In this report, we present 4 cases referred to the neurology department of Uludağ University with neurological symptoms. Patients were evaluated with electroencephalogram and magnetic resonance imaging, and performed brain biopsies for further investigation. For definitive diagnosis of Creutzfeldt-Jakob disease, accumulation of prion protein in brain was detected immunohistochemically. Patients died within weeks in consequence of rapid progression of the disease.
Although Creutzfeldt-Jakob disease is an infrequent disorder, when a patient presents with characteristic clinical symptoms such as rapidly progressive dementia with myoclonus, the diagnosis of Creutzfeldt-Jakob disease should be taken into consideration.
Although, it is usually sporadic, it has a familial pattern in about 10–12% of the cases, presenting as an autosomal dominant inheritance[2]. It is recognized as a dominantly contagious or communicable disease, but it is of special importance because it is inevitably fatal and has been iatrogenically transmitted to patients and possibly to medical staff as well. Here we report 4 cases of sporadic CJD which were proven by brain biopsies histopathologically.
Case 2
A seventy-five year old woman presented to the neurology
department of our institute with deterioration of general
health status and stupor. Her first complaint was dizziness
that had started 6 months ago. She was diagnosed as
Parkinson’s disease and dementia in two different centers.
Meanwhile, rigidity of upper extremity, myoclonus in
arms and legs and hallucinations had occurred in a short
period. These symptoms were considered to indicate acute
dystonia due to the side effects of medications used for
dementia. She came to the emergency department with
loss of consciousness. Triphasic slow waves were seen
on EEG examination. MRI findings were interpreted as
hydrocephaly or changes of ischemia that were expected
due to her age. There were no infectious agents in the
CSF. Brain biopsy was performed to diagnose the disease.
The patient died because of cardiac arrest 2 weeks after
admission to our institute.
Case 3
A fifty-seven year old woman who suffered from
aggressiveness and lack of communication for 2 years had
heat intolerance and weight–loss without loss of appetite.
Emotional agitation, delirium and dementia developed
rapidly, and she was referred to our institute. EEG revealed
normal activity. Cranial MRI studies of the patient
performed one month after the onset of the dementia showed
strongly marked cerebral cortical sulcus, abnormal hyper–
intensities in the left nucleus lentiformis on T2–weighted
and FLAIR images. She also had fever that decreased with
amoxicillin–clavulanic acid administration. The blood tests
for the infectious diseases were negative. Brain biopsy was
performed to explain the hyper–intensities in the basal
ganglia. She experienced sudden respiratory insufficiency
and died one month after her hospitalization.
Case 4
A sixty-two year old woman had been suffering loss of
appetite, weakness and right upper quadrant pain for two
months. While she was investigated for her gastrointestinal
symptoms, she mentioned vertigo and hallucinations. 2
months after her first symptom, she had speech problems
and difficulties in walking and standing. Waking EEG
studies revealed diffusely active theta and delta activity
that was supportive for encephalopathy and she was
hospitalized. There were confluent expansive hyper–
intensities in the periventricular and supraventricular white
matter and subcortical white matter on T2–weighted and
FLAIR MRI studies. A brain biopsy was performed. Within
3 months of the onset of symptoms, the patient died due to
respiratory failure.
Neuropathologic examination
In gross sections, the biopsies were fragmented grey–white
brain tissues. Excisional brain biopsies were performed and
put in 10% formalin fixation for 24 hours followed by the
preparation of 5 micrometer–thick, paraffin–embedded
sections. For routine neuropathologic examination, sections
were stained with haematoxylin and eosin (H&E)
and immunostained against prion protein (PrP) using the
monoclonal antibody 12F10 (dilution 1:250) that binds to a
region of human PrP downstream of the neurotoxic domain
adjacent to helix region residues. Immunohistochemistry
for PrP was carried out on deparaffinized and rehydrated
sections immersed in 98% formic acid for one hour.
On microscopic examination, widespread spongiform degeneration characterized by large confluent vacuoles of varying sizes in the neuropil of the cerebral cortex, pink neuronal changes in the neurons, and gliosis in the cortical grey matter were seen all four cases (Figure 1). Although the cerebral white matter was well preserved and without myelin pallor, some mild gliosis were observed. Pathologic diagnoses were confirmed by the Neurology Institute of Vienna University by immunohistochemically demonstrating the synaptic accumulation of 12F10 prion protein (Figure 2). Glial fibrillary acidic protein was positive in areas of reactive astrocytosis. Florid plaques, kuru plaques, senile plaques, neurofibrillary tangles or Lewy bodies were not observed. There were no vascular lesions.
Figure 2: Diffuse synaptic deposition of PrP in grey matter immunohistochemically (x200).
