Sapiah S. and Hamidon B.B.
Department of Medicine, Faculty of Medicine Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur, Malaysia
A 72-year old Englishman was admitted with rapid deterioration in cognitive function, gait disturbance, and cerebellar signs and lapsed into a coma within one week of admission to the hospital. He had long-standing hypertension and hypercholesterolaemia, for which he was on regular medication. He had suffered recurrent episodes of stroke between September 1997 and May 2001. Three months prior to presentation, he became forgetful and generally mentally slow, affecting his daily activities. He was also noted to have fluctuations in his conscious level, associated with myoclonic jerks of the limbs. The brain MRI revealed hyperintense lesions on T2- weighted images in the periventricular region, left corona radiata, centrum semiovale, pons, midbrain and right thalamus. The electroencephalograph revealed periodic sharp wave complexes, strongly suggestive of Creutzfeldt-Jakob disease. However, we were not able to get a tissue diagnosis or send the cerebrospinal fluid for protein 14-3-3.
KEYWORDS: Creutzfeldt-Jakob disease (CJD); Dementia; Alzheimer disease (AD); Vascular Dementia
Creutzfeldt–Jakob disease (CJD) is a rapidly progressive and ultimately lethal dementing illness caused by an infectious protein named prion. Besides cognitive decline and behavioural abnormalities, various other neurologic deficits usually appear. Myoclonic jerking, in particular myoclonus, is seen most commonly. The lack of a characteristic clinical course makes the diagnosis difficult, but the potential transmissibility necessitates early recognition of the disease. [1] MRI abnormalities of the brain can aid in establishing the diagnosis. [2, 3] These disorders have common pathologic features, including, spongiform change in the brain associated with astrogliosis, neuronal loss, and the deposition of proteinase-resistant amyloid protein (PrP) in brain plaques. CJD occurs sporadically with a frequency of approximately one case per million populations per year. [4] In addition, there are a number of genetically determined forms of spongiform encephalopathy caused by mutations in the PrP gene. [4, 5]
CASE REPORT
A 72-year-old Englishman was admitted to the hospital in July 2001 with a history of relatively rapid deterioration of cognitive functions of three months duration. His children noticed that he had increasing forgetfulness and poor concentration and experienced difficulty performing routine activities. He had fluctuations in his memory and orientation, and had frequent falls due to gait instability. He was also noticed to have intermittent stiffness of both upper limbs, described as “spasms” with superimposed jerky movements, which normally occurred when his conscious level was reduced. Each episode lasted for a few minutes. At the same time he was also noted to have urinary incontinence but there was no bowel incontinence.
He was diagnosed with hypertension and hypercholesterolaemia 20 years previously and was on regular medication and follow-up. He sustained his first cerebrovascular accident in September 1997, when he presented to another hospital with sudden right hemiparesis and slurring of speech. He received a thrombolytic agent and recovered well. Magnetic resonance imaging (MRI) of the brain revealed left pontine, midbrain and thalamic infarcts. He was referred to our hospital for further management and had remained well throughout. In August 1998, he developed dizziness when ambulating and loss of balance, and sustained a fall. Examination at that time did not reveal any new focal neurological deficit. He sustained another episode of slurring of speech in May 2001 which resolved spontaneously after 20 minutes. Brain MRI done at a different hospital revealed hypointense lesions in the right centrum semiovale, left cerebellar hemisphere and pons, which were consistent with new infarcts. Since then he was noted to have deterioration in his cognitive function.
He was married to a Malaysian and had been living in Malaysia since the 1950’s and had held various positions in the government. He retired as an assistant to the director general of the ‘Jabatan Orang Asli’. He used to travel to the UK regularly and his last trip was in 1996. No history of ingestion of internal organs was obtained from the family members. He had stopped smoking and drinking alcohol for a long period, and there was no significant family history of note.
Examination revealed a drowsy but arousable Englishman. His Glasgow coma score (GCS) was 14/15 (E3, V5, M6). His blood pressure was 146/96 mmHg, and pulse 72 bpm, and he was afebrile. His pupils measured 3mm, equal and reactive. The extraocular movements were full. The 9th and 10th cranial nerves were impaired bilaterally. Muscle tone was increased in all four limbs. All deep-tendon reflexes were increased, and the plantar responses were extensor bilaterally. Myoclonic jerks were occasionally observed on tactile stimulation. The gait could not be tested.
