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Fall 1998, Vol.5, No.2
NEUROLOGICAL CASE PRESENTATION CONFERENCE (CPC) APRIL 1998 Case presented by: Gerard Dynes M.D. Case Presentation A 55-year-old man presented with lack of coordination, ataxia, diplopia and excessive salivation. The patient had been well until the fall of 1995, when he began to experience slowness with activities and a lack of coordination with tasks like buttoning his buttons. He noticed a deterioration in his handwriting. He had difficulty getting out of bed, and over several months his balance had deteriorated so that he needed a cane to walk and was unable to sit at a table without supporting himself with his hand. He noted excessive salivation without dysphagia. Rarely, he noted horizontal diplopia while watching television. He denied orthostatic symptoms, bladder or bowel dysfunction, but was impotent since presentation. There was no reported history of seizures, weakness, hearing loss, fever or night sweats, arthritis or gastrointestinal symptoms. He denied memory difficulties, but his family had noted forgetfulness. He was seen at another institution in November of 1995, shortly after he stopped working as a school custodian because of his symptoms. His neurological examination there was notable for slurred speech, mild dysmetria, dysdiadochokinesis, a wide-based unsteady gait and difficulty performing tandem gait. The complete blood count (CBC), routine chemistries, urinalysis, liver and thyroid function tests were all normal. His spinal fluid was acellular with a normal glucose of 67 mg/dl and a mildly elevated protein of 56 mg/dl. Cerebrospinal fluid (CSF) bacterial, fungal and acid-fast bacillus (AFB) cultures and cytology were negative, and the CSF Venereal Disease Research Laboratory test result (VDRL) was nonreactive. CSF immunoglobulin and myelin-basic protein were normal. Magnetic resonance imaging (MRI) of the brain, dated November 28, 1995, showed generalized atrophy of the cerebral hemispheres, brain stem and cerebellum that was greater than expected for his age. Electroencephalogram (EEG) in November 1995 was normal. Computerized tomography (CT) scan of the chest showed a small non-significant right lung nodule, and CT of the abdomen was normal. The patient's prior medical history was significant only for glaucoma of two years duration and a spontaneous pneumothorax. In 1981 he had undergone lobectomy for lung blebs and had required transfusions. He had a prior 22-pack-year smoking history, but had stopped smoking in 1983. He had been a heavy beer drinker until the early 1980s. Current medications included oral buspirone and timolol eye drops. His family history was negative for Parkinsonism, ataxia or other neurological disease. His father had bilateral optic nerve damage attributed to a fall. Both of his parents died of cancer and a brother had throat cancer. The patient was unmarried, had no children, and lived with family on Long Island. The patient was first evaluated at Columbia-Presbyterian Medical Center in January of 1996. Examination revealed a blood pressure of 140/82 mmHg without orthostasis. The heart rate was regular at 72 beats per minute, temperature was 98.8°F, and his weight was 148 lbs. There were no Kaiser Fleischer rings, goiter, heart murmur or organomegaly. He was alert with slow, hypophonic, dysarthric speech. There was no voice tremor. The patient's responses were slow, but language function was normal. He was disoriented to date, had difficulty with serial sevens, knew two out of five of the most recent U.S. presidents and remembered three out of three objects after five minutes only with prompting. A Modified Mini Mental Status Examination score was 37 out of 57. His pupils were equal, round, and reactive to light. Visual fields were full. Extraocular movements were full with jerky pursuits. There were no square wave jerks. There was facial hypomimia with decreased blink. He had normal facial sensation and strength. Hearing was also normal. The patient had increased saliva and a weak cough. A tongue tremor was noted along with slow tongue movements. On motor examination, the tone and strength were normal, but the patient was bradykinetic throughout. Sensation was normal to all modalities. Generalized clumsiness was noted with slight dysmetria on finger-nose-finger testing. There was no tremor, myoclonus or chorea noted. He could not arise from a chair without using his arms. Stance was wide-based with a tendency to retropulse. He had a wide-based, awkward, lurching gait. He could barely perform tandem gait and the pull test was positive. Deep tendon reflexes were normal and Babinski signs were absent bilaterally. Serum anti-Hu and anti-Yo antibodies were negative. A Vitamin B12 level was normal. A repeat MRI of the brain was unchanged. MRI of the thorax to evaluate the reported small nodule on chest CT was normal. Thyroid function