Fahr’s disease with neuropsychiatric symptoms and intermittent course: a case report

ABSTRACT Fahr’s disease is a rare neurodegenerative disorder with brain calcifications and neuropsychiatric symptoms. It can have variable phenotypic expression and intermittent symptomatology, making diagnosis challenging. In this report, we describe a young female patient presenting with symptoms of psychosis and confusion, which could be indicative of a delirium superimposed on the cerebral vulnerability associated with Fahr’s disease. Notably, about two years prior, she experienced multiple episodes of tonic-clonic seizures that spontaneously resolved without pharmacological intervention. She had no previous psychiatric history. Following comprehensive investigations, other organic causes were ruled out, and Fahr’s disease was diagnosed based on bilateral symmetrical brain calcifications seen on a head CT scan. Her treatment regimen encompassed antipsychotics and anticonvulsants. This case highlights the importance of considering Fahr’s disease as a differential diagnosis in patients with new-onset neuropsychiatric symptoms. The case also explores the atypical early onset and intermittent nature of symptoms in the absence of a positive family history, highlighting the complexity of Fahr’s disease. A multidisciplinary approach and regular follow-up are crucial for optimizing patient care and monitoring disease progression. Further research is needed to enhance our understanding of Fahr’s disease and develop standardized treatment strategies for this rare condition.


Background
Fahr's syndrome is a rare neurological condition characterized by abnormal calcium deposits in specific brain regions responsible for motor control, including the basal ganglia, cerebral cortex, thalamus, hippocampus, dentate nucleus, and cerebellar subcortical white matter (Donzuso et al., 2019).The cause of the abnormal calcium deposition is believed to be either abnormal brain calcium metabolism or metastatic deposition due to changes in the blood-brain barrier.Additionally, elevated levels of copper, zinc, magnesium, iron, and altered glucose metabolism have been observed in the basal ganglia (Rizvi et al., 2023).Fahr's syndrome can be categorized as primary (Fahr's disease) or secondary, with secondary forms associated with various conditions such as systemic lupus erythematosus, metabolic disorders, brain infections, toxin exposure, or an unknown cause (Carecchio et al., 2023).
The diagnostic criteria for Fahr's disease, based on Moskowitz et al. and Ellie et al., include progressive neurological dysfunction, bilateral calcification in specific brain regions, absence of biochemical abnormalities, absence of infections, toxins, or trauma, and a family history of autosomal dominant inheritance (Ellie et al., 1989;Moskowitz et al., 1971).
It is important to note that symmetrical basal ganglia calcification occurs in various familial and non-familial conditions.In most instances, basal ganglia calcification is considered "physiological" and is incidentally detected in up to 20% of individuals undergoing brain imaging without symptoms, especially in older adults (Donzuso et al., 2019).However, asymptomatic calcifications are generally confined to the Globus Pallidus.Therefore, neuropsychiatric dysfunction is necessary to diagnose Fahr's disease even when bilateral basal ganglia calcifications are present (Saleem et al., 2013).
Noteworthy aspects of this case include the atypical age of disease onset, intermittent symptomatology, and prominent neuropsychiatric manifestations.In addition, the article includes a concise review of the relevant literature on Fahr's disease and underscores the significance of considering Fahr's disease as a potential differential diagnosis in cases of acuteonset psychosis.

