A case of bilateral striato pallido dentate calcinosis presenting with unique gait

Dear Sir, Basal ganglia, cerebellum, motor, pre-motor, and supplementary motor areas, as well as the cerebellum, are involved in the control of ambulation. Calcifications in these regions can give rise to gait disturbances. We herein report a case of a peculiar gait and unique cueing maneuver due to abnormal mineral deposition. Case A 57-year-old male without prior comorbidities presented with a progressive, symmetrical gait abnormality for 6 years, associated with recurrent forward falls and mild slowing of his daily activities, leading to him taking longer than usual to complete them. There were no tremors, rigidity, swaying to either side while walking, or difficulty negotiating narrow passages. There was no significant family history. He subsequently developed progressive dysphagia and spastic dysarthria for 4 years, progressive behavioural disturbances in the form of disinhibition, inappropriate laughter, and aimlessly wandering, and recent memory disturbances for 1.5 years. He did not have any history of cerebellar dysfunction or seizures. Childhood and family history were not significant. Phenomenology of gait disorder—He was able to get up from a sitting position normally. He walked with quick, short steps with reduced ground clearance of the feet and bilateral striatal toes. He held his arms in front while walking and frequently raised his arm above his shoulder, waiving his palm around his head as if groping for some imaginary support. Occasionally, this manoeuvre was associated with a transient improvement in stride length and foot clearance [Video 1]. There was minimal bradykinesia in the left upper limb and lower limbs. {"href":"Single Video Player","role":"media-player-id","content-type":"play-in-place","position":"float","orientation":"portrait","label":"Video 1","caption":"","object-id":[{"pub-id-type":"doi","id":""},{"pub-id-type":"other","content-type":"media-stream-id","id":"1_qssw5z0l"},{"pub-id-type":"other","content-type":"media-source","id":"Kaltura"}]} Renal function tests, serum calcium, phosphorus, Vitamin D3, serum PTH, thyroid profile, alkaline phosphatase levels, and CSF analysis were normal. Neuroimaging showed typical symmetrical calcifications in the bilateral deep subcortical white matter, thalami, basal ganglia, and dentate nuclei [Figure 1]. Genetic testing could not be done due to financial constraints. He was treated symptomatically with levodopa-carbidopa, with partial improvement at the 6-month follow-up.Figure 1: Axial NCCT scan of the brain (a–c) showed multiple areas of calcifications in the bilateral dentate, lentiform, and pulvinar nuclei, both occipital cortices, periventricular, and deep white matter. Axial T2 MRI (d, e) showed calcifications in the corresponding areas seen on the CT scan. FLAIR images (f–h) showed additional white matter changes in those corresponding regions. Axial SWI images (i–l) showed blooming with PHASE reversal, suggestive of calcificationEndocrinopathies such as hypoparathyroidism and vitamin D deficiency were ruled out in our patient by normal levels of serum PTH, vitamin D3, calcium, and phosphorus. An unremarkable childhood and family history, the absence of seizure history, euthyroid status, and neuroimaging findings were against the possibility of underlying inherited congenital disorders such as Cockayne syndrome, Aicardi–Goutières syndrome, and Kenny–Caffey syndrome, which are important differentials for symmetrical basal ganglia calcifications. Acquired infections such as brucellosis were ruled out by CSF analysis and were also unlikely in our patient, given the prolonged course of the illness. Discussion Fahr’s disease, also known as bilateral striopallidodentate calcinosis (BSPDC), is characterized by abnormal calcium deposition in the basal ganglia, thalamus, dentate nucleus of the cerebellum, cerebral cortex, and subcortical white matter, which are involved in the regulation of movement. It manifests in the 4th–6th decade in an autosomal dominant inheritance pattern as a chronic progressive disorder with extrapyramidal and cerebellar features, along with neuropsychiatric manifestations. However, patients with “Fahr’s syndrome” have a younger age of onset, which is due to underlying metabolic disorders, infection, or toxin exposure.[1] The pathological abnormalities in BSPDC involve the pericytes and vascular smooth muscle cells of the cerebral microvessels. Calcific deposits occur in the tunica media of small- and medium-sized arteries, arterioles, and capillaries, sometimes resulting in luminal obstruction.[2] Fibrinogen deposits have been observed in perivascular tissue in the regions of brain calcifications, which are surrounded by reactive astrocytes and microglia, suggestive of blood–brain barrier dysfunction secondary to vascular injury along with a mild inflammatory component.