tests were normal; anti-microsomal and anti-thyroglobulin antibodies were negative. On April 1, 1996, a fluoro-deoxyglucose (FDG) positron emission tomography (PET) scan revealed preserved FDG uptake in the lentiform nuclei, brain stem and cerebellum, but patchily decreased uptake in the right thalamus and bilaterally in the frontal and opercular cortices. EEG showed generalized slowing without discharges. At a follow-up visit in April of 1996, the patient had worsened. He had new complaints of worsening gait, falls, increased forgetfulness and difficulty sleeping. On examination, cognition had declined and a Modified Mini Mental Status Examination score was 34 out of 57. He had worsened dysarthria, generalized ataxia, titubation, and a lurching, wide-based gait. By August of 1996, the patient's mental status had deteriorated so that he required nursing home care. He displayed confusion, tearfulness, and tendencies to wander and expose himself. He was noted to be cachectic and his weight was 111 pounds. He had significant dysarthria, drooling and difficulty swallowing. By November of 1996, repeat MRI with gadolinium was unchanged and four-vessel angiography of the head was normal. He had an open-cerebellar biopsy that was normal. Repeat CSF testing was reported as normal. The spinal fluid was examined for 14-3-3 protein (abnormal in Creutzfeld-Jakob Disease, CJD) but this was negative. Repeat EEG demonstrated only generalized slowing. The patient died in early February 1997, 18 months after the onset of illness. An autopsy was performed. Differential Diagnosis Dr. Elan Louis: I would like to focus initially on the natural history, the neurological signs themselves, and the family history. The most striking feature of this case was the time course. The time interval between the onset of symptoms and death was only 18 months. The patient first presented in August of 1995 with slurred speech and died in February of 1997. In terms of the neurological signs, we were told that there were cerebellar signs, dementia and Parkinsonism (predominantly bradykinesia). In terms of cerebellar signs, the following descriptors were used: dysmetria on finger-to-nose testing, wide-based stance, lurching gait, "could barely tandem", titubation, dysarthria and dysdiadochokinesis. In terms of dementia, we were told that the patient's score on a Modified Mini Mental Status Examination initially was 37 out of 57, and that the patient was wandering and exposing himself, requiring nursing home placement due to his dementia towards the end of his life. In terms of the Parkinsonism, again, there was no mention of rigidity or tremor. In fact, we were told that his tone was normal. But there were multiple descriptors of bradykinesia, including hypophonia, masked facies, decreased blink, bradykinetic motor examination and drooling. While we are on the topic of "bradykinesia", I would like to make a few brief comments as an aside. One of the truths that I learned from Dr. Lewis Rowland when I was a resident was that many terms have been used to describe problems with the cerebellum, including "ataxia", "dysmetria", "dysdiadochokinesis", "overshoot", "absence of check", "titubation", "unsteadiness", and "incoordination." In reality, these various terms are all used to describe the same phenomenology, namely a problem with the force and timing of motion. In fact, one could simply use the term "ataxia" rather than all of these cumbersome terms. The converse situation exists in terms of our terminology for bradykinesia. In fact, there are many extrapyramidal phenomena for which we use to term "bradykinesia", and as a result, valuable clinical information is lost. For example, decreased spontaneous movement is referred to as "bradykinesia", as is slow movement, decreasing amplitude during rapid alternating movements (RAMs), pauses during RAMs, and the stickiness of RAMs typically seen in Parkinsonism. In general, it would be more useful to avoid using the term "bradykinesia", but rather, to use more detailed and descriptive terms. In terms of the family history, it is important to note that this was negative. This excludes several diagnostic possibilities. In summary, we should be considering the differential diagnosis of an adult-onset, rapidly-progressive and fulminant, cerebellar, extrapyramidal dementing illness. The differential diagnosis includes CJD, familial fatal insomnia (FFI), thalamic degeneration, paraneoplastic disorders, Whipple's disease, subacute sclerosing panencephalitis (SSPE), Alzheimer's disease and Wernicke-Korsakoff's syndrome. I have organized these diagnoses in such a way so that we can see whether they are (1) rapidly progressive, and whether they (2) present with cerebellar signs (3) extrapyramidal signs or (4) dementia. Most of these disorders are rapidly progressive, if not always then at least sometimes. To be included in this differential list, at least three