Case presentation
In May 2022, a 27-year-old Iranian female presented at the emergency department with a four-day history of symptoms including bizarre behavior, suspiciousness, depression, irritability, impaired sleep, and agitation.These symptoms emerged following her recent marriage and had been progressively worsening.Approximately two years ago, she encountered three episodes of tonic-clonic seizures within a four-month period; however, she did not pursue medical evaluation or receive any treatment and remained seizure-free for the subsequent two years without any treatment.The patient was the only child of a non-related couple.She had completed high school without encountering any specific learning challenges and was not inclined to pursue further education.She had no previous history of psychiatric disorders.His parents did not report any medical or psychiatric issues in their family history.
During the mental status examination, the patient exhibited confusion and agitation, with irrelevant speech, loosening of association, impaired attention, persecutory delusions, and auditory hallucinations.Neurological examination did not reveal any signs of neck rigidity, motor dysfunction, or focal deficits.Pupils were normal in size and reactive.Initial vital signs were within normal ranges: blood pressure (BP): 110/70 mmHg, pulse rate (PR): 100 beats per minute, respiratory rate (RR): 20 breaths per minute, oxygen saturation (SpO2) in room air: 97%, and body temperature (T): 37°C.No dental problems or clinical indications indicative of hypocalcemia, such as carpopedal spasms during blood pressure measurement, were detected on examination.No aberrant examination results pertaining to the neck or thyroid were identified.The chest X-ray and electrocardiogram (ECG) results were normal.Bedside blood sugar (BS) level was 6.7 mmol/dl.Although the patient did not display a fever during her hospitalization, her family reported elevated temperatures at home, although they were not quantified.
Laboratory investigations, including complete blood count (CBC) with differential counts, electrolytes (sodium, potassium, calcium, magnesium, phosphate), blood urea nitrogen (BUN), creatinine, fasting plasma glucose (FPG), liver function tests (LFT), thyroid function tests (TFT), Beta-Human chorionic gonadotropin (Beta-hCG), and venous blood gas (VBG) tests, all yielded normal results.Urine toxicology screening for various drug and substances came back negative.Erythrocyte sedimentation rate (ESR = 22) and C-reactive protein (CRP = 10) were slightly elevated.Urine analysis indicated the presence of 3-5 white blood cells (WBCs) and 6-8 red blood cells (RBCs).Urine culture revealed a positive result for staphylococcus saprophyticus with a colony count of 100,000 for which clindamycin was administered.Serum viral markers (hepatitis B surface antigen, hepatitis C antibodies, and HIV 1&2 antigen and antibody), RPR-VDRL (Serologic Tests for Syphilis), and heavy metal screening were negative.Serum ceruloplasmin level and 24-hour urinary copper test results were within the normal range (Table 1).A brain computerized tomography (CT) scan without contrast was performed, revealing bilateral symmetrical calcifications in the basal ganglia, thalamus, pons, dentate nuclei, white matter subcortical, and cerebellar cortex (Figure 1).To rule out secondary causes of brain calcifications, tests for parathyroid hormone (PTH), calcitonin, and vitamin D were conducted, all of which showed normal results.Due to a decline in her mental status, a lumbar puncture (LP) was performed to exclude central nervous system (CNS) infections.Cerebrospinal fluid analyses for bacteria, virus, and parasites were negative.Additionally, antibodies associated with autoimmune encephalitis were negative.Owing to the profound cultural stigma perceived by the family regarding an epilepsy diagnosis for their young daughter, they refrained from granting consent for an EEG evaluation.
Upon thorough review of the patient's clinical history and results from the investigations, a diagnosis of Fahr's disease was determined.The patient's emergent manifestation of psychotic symptoms, disrupted attention, confusion, and heightened agitation suggested a concurrent diagnosis of delirium.This delirium may have been induced by the urinary tract infection or exacerbated by the psychological stress linked to the patient's recent nuptials.It is significant to consider these symptoms considering the potential compromised cognitive reserve inherent to Fahr's disease.Molecular genetic testing was not performed due to financial constraints faced by the patient's family.
The patient was started on 5 mg/day of olanzapine and 1000 mg/day of sodium valproate, both in tablet form.The patient's state of consciousness improved on the third day of hospitalization and over a period of two weeks, the patient's psychotic and behavioral symptoms subsided.