[3] These areas of calcinosis primarily comprise calcium along with iron, magnesium, aluminium, and zinc. Etiologies of basal ganglia calcification can be divided into “primary forms, i.e, Fahr’s disease,” which occurs in the absence of any metabolic disorders and manifests as sporadic or autosomal dominant forms due to mutations of genes such as SLC20A2 (most commonly implicated), PDGFB, and PDGFRB, and “secondary forms, i.e., Fahr’s syndrome,” which occurs due to an underlying metabolic, toxic (e.g., lead and carbon-monoxide), or sometimes infective (e.g., Brucella, Toxoplasma, TORCH complex) etiology. The most common cause for basal ganglia calcifications is an abnormality of calcium/phosphorus metabolism, namely primary or idiopathic hypoparathyroidism and secondary hypoparathyroidism. Idiopathic hypoparathyroidism is due to atrophy, absence or replacement of the parathyroid glands by fatty tissue. Secondary hypoparathyroidism is often a complication of total or subtotal thyroidectomy. Neurological features are often heterogenous and have a poor correlation with the area of brain affected by calcification. Blood vessels of multiple organs, particularly the brain, can be involved in calcification in patients with HIV. Detection of intracranial calcifications (basal ganglia, dentate nucleus, and white matter) in patients from endemic areas should raise the possibility of CNS involvement in brucellosis, a common zoonotic disorder. Various autoimmune disorders, particularly neuropsychiatric SLE, can cause calcifications in multiple intracranial areas (basal ganglia, centrum semiovale, cerebellum, and cortex) in 30% of cases. Besides these, other genetically inherited conditions can manifest as basal ganglia calcifications (e.g., Aicardi–Goutières syndrome, Cockayne syndrome, neurodegeneration with brain iron accumulation (NBIA), and mitochondrial disorders such as MELAS). Rarely, mutations in XPR1, MYORG, and JAM2 genes present with young-onset parkinsoninsm with or without cognitive impairment and movement disorders such as dystonia and chorea. NBIA, particularly pantothenate kinase-associated neurodegeneration (PKAN) and beta propeller-associated neurodegeneration (BPAN), must be considered in the differential diagnoses when calcification is confined to the bilateral globus pallidi along with slowly progressive extrapyramidal features and neuropsychiatric symptoms.[4] Patients with BSPDC present with cognitive impairment, psychiatric manifestations, seizures, dysarthria, parkinsonism, tremors, dystonia, and ataxia. The basal ganglia, cerebellum, motor, pre-motor, and supplementary motor areas are involved in the control of ambulation. The basal ganglia play a pivotal role in regulating step length and the timing of internal cues required for each step. Volitional control of motor movements is regulated through the interaction between the basal ganglia and motor cortex, with the planning and execution component controlled by basal ganglia-thalamo-cortical interactions. The cerebellum, particularly the intermediate portion, along with inputs from spinocerebellar tracts and motor cortex, regulates the timing and amplitude of limb movements.[5] Calcifications in these regions can give rise to gait disturbances, as seen in our patient. The diagnostic approach to basal ganglia calcifications must consider clinical features along with radiological findings, relevant biochemical tests, and CSF studies, classifying them as either the “primary” or “secondary” form. Single, small, symmetrical, faint calcifications, confined to the globus pallidi are suggestive of age-related physiological calcifications, which are mostly asymptomatic, whereas diffuse, coarse calcifications are pathologic and warrant further evaluation. After excluding secondary causes, if there is a positive family history with an autosomal dominant inheritance pattern, genetic studies should be considered. An approach to disorders with basal ganglia calcifications has been discussed in Figure 2 and Table 1.Figure 2: Flowchart for clinical approach to disorders with bilateral basal ganglia calcificationsTable 1: Genetic disorders associated with basal ganglia calcifications and their clinical and radiological findingsManagement is mainly symptomatic and focusses on addressing underlying toxic, metabolic or infective etiologies, if any. Parkinsonian features can be managed with levodopa-carbidopa, although the response may be minimal. Mood stabilizers and antipsychotics are useful for patients with neuropsychiatric manifestations.[4] Till date, there is no evidence-based treatment available for intracranial calcifications. Oliveira et al.[6] studied the effect of bisphosphonates (alendronate) in their case series of seven patients with primary brain calcifications, noting a variable response. Symptomatic improvement was observed mainly in the reduction of headache and tremor intensity. Seizures can be managed with antiepileptic drugs. Newer antiepileptic drugs such as levetiracetam, lamotrigine, and gabapentin are preferable for patients with Fahr’s disease, particularly for hypocalcemic seizures in Fahr’s syndrome secondary to hyperparathyroidism and pseudohypoparathyroidism. Drugs such as phenytoin, carbamazepine, and phenobarbitone should be avoided in these cases, as they alter vitamin D metabolism and interfere with calcium metabolism.[7] Acknowledgement None. Author contribution A. Research project: Conception: Priyanka Samal, Sanjeev Kumar Bhoi Organization: Priyanka Samal, Menka Jha Execution: Archisman Haldar, Priyanka Samal, Menka Jha B. Statistical analysis: Design: Execution: Manoj Nayak Review and Critique: Menka Jha, Manoj Nayak C. Manuscript preparation: Writing of the first draft: Archisman Haldar Review and Critique: Priyanka Samal, Manoj Nayak, Sanjeev Kumar Bhoi. Ethical compliance statement We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.