of the above four features had to be present. Therefore, I did not include diagnostic entities such as Parkinson's disease. I will begin by discussing CJD. Our patient's illness progressed over an 18-month period and ended in death. What is the typical time course of CJD? One study (Tsuji et al.) examined 38 Japanese patients, all of whom had pathologically-verified CJD, and noted that the mean disease duration was 16.6 months. They also noted that the age of onset was positively associated with the duration of illness. According to these authors, in their subjects who were between the ages of 51 and 55 years (which is the age of our patient at the time of his onset), the duration of illness was 19-24 months, similar to that of our patient. Will et al. studied 162 British CJD patients, the majority (121) of them with pathologically confirmed CJD, and noted that the duration was bimodally distributed, with a subacute group having a mean duration of 5.5 months, and an intermediate group with a mean duration of 33.4 months. Finally, Brown et al. studied a group of 230 French patients, all with pathologically-confirmed CJD, and noted that the mean duration of illness was only 7.6 months, but the standard deviation was wide (12.4 years). In summary, I think that our patient's illness had a time course that was consistent with these reports. Our patient had cerebellar signs, bradykinesia and dementia. How prevalent are these signs in CJD? When we consult the three referenced studies from Japan, England and France, we find that cerebellar signs are present in approximately one-half of the reported patients, ranging from 42% to 61%. In terms of Parkinsonism, 91% of the Japanese patients had "rigidity or tremor". It is not clear whether the term "rigidity" referred to paratonic rigidity, extrapyramidal rigidity or to spasticity. It is not clear whether the term "tremor" referred to rest tremor or action tremor. According to the study of Will, 3% of CJD patients had extrapyramidal features, rigidity, bradykinesia or tremor. According to Brown et al., 67% of CJD patients demonstrated rigidity, chorea or athetosis. In summary, between 3% and 91% of CJD patients demonstrated extrapyramidal features. Usually when there is this much of a discrepancy between study results, there is a lack of agreement in terms of the definitions and nomenclature. For example, it was not specified in these studies whether the term "rigidity" referred to mild forms of rigidity (for example a rating of +1 on the Unified Parkinson's Disease Rating Scale) or to more moderate or severe forms of rigidity. Further research is really needed at this time to examine the extrapyramidal features of CJD. Finally, according to our three references, dementia was present in almost all CJD patients (96-100%). We have more to discuss in terms of CJD. In our case, the characteristic periodic complexes were not observed during any of the three EEGs. These EEGs were performed early in the course, midway through the illness, and towards the end of the illness at 15 months. What is the sensitivity of EEG in CJD? In other words, of all the cases of pathologically confirmed CJD, what percentage will have periodic EEG activity? One interesting paper by Chiafolo studied 27 cases of CJD, the majority of them (23) pathologically confirmed and the remaining cases reporting a positive family history. These authors reported the percentage of cases with periodic EEG activity during different phases of the illness, including the prodromal phase, during a phase when the disease was fully developed, and during the terminal phase of illness. In the prodromal phase, 67% of cases either did not demonstrate periodic EEG activity or the presence of this activity was doubtful. Even during the fully developed phase of illness, 6% of cases did not demonstrate periodic EEG activity. In the terminal phase, 22% of cases either did not demonstrate periodic EEG activity or the presence of this activity was doubtful. Brown and colleagues noted that periodic EEG activity was present in only 56% of CJD patients; however, these authors did not report serial EEG results. Will and colleagues, dividing patients into those with subacute versus intermediate duration of illness, noted that 107 out of 127 (84%) in the subacute group developed periodic EEG activity. Interestingly, in the intermediate group, only 22% demonstrated periodic EEG activity. Myoclonus is supposed to be an important diagnostic feature in CJD, but it was not present in our patient. What is the prevalence of myoclonus in CJD? The prevalence ranges between 73% and 93%. Interestingly, in Will's intermediate group, as few as 73% of the patients demonstrated myoclonus. The 14-3-3 protein, characteristic of CJD, was not detected in the CSF of our patient. What is the sensitivity of this biological marker? There is a study by Hsich et al. that examined the results from 34 patients with pathologically confirmed CJD, and found that this marker was present in the CSF of 91% of those patients. These authors also included results from an additional 37 patients with clinically rather than pathologically- diagnosed CJ; hence, there were a total of 71 cases in this combined group. They reported that 68 of 71 or 96% had this marker. 