Diagnosing Fahr's Disease
Fahr Beyond is privileged to have as medical leads Professor Bhatia and Dr Batla both based at the National Hospital for Neurology and Neurosurgery in London, UK. Furthermore, we have communication with other leading Neurologists and Neurosurgeons in four different National Health Service Trusts across the UK.
Not only that we stay up to date with the current medical and academic literature on Fahr's and Fahr's like conditions.
Fahr's usually is only evident on a Computerised Tomography scan, it has been noted that Magnetic Resonance Imaging scans can miss the disease. Fahr's has quite a unique CT trace, showing areas of calcification in the Basal Ganglia and the Frontal Cortex
These short videos below provide information on the clinical presentations of Fahr's, how it is/should be diagnosed and how the disease can be managed by clinicians in the UK.
What is and what is not Fahr’s
Since calcification in brain was first described by Theodor Fahr, brain calcification is referred to as Fahr’s. Fahr's disease refers to the idiopathic calcification of the basal ganglia without a secondary (non-genetic) cause. 'Idiopathic basal ganglia calcification' (IBGC) is another term that offers a more accurate description of this condition. The other common term used is Primary familial brain calcification (PFBC) which better identifies with familial cases of brain calcification which are most commonly genetic in origin. Within the last few years, pathogenic genetic mutations for IBGC have been described and the number of these mutations is rapidly expanding.
Fahr’s syndrome is often used to describe brain and more specifically basal ganglia calcification, which may be due to several underlying aetiologies. It is not uncommon to find brain calcification I clinical setting as 1% of patients have some calcification on CT scans of head. Some of the people who have a scan abnormality might have had this done for investigation of other clinical situations such as head injuries or headaches. Usually in addition to brain calcification people with Fahr’s syndrome will have neurological and or psychiatric clinical features. These may range from mild headaches a severely disabling syndrome with parkinsonism, cognitive dysfunction, and loss of independence. Some people with brain calcification and neuropsychiatric features are secondary to other metabolic disturbances. The causes of brain calcification include disorders of parathyroid such as hypoparathyroidism which leads to hypercalcemia. The causes of brain calcification are listed in table below:
Table 1. Causes of basal ganglia calcification
1% Scans
(pathological in persons younger than age 40 years unless proved otherwise)
Idiopathic
• Ageing: common, globus palidus most commonly affected
• Fahr's Disease
Toxic
• Ageing: common, globus palidus most commonly affected
• Fahr's Disease
Radiation therapy
Chemotherapy
Infections
• Toxoplasmosis, other (syphillis, varicella-zoster, parvovirus B19), Rubella, Cytomegalovirs and Herpes infections (TORCH) infection
• CNS Tuberculosis
• Acquired Immunodeficiency Syndrome (AIDS)
• CNS Toxoplasmosis
Metabolic
• Parathyroid disorders:
1. Hypoparathyroidism
2. Pseudohypoparathyroidism
3. Pseudo-pseudohypoparthyroidism
4. Hyperparathyroidsm
Birth Hypoxia
Inherited
• Mitochondria diseases e.g. mitochondria encephalopathy with lactic acidosis and stroke-like episdes (MELAS)
• Cockayne Syndrome
• Pantothenate kinase-associated neurodegeneration (PKAN)
How to diagnose Fahr’s
Clinical history and examination can be very helpful. Movement disorders are the most common features and were seen in 55% of the symptomatic patients with parkinsonism (57%), chorea (19%), tremor (8%), dystonia (8%), athetosis(5%), and orofacial dyskinesia (3%). Other perhaps less common features include: cognitive impairment, cerebellar signs, gait disorders, speech disorders, pyramidal signs, psychiatric features, sensory changes, and pain.
Neuroimaging is an almost essential part of a Fahr’s diagnosis. It is not uncommon to have a CT scan showing calcification as a hyperdense lesion in the basal ganglia region. MRI brain can also pick up ‘blooming’ on GRE sequences or hypointensity on T1W imaging. This could also be seen with iron deposition. It can be difficult to see calcification on T2W and FLAIR sequences and the MRI brain can be reported as normal in people with Fahr’s. CT scan is preferred to document a radiological diagnosis in cases of doubt. Based on the table of causes above there are some clues to differential diagnosis in doubtful cases.
