Initial Manic Presentation in Creutzfeldt-Jakob Disease: A Case Report

Abstract

Patient: Female, 65-year-old

Final Diagnosis: Creutzfeldt-Jakob disease

Symptoms: Diplopia • dizziness • emotional lability • forgetfulness • hallucinations • headaches • insomnia • myoclonus • tremor

Clinical Procedure: —

Specialty: Neurology

Objective: Rare disease

Background

Creutzfeldt-Jakob disease (CJD) is a rare and fatal neurodegenerative condition caused by misfolded prion proteins. It most commonly presents with rapidly progressive dementia and neurological deterioration. While psychiatric symptoms are not unusual in the early stages of CJD, it is very uncommon for the disease to begin with manic features as the primary presentation.

Case Report

We describe the case of a 65-year-old woman who initially developed symptoms consistent with mania. These included an elevated mood, emotional instability, and insomnia. Over time, her clinical condition worsened, and she began to experience hallucinations, along with a noticeable motor decline. Due to the atypical nature of her initial symptoms, she was first treated for viral encephalitis, which contributed to a delay in establishing the correct diagnosis. Subsequent investigations played a key role in clarifying the underlying pathology. Brain magnetic resonance imaging (MRI) revealed characteristic findings of CJD, including cortical ribboning and changes in the basal ganglia. Electroencephalography (EEG) showed periodic sharp-wave complexes, further supporting the diagnosis. Cerebrospinal fluid analysis tested positive for prion protein using real-time quaking-induced conversion (RT-QuIC), confirming a final diagnosis of sporadic CJD (sCJD).

Conclusions

Although rare, mania can be an early sign of CJD. This case illustrates the diagnostic challenges that arise when psychiatric symptoms dominate the initial clinical picture. It emphasizes the importance of maintaining a broad differential diagnosis when evaluating new-onset psychiatric symptoms in older adults, especially when these symptoms are accompanied by a rapid decline in cognition or motor function. Early consideration of CJD in such scenarios may help expedite diagnosis, avoid unnecessary treatments, and provide clarity for patients and families facing a progressive and life-limiting illness.

Introduction

Prions, which are misfolded proteins that trigger misfolding in normal proteins, are the cause of the uncommon, progressive, and deadly neurological disease known as Creutzfeldt-Jakob Disease (CJD). Sporadic CJD (sCJD), familial CJD (fCJD), iatrogenic CJD (iCJD), and variant CJD (vCJD) are among the disease’s subtypes, each of which has unique epidemiological and clinical traits. About 85% of cases of CJD are sCJD, the most prevalent form, which usually affects people in their middle to late decades of life [1]. About 10–15% of cases are familial and are associated with mutations in the PRNP gene, whereas iatrogenic cases are caused by medical procedures such as growth hormone therapies or contaminated surgical equipment [2]. The clinical presentation has a wide array of symptoms and signs such as psychiatric, myoclonus, ataxia, and corticospinal tract involvement. The onset of psychiatric symptoms depends on the type of CJD. It occurs early in the sporadic type and can manifest as depression, anxiety, and apathy [3]. In a recent systematic review (2024) of 43 CJD patients presenting with initial psychiatric symptoms, only 1 presented with mania [3,4]. The present case report adds to the literature and supports this unique presentation.

Case Report

We describe the case of a 65-year-old woman with a medical history of hypothyroidism, dyslipidemia, and asthma, without other significant medical history (no recent tick bites, prior surgical interventions, treatment with growth hormone, or other therapies associated with iatrogenic CJD). She had no prior cognitive impairment. Her symptoms began in March 2024 with forgetfulness, repetitive questioning, insomnia characterized by significantly reduced sleep for less than 3 hours per night, and marked emotional lability, including daily episodes of elevated mood and energy with laughter and frequent crying episodes occurring multiple times per day with abrupt and dramatic shifts in affect. In April, she developed constant headaches predominantly in the bilateral frontal and occipital regions, along with dizziness and diplopia. She was subsequently admitted to a private hospital for 3 weeks with an initial working diagnosis of herpes simplex virus (HSV) encephalitis based on the clinical picture and early MRI findings showing increased FLAIR signal in the left temporal lobe. She received acyclovir for 21 days and a single dose of pulse steroids, without improvement.