Four subtypes of CJD have been described to date including familial CJD, iatrogenic CJD, sporadic CJD and variant CJD. Familial CJD is linked to germline mutations of the PrP gene. Iatrogenic CJD, a transmissible form of the disease, is acquired from growth hormone from pooled pituitary glands or cadaver, dura mater grafts, or corneal transplantation. Sporadic CJD (sCJD), the commonest form of the disease, may arise as a result of random mutation or post–translational modification of the PrP gene. In addition, a new type of CJD, namely variant CJD, has been described in the United Kingdom[3]. Variant CJD differs significantly from previously described subtypes of the disease in having a younger age of onset, a prolonged duration of disease, a psychiatric presentation of the disease, and the absence of typical EEG features. Variant CJD has been linked to the consumption of meat from cattle with bovine spongiform encephalopathy[4].
The evolution of clinical symptoms and signs are the basis for the diagnosis of sporadic CJD. It usually occurs in middle and old age, and typically affects patients in the seventh decade of life. There are no specific symptoms at the onset of the disease. Most often, depressive personality changes, sleep disorders, and loss of weight occur. Impairment of cognitive functions or behavioral abnormalities are key symptoms and are found in most patients[5]. The disorder is fatal in short duration. Generally the causes of death are infection, heart failure, or respiratory failure usually within months. The clinicopathologic presentation of sCJD is influenced by several factors, including the prion strain and polymorphism of the PrP gene of the patient. Analyses of neuropathologic findings as well as of clinical features will provide a better understanding of such factors[6]. It has been proposed to classify CJD into six different subgroups (MM1, MM2, MV1, MV2, VV1, and VV2) to identify and understand the major disease groups[7]. Although such classification systems are helpful in understanding major sCJD subgroups, there remain individual cases that prove difficult to classify on this basis[8].
Because of the nonspecific symptoms, Alzheimer disease (AD) and dementia with Lewy bodies are considered the most important differential diagnoses in elderly patients. Their rapid disease course, in particular, can rarely be discriminated from CJD when myoclonus is present. On histopathological examination, occurrence of diffuse cortical vacuolization in AD and superficial cortical vacuolization in fronto–temporal dementia cause difficulty in diagnosis. Thus, further detailed clinicopathologic investigations of sCJD are needed[8]. The detection of the 14-3-3 protein in CSF and strong deposits of PrP in brain tissue help to elucidate the exact diagnosis of sporadic CJD[5]. We used the WHO 1998 criteria for the diagnosis of sCJD (Table I)[9].
Table I: WHO 1998 criteria for diagnosis of sCJD
Variable degrees of neuropathologic involvement are observed in the cerebral neocortex, subiculum, striatum, thalamus and cerebellar cortex, whereas the globus pallidus, hippocampus and dentate gyrus, brainstem and spinal cord are relatively spared (10, 11). Neuropathologic hallmarks of sCJD include spongiform change in the neuropil, neuron loss, intense reactive astrocytosis and deposition of abnormal protease–resistant protein in the form of synaptic–type deposits[6].
There is no generally accepted treatment for CJD and the disease is invariably fatal but early diagnosis and treatment may make the symptoms easier to control. The most important issue is prevention as prions have been transmitted to patients and possibly to the medical staff as well. Mechanisms of natural transmission of human CJD are not understood except for iatrogenic cases. The agents are highly resistant to complete inactivation by exposure to heat, ultraviolet and ionizing radiation, or a variety of chemicals that disinfect conventional viruses. Precautions are the use of gloves, and maximal protection of people who come into contact with contaminated tissue (e.g. pathologist, histological laboratory worker and neurosurgeons). For laboratory research, the tissue must be submerged in 92–98% formic acid for 1 hour. All used materials and instruments must be decontaminated using NaOH, NaClO, guanidine thiocyanate, or steam autoclaving[12,13]. In our cases, these specific safety precautions were performed to avoid accidental transmission and to avoid any infectivity.
Our cases had no family history of the disease, did not receive human hormones prepared from pooled pituitary glands or cadaver, did not undergo electrocorticography with a previously used probe electrode, and had not undergone dura mater graft or corneal transplantation, so we eliminated the iatrogenic form CJD and the familial form CJD as well. Our patients were in an older age group at onset and had a shorter clinical history than patients diagnosed with variant CJD. We diagnosed our 4 patients as sporadic CJD with their MRI findings, EEG findings, detection of 14-3-3 protein in the CSF and histologically confluent vacuole–type spongiform change of varying severity in the cerebral cortex. Demonstrating the accumulation of PrP immunohistochemically in brain tissue and also using the WHO 1998 criteria, we grouped our 4 cases into the ‘Definite CJD’ group.
ACKNOWLEDGEMENT
We would like to give our very special thanks to Prof. Dr.
Herbert Budka, director of Neurology Institute of Vienna
University, who kindly provided immunohistochemical
studies of our cases.
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