecular disulfide bridge (S–S) are shown, as well as the two locations for N-glycosylation (N). The polymorphic codon 129, which may be either methionine (M) or valine (V), is indicated. When PrP takes up the pathologic conformation (PrPSc), the alpha-helical domains change conformation and the protein acquires the property of partial resistance to digestion with proteinase K. The two arrows indicate the approximate points at which the proteinase K clips the molecule (type 1 PrPSc is associated with the cleavage site and a larger fragment).
Figure 4. Western Blotting of Tissue Homogenates for PrP.
Tissue from the patient and controls is shown as follows: lane 1, occipital cortex; lane 2, reference case, type 1 PrPSc; lane 3, reference case, type 2 PrPSc; lanes 4,5, and frontal cortex; lanes 7 and 8, cerebellum. Lanes 1, 2, 3, 5, 6, and 8 were digested with proteinase K before loading onto the gel. The higher molecular weight bands reflect the presence of mono- and di- N–linked glycosylation of PrP. The PrPSc in these homogenates has more glycosylated than diglycosylated forms. These data provide additional support for the diagnosis of prion disease.
This autopsy was limited to the brain; therefore other tissues could not be examined for the presence of PrPSc. In cases of vCJD, but not other forms of prion disease, the accumulation of PrPSc in lymphoid tissue has been observed,21 possibly before the development of neurologic disease.22
Sequencing of the PRNP gene showed no mutations, ruling out the diagnosis of familial Creutzfeldt–Jakob disease; the patient was homozygous at codon 129 for methionine, which is the genotype that is associated with an increased risk of sporadic Creutzfeldt–Jakob disease and has also been observed in all cases of vCJD to date. Six different combinations of the codon 129 polymorphisms and the molecular types of PrPSc have been described in cases of sporadic Creutzfeldt–Jakob disease, with some correlations with clinical and neuropathological patterns of disease.23,24 The final neuropathological and molecular diagnosis in this case is prion disease (sporadic Creutzfeldt–Jakob disease with MM1 ) PrPSc. This is the most common type, with the typical symptoms of Creutzfeldt–Jakob disease and distribution of pathological findings.
To date, all of the cases of both classic and variant Creutzfeldt–Jakob disease have been in patients who were homozygous for methionine at codon 12925; whether this implies an absolute protection for persons with other genotypes at this site or simply a difference in incubation time remains to be seen.26
Dr. Lloyd Axelrod (Internal Medicine): What is the neuropathological basis for the fasciculations in this patient?
Dr. Frosch: Spongiform changes may be seen in the spinal cord gray matter, with neuronal loss from the anterior horns; however, the spinal cord was not examined in this case.
Anatomical Diagnosis
Prion disease (sporadic Creutzfeldt–Jakob disease with MM1) PrPSc.
Dr. Johnson reports having served on the Cephalon Medical advisory board and having equity ownership in Cephalon; he reports serving as a consultant for Millennium.
Source Information
From the Department of Neurology, Microbiology, and Neuroscience, Johns Hopkins University School of Medicine and Bloomberg School of Public Health, Baltimore (R.T.J.); the Departments of Radiology (R.G.G.) and Pathology (M.P.F.), Massachusetts General Hospital, Boston; and the Departments of Radiology (R.G.G.) and Pathology (M.P.F.), Harvard Medical School, Boston.
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