Cerebellar Agenesis: A Rare Cause of Seizure Disorder in a Young Boy
The role of cerebellum is to control motor, cognition and behaviour. Cerebellar action in generation and modulation of epilepsy is lesser known. Dysfunctional cerebellum has been found linked with disinhibition of epileptic activity in the cerebral cortex,and the highly disputed matter of cerebellar epilepsy. Cerebellar hypoplasia is incomplete development of cerebellum while Cerebellar agenesis is complete or partial absence of cerebellum with normal development of cerebral structures. Etiopathogenesis in favour of cerebellar agenesis is searched till now and remains unknown. Impairment of embryogenesis results into the congenital brain malformations and the anatomic defect or destructive brain lesions.
A young boy of very low socioeconomic status of aged fourteen years presented to us with complaints of mild headache and dizziness from two days along with one episode of generalised tonic-clonic seizure one day back. It was without fever, vomiting and blurring of vision. On further history, he was also having such episodes of seizure on multiple occasions since one year. He never visited any doctor for these complaints. There was no history of head injury, tubercular contacts, febrile illness and any other chronic diseases. There were no antenatal consultation and medication during pregnancy of his mother. Parents had no history of any neurological problems. His2elder sisters and 2younger brothers never have any neurologically complaints. According to her mother, he was normally delivered at home, his birth weight was about 2.8 kilograms. On general examination, he was conscious and oriented with Glasgow coma scale of E4V5M6. Balance and gait were normal. There was absence of ataxia, dysarthria and nystagmus. No any motor deficit was present. Hypotonia was also absent. No psychomotor delays were there. His visual abilities, expressive language, working memory and affective behaviour all were normal. Intelligent quotient (IQ) was also normal at age. He was afebrile. Neck rigidity and kerning's sign were absent. Blood pressure (BP) was 126/76mmHg, pulse rate was 78/minute regular with normal volume. All other systems were within normal limit. Lab investigations were normal. All metabolic and infective causes of seizures were ruled out. Electroencephalogram (EEG) was suggestive of abnormal awake records with generalised slow down [Figure 1].
We decided to do magnetic resonance imaging (MRI), which showed hypoplastic left cerebellar hemisphere and left half of cerebellar vermis with CSF density within it. It was suggestive of unilateral cerebellar hypoplasia/partial cerebellar agenesis [Figure 2].
T1-weighted successive coronal MRI images reveals that there is no recognizable cerebellar structure on left side and there posterior fossa is filled by CSF with no mass effect. Mesencephalon, pons, and medulla oblongata were present. The pons, medulla oblongata was attenuate and no hindbrain herniation. Tentorial attachment and straight sinus are normal. Supratentorially, the pattern of cortical gyri was normal as was the corpus callosum, aqueduct. The shape and relative proportions of the third ventricle and lateral ventricle were preserved and no hydrocephalus.
All other parts of the brain were anatomically within normal limits. Karyotyping or genetic testing could not be performed due to poor economic condition of patient. Patient was given antiepileptic leviteracetam 250 mg twice a day and managed conservatively. He showed gradual improvement on medication. There was no recurrence of even a single episode of GTCS after 2 years of follow-up.
Cerebellar hypoplasia is a result of defective neuronal proliferation and neuronal migration during nervous system development at the time of embryogenesis. Cerebellar hypoplasia may be also due to atrophy ofopposite sided cerebral cortex or may be linked with autosomal recessiveandX-linkedgenetic disordersliketrisomy 13 (Patau Syndrome), trisomy 18(Edward syndrome), Werdnig-Hoffman and Tay-Sachs disease. Joubert's syndrome and Gillespie syndrome are autosomal recessive conditions. There are a number of congenital conditions where cerebellum involvement is very common. Commonest are Dandy-Walker malformation and Chiari malformation. VLDLR-associated cerebellar hypoplasiais an inherited condition with an unusually small and lesser developed cerebellum. VLDLR is a gene which makes a protein known as very low density lipoprotein (VLDL) receptor. An extremely rare syndrome due to mutations in thePTF1Agene, results in cerebellar agenesis and agenesis of the pancreas, causing neonatal diabetes mellitus and inherited as autosomal recessive disorder.
Some researchers found small size of volumes of white matter of cerebellum in newly diagnosed patients of epilepsy. Alteration in the white matter of cerebellum means it is susceptible structure and may be associated with generation of partial epilepsy. Lawson et al. also found decrease in brain volume at onset of epilepsy and this was not because of intractable seizures.
Reduction in cerebellar volumes and overall generalized tonic-clonic seizures (GTCSs) with their frequency are significantly correlated. Prolonged seizure and discharges via cerebrocerebellar pathway causes hypoxic-ischemic nerve cell injury with loss of purkinje cells which is responsible for brain volume reductions.
Peri-ictal cerebellar hyper perfusion similar to crossed cerebellar diaschisis in case of supratentorial stroke and permanent atrophic changes were also found.
In one of the studies, it was observed that seizure patients have hypometabolism in contralateral cerebellum, frontal lobes and in both temporal lobes at seizure onset. In a few of studies, it was also found that damage to cerebellum indirectly can cause epileptic seizures because it have inhibition on paroxysmal epileptic activity. Hence damaged cerebellum is unable to inhibit epileptic seizures.
On behalf of all above studies, it was summarised that pathologic cerebellar alterations with significant cerebellar atrophy, decreases cerebellar inhibition of dentatothalamic-cortical tracts. It was hypothesized that decrease in inhibitory Purkinje cell output to the dentate nucleus leads to this reduced inhibition.
On the basis of clinical findings, it is very difficult to make diagnosis of congenital brain malformations. Impairment in chromosomal balance, hypoxia or noxious exposure during embryogenesis may be responsible for congenital abnormality. Computed tomography scan (CT Scan) and MRI makes the diagnosis. Cerebellar agenesis/hypoplasia can be defined by so many causes such as rare autosomal recessive diseases. Systemic degenerative diseases and non-progressive central nervous system malformations also have hypoplastic cerebellar features. Unilateral cerebellar agenesis may be an incidental finding at radiography.
In the foetus and neonatal mammals, by cytotoxic drugs, viruses, and sub lethal doses of radiations, cerebellar hypoplasia can be induced experimentally. Intra-uterine necrosis as a cause of cerebellar hypoplasia is often associated in human neonates. Loss of afferents deprives cerebellum of synaptic connections or insult destroying brain stem are two postulated criteria for development of cerebellar hypoplasia.Angiogenesis failure and intracranial bleed in foetus due to immune basis may be other causes for this case. But the main cause is unknown till now.
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[Figure 1], [Figure 2]