96%, however, is not 100%. Some false negatives existed. What is the biological meaning of this marker? I will quote directly from the paper by Hsich et al. "We don't know why the detection of the 14-3-3 protein in the CSF is a useful and specific biochemical marker for transmissible spongiform encephalopathy. The role of 14-3-3 in the pathophysiology of CJD has yet to be determined. This highly conserved protein is found in a broad range of species, including yeast, plants, insects and mammals, and has a wide variety of functions. In humans and other mammals, 14-3-3 is a normal neuronal protein, consisting of several isoforms, and it plays a part in the conformational stabilization of other proteins. Since misfolded prion proteins are the central feature of CJD, an intriguing additional interpretation for the presence of 14-3-3 is that the protein may be centrally involved in the molecular pathological features of transmissible spongiform encephalopathy. We believe that the presence of 14-3-3 in the CSF may be due to massive neuronal disruption and the leakage of brain proteins into the CSF." I would like to discuss the thalamic variant of CJD. Our patient had decreased uptake in the right thalamus on an FDG PET study. A thalamic form of CJD exists, although it is rare. Patients have dementia and ataxia and spongiform lesions are generally restricted to the thalamus, or at least are most severe in the region of the thalamus. Martin described a number of cases of thalamic CJD including a 50-year-old man with dementia, ataxia, myoclonus and chorea. Interestingly, there were no periodic complexes on EEG. The patient died after six months. At autopsy, there was extensive bilateral symmetrical degeneration of many thalamic nuclei with spongiform changes. This was the major pathological finding. Martin described several similar cases including a 56-year-old man with dementia, myoclonus and chorea who died after six months and who had the same pathological changes as case number one, and a 65-year-old man with dementia, ataxia and myoclonus who died after six months. I have several questions regarding the thalamic variant of CJD. In this form of CJD, is the EEG less likely to show periodic complexes due to the limited pathology (the pathology is limited to the thalamus and does not involve the cortex)? Secondly, is the 14-3-3 CSF marker less likely to be positive due to the limited extent of neuronal disruption (again, the pathology is limited to thalamic nuclei)? I could not find answers to these questions in the neurological literature. While I am discussing prion diseases and the thalamus, another diagnostic possibility includes FFI. This is a familial autosomal-dominant prion disease, characterized by severe insomnia, dysautonomia, and cerebellar signs but no dementia or Parkinsonism. The pathological changes occur in the thalamus. Our patient did not have a familial disorder, did not have severe insomnia, and did not have dysautonomia. So this is not likely to be the diagnosis. While we are on the topic of the thalamus, we should discuss the rare entity of pure non-spongiform thalamic degeneration. This comprises a hodgepodge of clinically dissimilar cases that demonstrate dementia and variably demonstrate either ataxia, pyramidal signs or Parkinsonism. They progress over a variable period of time, from nine months to 26 years. They are united by similar pathological changes, most predominant in, but not exclusive to, the thalamus. One of the understatements in the literature, made by Martin, who has written extensively on this disorder, is that "there is a very pressing need to improve the clinical knowledge of these cases." Paraneoplastic disorders are also within the differential diagnosis. Our patient died after an illness of 18 months duration. What is the typical time course of paraneoplastic disorders? Most patients with paraneoplastic cerebellar disorders progress at a similar subacute rate. However, rather than continuing to progress to death, many of the patients reported in the literature experience a prolonged plateau during which the disease may stabilize. So the mode of progression seen in our case is not typical for patients with paraneoplastic cerebellar disorders. In addition, our patient had cerebellar signs and prominent bradykinesia. Does Parkinsonism ever accompany paraneoplastic cerebellar disorders? Posner noted that 50% of patients with paraneoplastic cerebellar degeneration demonstrated signs and symptoms referable to other areas of the nervous system, including hyperreflexia, Babinski