Discussion and conclusions
This case report highlights the emergence of new-onset psychiatric symptoms in a young woman.The new onset of psychosis, a prior history of seizures, and the patient's state of confusion prompted an extensive medical investigation to exclude organic etiologies.Subsequent medical investigations discerned an active urinary infection, as evidenced by a positive urine culture, and reported fever.It is postulated that the observed psychosis and cognitive disturbances could be attributable to delirium syndrome triggered or exacerbated by the urinary tract infection, superimposed on a diminished cognitive reserve characteristic of Fahr's disease.
While the age of onset may suggest conditions within the psychotic spectrum, especially in light of the patient's recent significant life event, it's imperative to consider her unique presentation holistically.The absence of prior psychiatric history, presence of specific and bilateral brain calcifications, and the rapid symptomatic relief post-treatment strongly indicate Fahr's disease over primary psychiatric disorders.Although primary psychotic disorders and interictal psychosis remain essential differentials, when juxtaposed against the comprehensive clinical and investigative findings, they appear less probable than Fahr's disease in this case.
Several other differential diagnoses were considered and carefully ruled out to arrive at the final diagnosis.CNS infections were considered due to their similar clinical features (Pourshahid et al., 2018).However, extensive laboratory tests, including serological tests and cerebrospinal fluid analysis, effectively ruled out these infectious causes.The investigation also took into account metabolic disorders, which can be associated with neuropsychiatric symptoms and calcifications (Rizvi et al., 2023;Saeedi et al., 2021).Conditions like Wilson's disease, hypoparathyroidism, and mitochondrial disorders were evaluated but ultimately excluded through appropriate laboratory tests such as copper studies, parathyroid hormone levels, and liver function tests.The possibility of neoplastic processes, including brain tumors, was also examined (Pourshahid et al., 2018).However, the absence of focal lesions or spaceoccupying masses on the brain CT scan helped eliminate neoplastic causes.Finally, Fahr's disease, a rare neurodegenerative disorder, was diagnosed based on the observed bilateral symmetrical brain calcifications on the CT scan, along with the absence of biochemical abnormalities, CNS infections, toxins, or trauma.This case holds significance due to the prominence of neuropsychiatric symptoms as the initial presentation, which emerged after a significant life stressor -the patient's recent marriage.Such a clinical presentation can potentially lead to misdiagnosis of primary psychiatric disorders and hinder the investigation of underlying medical factors.
Approximately 40% of Fahr's disease patients initially present with neuropsychiatric features ranging from mild difficulties in concentration and memory to changes in personality, behaviors, psychosis, or dementia (König, 1989;Neshan et al., 2022).The specific manifestation depends on the age of disease onset, with schizophreniform psychosis without neurological features being more prevalent in younger individuals (20-40 years) and dementia and movement disorders being common in later-onset cases (mean age of onset at 49 years) (Casanova & Araque, 2003).Patients with extensive basal ganglia calcification tend to have a higher frequency of neuropsychiatric disorders (Al Abbudi, 2020).
Notably, the case report discussed earlier presented an atypical early onset of Fahr's disease without a positive family history, further emphasizing the complexity of its clinical presentation.It's imperative to acknowledge that, despite the family's assertions of an absence of recognized medical or psychiatric antecedents, the cultural context might sometimes make it challenging for families to disclose such issues due to societal concerns and potential stigmas, especially concerning marriage prospects for females.While the disease is commonly transmitted as an autosomal dominant trait, it can also be inherited as an autosomal recessive trait or occur sporadically.Currently, four causative genes have been identified: SCL20A2, PDGFB, PDGFRB, and XPR1 (Sellami et al., 2018).Genetic testing can aid in confirming the diagnosis and identifying potential risks for family members (Carecchio et al., 2023).
Another noteworthy aspect of this patient's case is the intermittent nature of symptoms.Initially, the patient experienced seizures that spontaneously resolved without treatment and had not recurred in the past year.However, the disease has now reemerged with predominant psychiatric symptoms.While previous case reports often describe progressive manifestations, a review study suggests that neuropsychiatric symptoms associated with basal ganglia calcification secondary to parathyroid disorders can occur intermittently, with periods of spontaneous recovery when hypocalcemia is corrected (Casanova & Araque, 2003).Furthermore, a recent case report documented a Fahr's syndrome patient who had three episodes of psychotic and mood symptoms over a span of three years (Dennis et al., 2023).Similarly, Mohammedin A S et al. described a young patient with Fahr's disease and hypocalcemia-induced psychotic features, paralleling our case in aspects like early onset, episodic psychiatric symptoms, symptom-free intervals, and lack of familial Fahr's disease history (Mohammedin et al., 2021).However, contrasts exist.Our patient, academically, completed high school unimpeded, unlike the case in Mohammedin et al.She also lacked dental issues or clinical signs like carpopedal spasm indicative of hypocalcemia.Therapeutically, she responded swiftly to antipsychotics, and her biochemical markers (calcium and parathyroid hormone levels) were normal, in contrast to the other patient.Clinically, no neck or thyroid abnormalities were found, highlighting the nuanced presentations of similar diagnoses.
The episodic nature of the symptoms of Fahr's disease adds complexity to the diagnostic procedure and underscores the need for extended monitoring.Thus, even after arriving at a diagnosis of Fahr's disease, ongoing monitoring and reassessment of the patient's condition are crucial.As the disease progresses, new symptoms may arise, necessitating further evaluation to distinguish them from potential comorbidities or complications.Regular follow-up visits and multidisciplinary collaboration among healthcare professionals remain vital for optimizing patient care and effectively managing potential complications (Rizvi et al., 2023).
Currently, there is no definitive cure for Fahr's syndrome, and treatment options remain non-standardized.Therefore, management primarily focuses on symptomatic relief and improving the patient's quality of life.A multidisciplinary approach involving caregivers, genetic counselors, psychiatrists, neurologists, endocrinologists, and other specialized medical professionals is crucial (Donzuso et al., 2019).The treatment options depend on the type and severity of symptoms and may include anticonvulsants, antipsychotics, antidepressants, mood stabilizers, or physiotherapy (Tai & Batla, 2015).The prognosis of Fahr's disease is variable and depends on several factors, such as the age of onset, the extent of brain calcification, the presence of comorbidities, or the response to treatment (Rizvi et al., 2023).
Overall, this case underscores the importance of considering Fahr's disease as a potential underlying cause in patients presenting with new-onset psychiatric symptoms.The diverse clinical manifestations and intermittent symptomatology highlight the need for comprehensive evaluations and a multidisciplinary approach to accurately diagnose and manage this rare neurodegenerative disorder.Further research is warranted to enhance our understanding of the underlying mechanisms and identify optimal treatment strategies for Fahr's disease, particularly in cases with atypical presentations like the one described here.

Figure 1 .
Figure 1.Axial brain CT scan without contrast revealing bilateral calcifications in the basal ganglia, thalamus, subcortical white matter, dentate nuclei, and cerebellar cortex.

Table 1 .
Laboratory data on admission.