She presented to our institution in June with progressive deterioration. She required assistance with ambulation and exhibited tremors, myoclonic jerks, and visual and tactile hallucinations (eg, perceiving cracks in the house she feared falling into and feeling insects crawling on her arm) that occurred 3–5 times per week and typically lasted from a few minutes to less than an hour, causing significant distress, including fearfulness and increased agitation. She also became apathetic, showing no interest in food, water, or using the bathroom. Upon admission, her neurological examination was limited due to her clinical condition and difficulty following commands. She was conscious, with spontaneous eye-opening, displaying intermittent inattentiveness. Comprehensive mental status examination, cognitive function, and language assessment were not feasible. She was oriented to person and family but disoriented to time and place. She exhibited blunted emotions, with episodes of inappropriate laughing, crying, and expressions of affection towards her daughters. Her speech was clear but low in tone and amount, consisting of few words, without dysarthria. She could follow simple commands with multiple repeated stimuli and assistance from her daughters but was unable to follow complex commands.

Primitive reflexes (glabellar, rooting, palmo-mental) were absent. Her pupils were equal, regular, and reactive bilaterally, with an intact visual threat response in all 4 quadrants. Extraocular movements were full in the horizontal plane without obvious limitations, and no facial asymmetry was observed. Generalized rigidity was noted in all limbs, and muscle power could not be accurately assessed. Deep tendon reflexes were brisk at the biceps bilaterally, with other reflexes being +2 and symmetrical. No pathological reflexes were noted, and the Hoffman sign was negative. Plantar responses were downgoing bilaterally. Pain response was intact in all limbs. Coordination assessment was not feasible, and she required bilateral assistance for ambulation. Several diagnostic possibilities were considered given the subacute onset of neuropsychiatric symptoms initially manifesting as emotional lability, insomnia, and cognitive decline followed by progressive motor deterioration, hallucinations, and myoclonus. Autoimmune or paraneoplastic encephalitis was suspected, and she was empirically treated with a combination of intravenous immunoglobulin (IVIG) and intravenous methylprednisolone (IVMP), administered on alternating days for a total of 5 doses each. However, this treatment yielded no improvement. Other considerations included toxic-metabolic encephalopathies, rapidly progressive dementias, and psychiatric disorders. However, normal metabolic panels, absence of toxin exposure, and the rapid progression with prominent neurological signs made these diagnoses less likely. A comprehensive diagnostic approach was undertaken to evaluate these possibilities, as outlined below.

Investigations

While at the private hospital, she underwent a lumbar puncture, EEG, and brain MRI. Her cerebrospinal fluid was colorless and clear, showed no pleocytosis, and the protein and glucose levels were within normal ranges (Table 1), with no culture growth. The autoimmune panel from the CSF was negative for AMPA, amphiphysin Ab, AGNA, ANNA, CASPR, CRMP, DPPX Ab, GABA, GAD65, mGlur1, LGI, NIF, NMDA, PCA, and septin antibodies. EEG showed diffuse slowing, suggesting a widespread encephalopathy. MRI of the brain (without contrast) revealed subtle areas of restricted diffusion in the right basal ganglia, left temporal lobe, and posterior parietal cortex, with increased FLAIR signal in the left temporal region.

Table 1.

Results of cerebrospinal fluid analysis.

	Result	Reference range
White blood cell count	0 cells/μL	0–5 cells/μL
Red blood cell count	13 cells/μL	0 cells/μL
Glucose level	67 mg/dL	40–70 mg/dL
Protein level	36 mg/dL	15–45 mg/dL

When she was transferred to our hospital, we carried out an extensive evaluation. Routine lab tests – including complete blood count, liver and kidney function tests, electrolytes, markers of inflammation, and infection screening – all came back normal (Tables 2, 3). A repeat brain MRI, compared with the earlier one, showed worsening: there were now asymmetrical areas of restricted diffusion in the cortex, along with T2/FLAIR signal changes and increased involvement of the caudate nuclei and putamen on both sides (Figure 1). Her repeat CSF analysis was again unremarkable – no pleocytosis, and normal protein and glucose levels (Table 4). However, this time, RT-QuIC testing returned positive, confirming the presence of abnormal prion protein.

Table 2.

Blood work-up at clinical presentation.

	Result	Reference range
WBC	9.160×109/L	4–11×109/L
RBC	5.1×1012/L	4.2–5.5×1012/L
Hgb	143.0 g/L	120–160 g/L
Platelet	291.0×109/L	140–450×109/L
ESR	16 mm/h	0–40 mm/h
ALT	12.70 unit/L	0–33 unit/L
AST	34.80 unit/L	0–32 unit/L
Creatinine	94.00 mcmol/L	45–84 mcmol/L
Calcium	2.33 mmol/L	2.10–2.55 mmol/L
Chloride	104.10 mmol/L	98–107 mmol/L
Potassium	4.21 mmol/L	3.50–5.10 mmol/L
Sodium	139.00 mmol/L	136–145 mmol/L
Magnesium	0.88 mmol/L	0.70–1.10 mmol/L

Table 3.