signs, and "extrapyramidal signs." While we are discussing paraneoplastic disorders, I should comment on the fact that the anti-Yo antibody result was negative. This patient, being a male, was less likely to have anti-Yo antibody. This antibody is associated with tumors of the ovary and breast in greater than 85% of the cases. The number of men with anti-Yo antibodies could probably be counted on one hand. This is important, because in Posner's comparison of paraneoplastic cerebellar degeneration with and without anti-Yo antibodies, those without these antibodies were more likely to present with other neurological features, such as extrapyramidal signs. Our patient, however, not only had mild bradykinesia, but the bradykinesia was very prominent. My question remains, can Parkinsonism accompany paraneoplastic cerebellar disorders? There is one study by Golbe, reporting a 42-year-old woman with infiltrating ductal carcinoma of the breast. Her signs included prominent Parkinsonism, dystonia with possible cerebellar signs and minimal ataxia. The patient died after an illness of four months duration. However, Golbe's case was not a typical case of a paraneoplastic cerebellar disorder by any means. There were no anti-Purkinje cell antibodies. Also, there were pathological changes in the globus pallidus and substantia nigra. I think we can conclude that while paraneoplastic cerebellar disorder may present with prominent Parkinsonism, that this is obviously exceptionally rare. I would like to make one more comment about paraneoplastic disorders. Our patient did not have anti-Yo or anti-Hu antibodies, and a tumor was never discovered. Could the diagnosis still have been a paraneoplastic cerebellar disorder? I think we all know that in many patients with paraneoplastic disorders, no antibody or tumor is ever discovered. The next diagnostic entity is Whipple's disease. This patient had cerebellar signs and dementia. What are the clinical features of Whipple's disease? In a study published in Annals of Neurology, we studied 84 cases of CNS Whipple's disease. Cognitive changes were noted in 71% of patients. Ataxia, however, was only present in one of five, and while Parkinsonism may occur, but it is extremely rare and I don't recall a case in which the Parkinsonism was as prominent as in our case. SSPE is in the differential diagnosis as well. Again, our patient had rapidly progressive cerebellar signs, Parkinsonism and dementia. What are the clinical features of adult-onset SSPE? We all know that childhood-onset SSPE begins as a form of chronic measles encephalitis, and that the patient presents with personality changes and declining school performance, eventually resulting in a chronic vegetative state. The adult-onset form is somewhat different. Singer and Lang reviewed the clinical features of 13 cases of adult-onset SSPE. The age of onset (20 - 35 years) was relatively young, much younger than in our patient. The time course from the onset of symptoms until death was usually between one and two years. Only one-half of their cases had Parkinsonism, few had cerebellar signs, and only about one-half had dementia. This is also an extremely rare disorder. Wernicke-Korsakoff's syndrome is a diagnostic possibility as well. What is the time course of untreated Wernicke-Korsakoff's syndrome? In Victor's book on Wernicke-Korsakoff's syndrome, 37 deaths occurred in the acute stage of the illness. But these really occurred very acutely, from 1 to 24 days after the onset of illness, with a mean of only 8 days. This time course is far more acute than that of our patient. Victor noted that there were 56 other deaths during what he referred to as the chronic stage of the illness, many months to many years after the onset of illness, with a mean of 3.2 years. In this group, the patients died not as a result of the neurological manifestations, but due to liver failure, cancer and overwhelming infections. Therefore, I do not think that the time course seen in Wernicke-Korsakoff's syndrome really fits with what our patient had. However, I would like to examine some of the clinical features of Wernicke-Korsakoff's syndrome. Harper reported eye motion abnormalities in only 29% of patients. This did not include nystagmus, which would have increased the proportion with eye findings considerably. Ataxia was present in only 23% of cases, and cognitive changes in 82%. The classic triad of eye motion abnormalities, ataxia, and cognitive changes was present in only 10% of cases. Parkinsonism was present in none. In Victor's book, reporting 232 cases, 78% demonstrated eye motion abnormalities (not including nystagmus). Again, none had Parkinsonism. So to summarize, we may find reasons to exclude many of the diagnostic possibilities that I have discussed. Against FFI are the lack dysautonomia, insomnia, and family history. Against thalamic degeneration, are the time course and the