He scored 30/30 on the mini mental state examination (MMSE) on the day of admission, but was noted later to have fluctuations in his orientation level. A month before his admission he was seen in the clinic and had scored 17/30 on the MMSE, which indicated dementia. He had a brain CT but apart from hypodense lesions in the left corona radiata, and left cerebellum, and cerebral atrophy, there was no subdural haematoma or hydrocephalus to explain his forgetfulness, gait problems and his urinary incontinence. One week after admission his conscious level deteriorated and he lapsed into coma, and never regained consciousness.
Investigations showed a hemoglobin of 13.0% , white cell count 8.3 x 109/l, platelet 4209 x 109/l, blood urea 4.7 mmol/l, serum potassium 3.6 mmol/l, sodium 136 mmol/l and creatinine 81 mmol/l. His liver function test showed total protein of 65 g/dl, albumin 39g/dl, alkaline phosphatase 177 iu/l and alanine transaminase 45 iu/l. The urine was normal. An electroencephalographic examination, performed while the patient was comatose, exhibited no alpha rhythm with very mild background asymmetry. The record was dominated by 4 – 7 c/s theta activity intermixed with a small to moderate amount of polymorphic slow activity, more on the left. There were frequent bilateral and independent, sharp and slow wave complexes in both hemispheres, recurring every 1 –1.5 seconds. These findings were in keeping with the clinical diagnosis of CJD. However the cerebrospinal fluid for protein 14–3–3 could not be sent, as it was not done in Malaysia, and a biopsy of the brain was not performed, in accordance with the family’s wish.
DISCUSSION
This 72-year-old man presented with relatively rapid deterioration in cognitive function, followed by more rapid deterioration in conscious level. Signs and symptoms of an upper-motor-neuron lesion, cerebellar involvement, and myoclonic jerks appeared in rapid succession. The rapid onset of this dementing process and the absence of a relevant family history suggest the diagnosis of either sporadic Creutzfeldt-Jakob disease or an atypically fulminant form of a more common neurodegenerative disease characterized by prominent dementia and varying degrees of ataxia, and myoclonic jerks. The differential diagnoses included vascular dementia, dementia with Lewy bodies (DLB), Alzheimer’s disease (AD), and Familial Fatal Insomnia (FFI).
Multi-infarct dementia and diffuse white matter dementia are common causes of vascular dementia. Individuals who have had recurrent strokes may develop chronic cognitive deficits. The occurrence of dementia depends on the total volume of damaged cortex. They usually have a history of hypertension, diabetes, coronary artery disease, or other manifestations of diffuse atherosclerosis. Physical examination will reveal focal neurological deficits, depending on the previous infarct sites and the recurrent strokes will result in a stepwise progression of the disease. [6] Our patient fulfilled these criteria, but the rapid progression to coma without a new substantial infarct on CT and the findings on EEG make the diagnosis of vascular dementia unlikely.
Lewy bodies are intraneuronal eosinophilic inclusion bodies that are seen in the brainstem and cortex of patients with Parkinson’s disease and some patients with dementia. The core clinical features of DLB are fluctuations in cognitive function with pronounced variation in attention and alertness, recurrent visual hallucinations, and parkinsonian signs. [6] However, probable diagnosis of DLB requires two of these features and our patient did not fulfill these criteria.
Alzheimer’s disease (AD) [6] is another common cause of dementia. It most often presents with subtle onset of memory loss followed by a slowly progressive dementia. However, it has a course of several years. In the initial stages, the memory loss may go unrecognized, or may be described as forgetfulness. Gradually the cognitive problems will interfere with daily activities. In the later stages of the disease, patients may remain ambulatory but wander aimlessly. They may also look parkinsonian, and in the late stages they become rigid, mute, incontinent, and bedridden. Myoclonic jerks may occur at this stage either spontaneously or in response to tactile stimulation. Because of the progressive dementia and myoclonic jerks, they can be mistaken as having CJD, but the course of the disease which can range from one to 25 years makes the diagnosis of CJD unlikely.