Infectious work-up.

	Result	Reference range
Brucella culture	Negative	–
Acid-fast bacilli culture	Negative	–
Cryptococcus antigen	Negative	–
Hepatitis B surface antigen	Negative	–
Hepatitis B core antibody	Negative	–
Hepatitis B surface antibody	2 mIU/mL	<10 IU/L
Hepatitis C antibody	Negative	–
HIV 1&2 Ag/Ab	Negative	–
HSV 1/2 PCR	Negative	–
Syphilis antibodies	0.10 COI	<1.00 COI

Figure 1.

MRI brain showing FLAIR hyperintensity and corresponding diffusion restriction in the bilateral caudate nuclei and putamen, more on the right side, multiple areas of cortical diffusion restriction with mild T2 FLAIR hyperintensity in the bilateral frontal lobes and temporal lobes with involvement of the insular cortex, more on the right side. There is asymmetric bilateral parietal cortical involvement.

Table 4.

Results of cerebrospinal fluid analysis.

	Result	Reference range
White blood cell count	0 cells/μL	0–5 cells/μL
Red blood cell count	1100 cells/μL	0 cells/μL
Glucose level	63 mg/dL	40–70 mg/dL
Protein level	40 mg/dL	15–45 mg/dL
RT-QuIC	Positive	–

Over the course of her stay, she underwent 6 EEGs between June 5 and July 17, each showing a progressively abnormal pattern of brain activity.

EEG on 05/06/2024 showed weakly sustained, symmetrical 8 Hz alpha waves in the posterior regions while awake. There was persistent slowing in the anterior brain regions, especially over the right temporal lobe, seen as 1–2 Hz delta waves. Sharp waves were noted in both hemispheres, especially on the right. Two episodes of myoclonus affecting the left hand were observed but did not align with the electrical discharges.

EEG on 06/06/2024 showed a similar background with persistent slowing over the right hemisphere. Frequent sharp waves, mainly in the right hemisphere, were occasionally seen synchronously in the frontal regions. These discharges had no obvious clinical symptoms.

By 09/06/2024, the EEG revealed continuous, symmetric periodic discharges at 1–2.5 Hz, strongest over the frontal lobes. These were mixed with 2–4 Hz waves and occasional short-lived periods of brain activity suppression. Sounds triggered more rhythmic discharges and myoclonic jerks in the upper limbs.

On 10/06/2024, periodic discharges continued at 1–2 Hz over the frontal regions, layered over a background of 3–7 Hz activity. At times, this was replaced by slower theta waves, followed by brief suppression lasting up to 3 seconds. Myoclonic jerks were again triggered by auditory stimuli.

EEG on 18/06/2024 showed mixed frequency activity – 2–4 Hz waves interspersed with 5–7 Hz and low-voltage beta (13–20 Hz) waves, especially over the frontal and central regions. Continuous right-sided periodic discharges were seen, especially in the right frontotemporal area. No seizures were captured.

Finally, the EEG on 17/07/2024 (Figure 2) showed very slow generalized discharges at 0.5–1 Hz with a triphasic or biphasic shape on a background of suppressed activity. At times, these were replaced by theta and delta waves of low-to-moderate amplitude. Two prolonged discharges were associated with visible myoclonic jerks – one lasting 5 minutes and the other 2 – most prominent in her left arm. Neither light nor painful stimulation triggered any startle response.

Figure 2.

Generalized periodic discharges in a frequency of 0.5–1 hz.

Discussion

Clinical features of CJD include myoclonus, rapidly progressing dementia, and other neurological abnormalities such as ataxia; behavioral or mental symptoms are often present as well. Here, we report a patient with CJD who had unique psychiatric symptoms, including mania, which is rarely identified in the literature as an early presenting symptom [3].

Psychiatric symptoms are common in the early stages of CJD, although they are often hazy and hidden by the rapid loss of neurological function. Common psychiatric symptoms include depression, anxiety, and apathy. In some cases, more severe features such as psychosis, hallucinations, or delusional thinking occur and dominate the early clinical picture, thereby delaying a neurological diagnosis [3]. This case is unique because of the severity and persistence of the psychiatric symptoms, which initially delayed a neurological diagnosis.