Parkinsonism. Against paraneoplastic disorders are the prominence of dementia, the time course, the absence of an identifiable tumor or antibody, and the prominence of Parkinsonism. Against Whipple's disease are the prominence of the Parkinsonism and cerebellar signs, and the absence of any systemic signs such as arthritis or diarrhea. Against SSPE, other than its rarity, are the age of onset and the prominence of cerebellar findings. Against Alzheimer's disease, are the time course and the prominence of cerebellar findings. Against Wernicke-Korsakoff's syndrome are the absence of a history of alcohol abuse, the prominent Parkinsonism, and a course that was progressive, but not as rapidly progressive as in acute Wernicke-Korsakoff's syndrome. In addition, the classical cognitive findings (e.g., confabulation, poor short-term memory) were not present. Against CJD are the absence of myoclonus, the absence of periodic activity on EEG, and a normal 14-3-3 protein; however, we have seen that none of these is present in all cases of CJD. My final diagnosis is CJD, and possibly the thalamic variant of CJD because of the absence of periodic complexes on EEG, the absence of 14-3-3 protein, and the PET scan abnormality in the thalamus. References Bolla L, Palmer RM. Paraneoplastic cerebellar degeneration. Case report and literature review. Arch Intern Med 1997; 157:1258-1262. Brown P, Cathala F, Castaigne P, et al. Creuztfeldt-Jakob disease: clinical analysis of a consecutive series of 230 neuropathologically verified diseases. Ann Neurol 1986; 20:597-602. Bortone E, Bettoni L, Giorgi C, et al. Reliability of EEG in the diagnosis of Creuztfeldt-Jakob disease. Electroencephalogr Clin Neurophysiol 1994;90:323-300. Chiolfalo N, Fuentes A, Galvez S. Serial EEG findings in 27 cases of Creuztfeldt-Jakob disease. Arch Neurol 1980;37:143-145. Dalmau J, Posner JB. Neurological paraneoplastic antibodies (anti-Yo; anti-Hu; anti-Ri). Neurology 1994;44:2241-2246. Gallassi R, Morreale A, Montagna P, et al. "Fatal familial insomnia":neuropsychological study of a disease with thalamic degeneration. Cortex 1992;28:175-187. Golbe LI, Miller DC, Duvoisin RC. Paraneoplastic degeneration of the substantia nigra with dystonia and parkinsonism. Mov Disord 1989;4:147-152. Harper CG, Giles M, Finlay-Jones R. Clinical signs in the Wernicke-Korsakoff complex: a retrospective analysis of 131 cases diagnosed at necropsy. JNNP 1986;49:341-345. Hsich G, Kenney K, Gibbs CJ, et al. The 14-3-3 brain protein in cerebrospinal fluid as a marker for transmissible spongiform encephalopathies. N Engl J Med1996;335:924-930. Kornfeld M, Seelinger DF. Pure thalamic dementia with a single focus of spongiform change in the cerebral cortex. Clin Neuropathol 1994;13:77-81. Louis ED, Lynch T, Kaufmann P, et al. Diagnostic guidelines in central nervous system Whipple's disease. Ann Neurol 1996; 40:561-568. Lugaresi E, Medori R, Montagna P, et al. Fatal familial insomnia and dysautonomia with selective degeneration of the thalamic nuclei. N Engl J Med 1986;315:997-1003. Martin JJ. Thalamic degenerations. In: Handbook of Clinical Neurology, 1985:Chapter 33. Martin JJ, Yap M, Nei IP, et al. Selective thalamic degenerationreport of a case with memory and mental disturbances. Clin Neuropathol 1983;2:156-162. Mizusawa H, Ohkoshi N, Sasaki H, et al. Degeneration of the thalamus and inferior olives associated with spongiform encephalopathy of the cerebral cortex. Clin Neuropathol 1988;7:81-86. Pilz P, Erhart P. Thalamic degeneration. Acta Neuropathol Suppl (Berl) 1981;7:362-364. Posner JB. Paraneoplastic cerebellar degeneration. Can J Neurol Sci 1993;20 (Suppl 3):S117-122. Rosenmann H, Meiner Z, Kahana E, et al. Detection of 14-3-3 protein in the CSF of genetic Creuztfeldt-Jakob disease. Neurology 1997;49:593-595. Singer C, Lang AE, Suchowersky O. Adult-onset subacute sclerosing panencephalitis: case reports and review of the literature. Mov Disord 1997;12:342-353. Tsuji S, Kuroiwa Y. Creuztfeldt-Jacob disease in Japan. Neurology 1983;33:1503-1506. Victor M, Adams RD, Collins GH. The Wernicke-Korsakoff syndrome and related neurological disorders due to alcoholism and malnutrition. 2nd Ed. Philadelphia: FA Davis Company, 1971. Will RG, Matthews WB. A retrospective study of Creuztfeldt-Jakob disease in England and Wales 1970-1979 I: clinical features. JNNP 1984;47:134-140. CASE OC97-636
Gross examination:
Figure 1. Text-gross examination of brain. Note: All figures of histological sections are formalin-fixed, paraffin-processed and stained with hematoxylin-eosin. Pathology Discussion
I'll start with the pathology of the cerebellum. There was a brain biopsy that was done at an outside hospital, and the specimen was also sent to Massachusetts General Hospital for consultation. Both hospitals agreed that there was no evidence of prion disease. I'm not sure if any biochemistry was done, so I assume the analysis was just morphological.