FFI is an autosomal dominant disease characterised by severe untreatable insomnia, autonomic disturbances, cognitive decline, motor system deficits, and endocrine manifestations. The cognitive disorder, is an attention disturbance with short-term memory deficits, evolving towards a confusional state leading to dementia and finally death. Recently, six sporadic patients phenotypically similar to fatal familial insomnia but without family history and no mutations in PrP have been described. [7,8] However, the most prominent feature of FFI is insomnia resistant to treatment, which our patient did not have. Another feature, which was not present in our patient, was the autonomic disturbance. These make the diagnosis of FFI unlikely in this patient.
Our patient fulfilled the criteria for probable sporadic CJD. He presented with rapidly progressive dementia, myoclonus, cerebellar dysfunction (gait instability) and typical electroencephalographic (EEG) findings. CJD accounts for more than 85 percent of all cases of prion disease. [9,10] The disease occurs sporadically in almost 90 percent of cases, is inherited in less than 15 percent of cases, and is transmissible in less than 5 percent of cases. The disease appears to begin focally and then spreads to the entire brain. [12, 13, 14] The age at onset ranges from 16 to 86 years, with an average age of 61.5 years. [11, 12, 15] About one quarter of patients present with vague symptoms such as asthenia, insomnia, or mild anorexia, according to information elicited from patients after the diagnosis had been established in one study. [16] The second stage evolves over a period of weeks to months, and the predominant problems at this stage are cognitive (in 48 percent of patients), cerebellar (in 33 percent), behavioural (in 29 percent), visual (in 19 percent), and vertiginous (in 13 percent). [11] The final stage is characterized by akinetic mutism. [13]
Involvement of multiple systems and a rapidly fatal course (mean interval between onset and death, 8 months; median, 4.5 months) are the most characteristic clinical features of CJD. [11] Less than 10 percent of patients with pathologically confirmed disease live more than two years after onset.
Cerebellar dysfunction, present in this case, is relatively common in CJD. Ataxia is present initially in approximately a third of patients and develops eventually in up to two thirds. [16] The basal ganglia are involved in over half the patients. [16] Myoclonus appears in up to 84 percent of patients. [16]
The brain MRI features are helpful, since hyperintense signals in the cortex, basal ganglia, thalamus, or a combination of these sites on T2 - weighted, and proton-density-weighted images support the diagnosis of CJD. Similar changes have not been consistently reported with any of the other rapidly progressive dementia-myoclonus syndromes.
Other than the MRI findings, there are no noninvasive tests that support the clinical diagnosis of CJD. The importance of assigning a presumptive diagnosis based on the clinical triad of dementia, myoclonus, and triphasic waves on EEG cannot be overemphasized. The earliest EEG changes often consist of either diffuse or lateralized slowing of the background. Triphasic waves, spike-and-wave complexes, or both may appear subsequently, followed by the development of bilateral synchronous, high-voltage, periodic sharp-wave complexes. These complexes are initially intermittent but later become continuous, with a periodicity of approximately one per second. In up to 80 percent of cases, periodic sharp-wave discharges are present by the middle-to-late stages of the disease. In the terminal stage of the disease, they may become less prominent and may be superimposed on a slower, lower-voltage background. The patient in the present report had the typical evolution of this EEG features. However, the brain MRI failed to disclose the features reported to be characteristic of CJD.
At present, there is no effective treatment for CJD. Antiviral agents (amantadine, idoxuridine, methisoprinol, cytarabine, vidarabine, and acyclovir), interferon, anticonvulsants, antibiotics, amphotericin B, dapsone and corticosteroids have all been tried. [16, 17] Anthracycline has recently been reported to prolong the survival of hamsters inoculated with scrapie-infected brain homogenate, [18] . However, up till now, treatment remains supportive.
CONCLUSION
In a patient who presents with rapidly progressive dementia, cerebellar signs, myoclonus, and periodic sharp wave complexes on EEG without a significant family history, probable sporadic CJD should be the primary diagnosis. At present, there is no treatment available and patients normally succumb to the illness a few months after the onset.
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Correspondence:
Associate Professor Dr Hamidon bin Basri,
Department of Medicine,
Faculty of Medicine UKM,
Jalan Yaacob Latiff, Bandar Tun Razak,
56000 Cheras Kuala Lumpur
Tel: 603-91702306
Fax:603-91737829
E-mail: hamidon@mail.hukm.ukm.my