The diagnosis was complicated by the patient’s psychiatric symptoms. Similar situations, including psychotic disorders or affective illnesses, sometimes lead to early misdiagnosis. However, the fast progression of cognitive decline, the EEG findings of periodic discharges, and the early onset of neurological manifestations (such as ataxia and startle myoclonus) finally led to the diagnosis. This highlights the importance of closely monitoring people with unusual mental symptoms for neurodegenerative diseases, especially when such symptoms are accompanied by cognitive impairments.

A systematic review of 43 cases revealed that CJD is often misdiagnosed as psychiatric conditions like depression (32 cases), psychosis (5 cases), or mania (1 case). Neuropsychiatric symptoms were the most common feature prompting reconsideration of the diagnosis, appearing in all cases, followed by extrapyramidal signs (68.6%), cerebellar manifestations (65.7%), myoclonus (40%), and corticospinal tract involvement (34.3%) [3].

In our patient, neuroimaging further confirmed the diagnosis of sporadic CJD (sCJD), with characteristic signal abnormalities in the caudate nucleus and putamen with extensive cortical ribboning on diffusion-weighted MRI. These results are in line with studies showing that MRI abnormalities are among the most sensitive and specific diagnostic markers of sCJD [5]. Additionally, a CSF analysis utilizing RT-QuIC showed a positive result for the CJD prion proteins, which is used as a confirmatory test, with a sensitivity of 95% and a specificity of 100% [6].

CJD has an EEG evolution pattern that shows increasing alterations in line with the disease’s course [7]. The evolution of sCJD is divided into 3 stages. In stage I, there are neurological or psychiatric symptoms, with minimal neurological symptoms that do not significantly affect day-to-day functioning; myoclonus is uncommon. In stage II, there are varied degrees of cerebellar, brainstem, pyramidal, or extrapyramidal involvement, as well as notable impairment in higher cortical functions and sensorimotor integration, but it does not include dementia. In stage III, patients have myoclonus that is moderate to severe, dementia, and akinetic mutism, followed by death [7].

Early neurodegenerative involvement is indicated by EEG that frequently exhibit diffuse slowing or frontal intermittent rhythmic delta activity (FIRDA) in the early stages of the disease [8]. Periodic sharp-wave complexes (PSWC), a characteristic diagnostic feature of sCJD, becomes more noticeable as the illness progresses and usually show up in later stages. Changes from localized sharp waves to a generalized pattern may be part of the path to PSWC [8]. Individual disease dynamics and the subtype of CJD affect variations in the EEG evolution, with some instances completely lacking PSWC [9]. To track the progression of the disease and distinguish CJD from other neurological or mental disorders, these progressive EEG alterations are essential. It is important to distinguish periodic discharges from epileptiform activity because the former are stimulus-responsive and noticeable during wakefulness, whereas the latter frequently correspond with clinical seizures [7]. It is advised to use sleep EEG to improve diagnostic precision. The periodic discharges in stage III CJD are mostly triphasic in shape, and 66.7% of patients had a distinct posterior-anterior-posterior (PAP) lag pattern [7].

The etiology behind CJD’s psychiatric manifestations is unknown. Early prion-mediated damage to cortical and subcortical regions, particularly in the frontal and temporal lobes, is believed to have a role in psychiatric symptoms [3]. Mania might be a sign of thalamocortical or limbic network dysfunction. More research utilizing functional imaging and histopathological analysis is needed to better understand this possibility.

This case highlights how difficult it can be to recognize atypical CJD symptoms and the importance of interdisciplinary collaboration among neurologists, psychiatrists, and radiologists. Early identification of CJD is still crucial since it enables appropriate patient counseling and management. Early identification and symptomatic therapies can help patients and their families feel less physically and emotionally burdened, even though there is presently no cure [10].

Effective therapies for CJD are still elusive despite advances in our knowledge of the condition. The majority of current care is palliative, emphasizing supportive care and symptom alleviation. Although there are experimental strategies being studied, such as immunotherapies and anti-prion substances, clinical studies have not yet produced any noteworthy discoveries [10].

Conclusions

This case adds to the body of research by showing that mania can be the predominant and first sign of CJD. When considering a differential diagnosis for late-onset psychosis, doctors should consider neurodegenerative diseases, particularly if there are cognitive or motor symptoms. Early identification of these uncommon cases may improve diagnosis accuracy and expand our knowledge of the many clinical presentations of CJD.