The medulla showed remarkable degeneration of the inferior olivary nucleus. Fig. 5 shows a low-magnification view of the inferior olivary nucleus. Only a few surviving neurons are seen in this field. In the normal inferior olivary nucleus we would have an almost double row of large neurons following the serpiginous outline of this nucleus. What we see here is a relatively hypercellular nucleus, with much of the cellular composition made up of glial cells – mostly reactive astrocytes (Fig. 6). This tremendous gliosis is seen both in the white matter and in the gray matter portions of the inferior olivary nucleus. The thalamus is the major site of pathology. Fig. 7 and 8 respectively show a low- and high magnification view of the thalamus in the region of the dorsal medial nucleus. A single surviving neuron is present in the
The low-magnification view of the middle frontal gyrus [Fig. 11] is pretty bland. Some minor vacuoles, spongiform change if you want to call it that, is present. The severity is very mild and not enough to make a definitive diagnosis. Figures 12 and 13 are additional views at increasingly higher magnifications. Again, artifactual vacuolar spaces, especially around blood vessels and neuronal cells are also present. Some of the vacuoles appear to be clustered against the background neuropil and are very suspicious. The occipital and parietal lobes are largely unaffected, but the superior temporal gyrus shows some more of this type of vacuolar change (Fig. 14, 15, 16). The clustering of the vacuoles seen in Fig. 16 is highly suspicious for a spongiform encephalopathy. Figure 17 summarizes the microscopic findings in this case. Since the histopathological findings were suggestive of a prion disease we performed immunohistochemical staining with three different antibodies on all of the sampled cortical regions. All of the staining came out negative. But we know that immunohistochemistry for prion disease is relatively insensitive. MICROSCOPIC EXAMINATION:
Thalamus
Inferior olivary nucleus
Cerebellum
Figure 18. Text-summary of microscopic findings.
Figure 18. Western blot analysis for protease K-resistant prion protein. Lanes 1, 2 and 3 represent brain tissue samples from the case. Lane 4 is a positive control from a patient with sporadic CJD. The starting material was the same for all lanes. Lanes 1 and 2 show the characteristic profile of proteinase K-resistant prion protein in samples of frontal cortex and thalamus. The gold standard for CJD is still Western blot analysis of brain tissue. We sent frozen autopsy material from this case to the laboratory of Dr. Pierluigi Gambetti at Case Western Reserve Medical School for Western blot analysis. Figure 18 shows their results. The first three lanes represent material from our patient that has been treated with proteinase K, run on SDS-PAGE, and immunoreacted with an antibody directed against prion protein. Lane 1 is material from the frontal cortex, 2 is from the thalamus, and 3 is from the cerebellum. The fourth lane is of a sporadic CJD positive control. The amount of material loaded on each of the four lanes is about the same. A pattern of three characteristic bands is evident. The control lane appears to be overloaded (or overexposed) relative to the other three samples. In the most common form of sporadic CJD the bottom is seen at 21KD. The two upper bands are glycosylated forms of the protein. In our patient, we see the presence of protease K-resistant prion protein in the frontal cortex and in the thalamus. In the cerebellum, interestingly, there was no detectable protein, and that could account for the negative biopsy results. Interestingly, the mobility of the unglycosylated prion protein in this case is slightly different, and the Case Western laboratory classified this as a Type 2 mobility pattern. This pattern is seen in a small percentage of CJD cases, but also in prion diseases like fatal familial insomnia (FFI). Figure 19 shows some of the Western blot characteristics of the Type 1 and Type 2 prion protein. Type 1 has its fastest running band at 21 KD, whereas the Type 2 has the 19KD fingerprint. The results of the histopathology in this case are actually highly suggestive of FFI, because of the remarkable atrophy of the thalamus, the involvement of the inferior olivary nucleus, and of the cerebellum. The histopathological features of FFI are listed in Figure 20. In our case, the striatum was not involved. If this patient did have FFI, we would want to know if this patient had a mutation, and we would be looking for an aspartic acid to asparagine substitution at codon 178. In addition, on the same allele as the mutation, we would expect to have a methionine polymorphism at codon129, which would express as a FFI phenotype. A valine at codon129, in combination with the 178 mutation, would express as a familial CJD phenotype (Figure 21). Our patient did not have the 178 mutation. And so the proposed diagnosis is a thalamic form of Creutzfeldt-Jakob disease (Fig. 22). There appears to be a lot of confusion about classification and whether the thalamic form of CJD and primary thalamic degenerations are really different. The group at Case Western has come to the consensus that all these cases represent a form of prion disease that they call either the thalamic form of sporadic CJD, or a sporadic form of fatal insomnia fatal sporadic insomnia.