The radiological pattern of calcification may guide clinical diagnosis. Physiological calcification is usually limited to the globus pallidus and is bilateral and faint. Pineal gland, falx, arachnoid granulation and choroid plexus can also be calcified physiologically. If the calcification is more dense, involves the thalamus and dentate nucleus in a symmetrical pattern, and includes brainstem, cerebellum, cortical and areas of sub-cortical white matter, then IBGC should be suspected.
Dystrophic calcification can be seen with previous brain injuries due to varied causes such as brain trauma, surgery, previous strokes or hemorrhages. The location of dystrophic calcification is commonly a clue that this is not IGBC but a secondary calcification in and around the previously injured part of the brain (along with other changes suggesting injury and previous scans can be useful to compare. Calcification due to phakomatosis also follows some specific patterns and if present, these changes may be diagnostic. Subependymal nodular calcification points to tuberous sclerosis, gyriform cortical calcifications suggest Sturge Weber syndrome while nodular calcification in cerebellum, periventricular and a disproportionate calcification in choroid plexus suggests neurofibromatosis. With regards to congenital CNS infections, the onset and clinical presentation are mostly suggestive, but periventricular calcification is common. More specifically, leptomeningeal calcification suggests cryptococosis and tuberculosis. Calcific granulomas can be seen anywhere in the brain and may be due to neurocysticercosis, tuberculosis and sarcoidosis where they may be characteristically in the optic chiasm or pituitary stalk.
Hypoparathyroidism is one of the most common causes of basal ganglia calcification. Disorders of calcium metabolism must be excluded through blood tests before a diagnosis of idiopathic basal ganglia calcification is made. Table 2 provides guidance on interpretation of blood results of calcium, phosphate and parathyroid hormone levels to help diagnose underlying defects of calcium metabolism.
Table 2. Interpretation of levels for interpretation and diagnosis
If routine blood tests of metabolism and endocrine function are negative, it is important to consider idiopathic or familial brain calcification. Genetic testing for IBGC is possible, however it is not routinely available and must be limited to select cases where a genetic confirmation is needed after excluding secondary aetiologies of basal ganglia calcification
Management
Unfortunately, there is very limited evidence available to guide management of Fahr’s. Patient (and physician) education can prevent heightened anxiety or unnecessary admissions or investigations for physiological calcification. Symptomatic or secondary basal ganglia calcification is best treated by addressing the underlying cause such as hypoparathyroidism. Once clearly diagnosed, IBGC is best managed with the multi-disciplinary team (MDT) approach. After diagnosis, patients should undergo regular follow-up with the neurology team to monitor development or progression of symptoms. Other services offer invaluable input e.g. physiotherapy and occupational therapy for patients with a movement disorder, and psychiatric services for mood disorders and psychosis.
Pharmacological therapy can be divided into two broad categories of symptom control, which should be tailored to the individual, and disease modification.
Symptom control
Treatment of movement disorders is a main consideration in IBGC. Levodopa can be useful for patients with parkinsonism (bradykinesia, and rigidity, tremor or gait instability) while patients with dystonia may benefit from trihexiphenidyl or focal treatment with Botulinum toxin injections. Functionally disabling chorea may be improved with anti-choreic medication such as tetrabenazine. Patients who develop psychiatric features can be offered a mood stabilizer or an antipsychotic. Anti-epileptic medication should be considered in the presence of seizures.
Disease modification
Currently, there is no treatment regime to modify the disease process. There has been no success in targeting the deposition or removal of cerebral calcium (and other associated minerals). Disodium eidronate was used in one patient who demonstrated symptomatic relief but with no change in calcification on imaging. Use of nimodipine, a CNS specific calcium channel blocking agent, has been unsuccessful. Increasing understanding of underlying genetic pathophysiology of the disease may bring new avenues of treatment in the future.
References
Tai XY, Batla A. Fahr's disease: current perspectives. Orphan Drugs: Research and Reviews. 2015;5:43-49 https://doi.org/10.2147/ODRR.S63388
Batla A, Tai XY, Schottlaender L, Erro R, Balint B, Bhatia KP. Deconstructing Fahr's disease/syndrome of brain calcification in the era of new genes. Parkinsonism Relat Disord. 2017 Apr;37:1-10. doi: 10.1016/j.parkreldis.2016.12.024.