Histopathological hallmarks of FFI
anterior ventral nucleus mediodorsal nucleus
Figure 20. Texthistopathological hallmarks of fatal familial insomnia. D178N cis-129M ---------------FFI D178N cis-129V ---------------CJD Figure 21. TextPatients with an aspartic acid to asparagine mutation at codon 178 of the prion protein gene have familial prion disease. The clinical phenotype, however, appears to be dependent on the particular polymorphism present in codon 129. Methionine at this position results in a FFI phenotype while valine results in a CJD phenotype. Diagnosis: Sporadic form of fatal insomnia Figure 22. Text-final diagnosis.
[QUESTION OFF-MIKE] [QUESTION OFF-MIKE] QUESTIONER #2: Maybe I should explain why I asked the question. Because 50% of the normal population is homozygous at that codon, but over 90% of the patients who have acquired CJD are sporadic CJD. [QUESTIONER #3]: I have a problem here, because unless one has access to a PET scan, I'm beginning to wonder how one can make the localization of a thalamic disorder when a patient has either an early memory disturbance, sensory findings, or even eye findings. I wonder if any of the persons who saw this patient thought, from a clinical standpoint, that they were hearing things. Dr. Fetell: I was the first neurologist to see the patient. And the two leading diagnoses that we considered were paraneoplastic cerebellar degeneration and CJD, and more specifically, an ataxic form of CJD. After I saw the patient he was seen by Dr. Roy Jones at the Lahey Clinic. He didn't have a copy of my report, and the family wanted a completely blind second opinion. When he finished his assessment, we both came to the conclusion that he probably had CJD. Dr. Jones had written a paper about diagnosing ataxic CJD by doing a cerebellar biopsy. A cerebellar biopsy specimen was sent to the Massachusetts General Hospital. It was negative. The patient was seen by Dr. Blair Ford in the movement disorder group here. Everybody agreed that the patient seemed to have a slow viral disease, but we were so puzzled. You know, in retrospect, so much of his clinical symptomatology was both cognitive and ataxic. Ataxia was far and away the most prominent sign. I know Dr. Louis spent a lot of time talking about the Parkinsonism. Maybe he developed that later. Initially, he didn't show much in the way of extrapyramidal signs. And it seemed to be a very difficult diagnosis to make. Three clinicians who saw him all agreed that CJD had to be the diagnosis, although we couldn't prove it. The ataxia was very prominent from the outset, and yet you're saying that the biopsy in November of '96 was normal. Then three months later when he died, he had a severe wipeout of Purkinje cells. Has somebody gone back to look at that biopsy? Pathologist: I have not had the opportunity to review the original slides, nor see the original report. The biopsy focus, as I understand it, was to look for spongiform change. And I'm not sure why they didn't do a Western blot analysis. [Dr Fetell?]: Of course, you have to look at the Purkinje cell layer. I find it hard to believe that was a normal biopsy. Pathologist: I would suspect the number of Purkinje cells on the biopsy was probably abnormal, but seeing loss of Purkinje cells on a biopsy is non-specific and you could not make a diagnosis of prion disease just with this change alone. [QUESTIONER OFF-MIKE] : Well non-specific, sure, but not negative. I think that's very misleading. I don't believe it was negative, and I think you ought to take a look at it and see, because that would be simply extraordinary. [QUESTIONER OFF-MIKE]: I don't think thalamic lesions cause cerebellar ataxia. In fact you can improve cerebellar ataxia with lesions in the VDL. I think this guy had a lot of cerebellar degeneration in the early points in the course, and the pathologist missed it. [UNINTEL QUESTION OFF-MIKE]:
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