Megalencephalic leukoencephalopathy with subcortical cysts: A report of four cases.

Megalencephalic leukoencephalopathy with subcortical cysts is an inherited autosomal recessive disorder with characteristic MRI features and a variable but mild clinical course. Frontal and temporal subcortical cysts are the diagnostic hallmark. It usually presents with pyramidal and cerebellar signs. Megalencephaly is usually detected early. Seizures may be present but are usually easily controlled. It has been reported commonly from a certain ethnicity of northern Indian origin, but its presence is global. We encountered four patients and describe the clinical and radiological features of these patients. Seizures though reported to be uncommon were seen in all our patients. Neuropsychiatric features have not been described as presentation so far but one of our patients had moderately severe depression. All the patients were diagnosed by MRI features and they responded well to symptomatic treatment.

Introduction

Megalencephalic leukoencephalopathy with subcortical cysts is clinically characterized by macrocephaly, mild motor developmental delay, and seizures. Later in life, patients may develop gradual onset of ataxia and pyramidal features. Mental capacities are usually preserved but there may be a mild deterioration later. A combination of clinical features and MRI features is required for arriving at the diagnosis. The condition is inherited in an autosomal recessive pattern and the gene locus has been mapped as MLC 1 gene at chromosome 22q.

The condition has been originally reported from India. In a meeting in Japan in 1991, Singhal et al. described 18 patients with megalencephalic leukodystrophy from India.[1] This was the first series to be reported. Van der Knaap et al. group from Netherlands later published a series of eight patients and described the clinical and MRI features.[2] Their description earned them the eponym Van der Knaap disease first used by Cavalcanti and Nogueira.[3] A Turkish study of 12 patients[4] soon followed and established the genetic nature of the disease with autosomal recessive inheritance and a locus at 22q. From India, Gorospe, Singhal and co-workers did detailed genetic analysis and established this disease as a distinct clinicopathological entity with common locus at MLC 1 gene in all the 31 patients described in the Agarwal community.[5]

We recently identified four patients of this disease. There was marked diversity in clinical presentation and striking similarity in MRI findings of these patients.

Case Reports

Case 1

A 16-year-old boy presented with seizures and difficulty in walking since four years [Table 1]. This boy originally hailed from rural Bihar but was now settled in Delhi. He had complex partial seizures with semiology suggestive of right temporal lobe with secondary generalization around 80% of the times. At the time of presentation, his seizures were under control with carbamazepine since 9 months. The difficulty in walking was due to spasticity. He had decline of the mental ability with a progressive loss of acquired knowledge and he had to be withdrawn from school. Developmental history was normal in the first few years, except an increased head size noted during infancy. His examination revealed a head size of 59.4 cm. He had spasticity of all four limbs and hyperreflexia with extensor planter response. He had mild handgrip weakness and proximal lower limb power of 4/5. He had no ataxia or sensory impairment. His MRI is shown in Figure 1a.

Table 1

Clinical and MRI characteristics of the four patients

Figure 1

(a) Axial T2 W image of case 1 showing multiple subcortical cysts and hyperintense white matter changes. (b) Sagittal T2W images of case 2 showing multiple temporal and frontal cysts and white matter changes. (c) Axial T1W image of case 3 showing characteristic cystic subcortical white matter appearing hypointense on T1

Case 2

A 5-year-old girl presented with progressive difficulty in walking and tightness of all limbs [Table 1]. She had mild developmental delay in the form of delayed sitting and walking and she could never run or climb stairs. She had clumsiness and frequent falls while walking. She had seizures of simple partial motor type beginning with right lower limb jerking and followed by generalization since 8 months of age. The seizures responded well to treatment with carbamazepine. The child had moderate impairment of cognitive and language abilities and could not go to school. Her brother (case 3) had similar features but much milder clinical course. Megalencephaly was not noted till presentation. The head circumference was 56 cm which was above the 95th percentile for age. The mental examination was suggestive of severe language impairment. The motor system examination was suggestive of severe spasticity with grade 4 power of all limbs. She had exaggerated reflexes and bilateral planters were extensor. She had severe incoordination much more than could be attributed to the mild limb weakness. She had a scissoring gait and walked on her toes. Her MRI [Figure 1b] showed temporal polar subcortical cysts along with other characteristic features suggestive of the disease.

Case 3

A 9-year-old boy presented with her sister (detailed above) [Table 1]. He had normal milestones and went to school on time. He had two episodes of generalized tonic clonic seizures at the age of 5 years. He had difficulty in running and could not engage in active sports at school. He had clumsiness while eating and had a very bad handwriting. His seizures were controlled with carbamazepine. He and his sister belonged to an Agarwal family from Delhi. On examination, his head circumference was 56.7 cm. His language and cognitive functions were preserved. His motor examination was suggestive of mild spasticity, normal power, and hyperreflexia with flexor planter response. He had normal sensory examination. Cerebellar signs were present bilaterally and were suggestive of dysmetria, past pointing, intention tremor, and dysdiadochokinesia. His MRI is shown in Figure 1c.

Case 4

A 34-year-old man presented with a history of depressed mood since 6 months interfering with his work [Table 1]. He had suicidal ideation and somatization. He had a history of generalized tonic clonic seizures since 8 years of age, well controlled on divalproex. He belonged to an Agarwal family from the state of Haryana. Poor scholastic performance was reported by the parents. His developmental milestones were delayed and a large head size was noted by the parents since childhood.

On examination, he had a head circumference of 59.5 cm. There was no weakness but mild spasticity was present in all four limbs. He had exaggerated reflexes and planters were bilateral extensor. There was no ataxia. His mental status examination was suggestive of depression. There was no evident cognitive dysfunction and his Mini mental status examination (MMSE) score was 28/30. His Hamilton Depression[6] score was 24 suggesting moderately severe depression. He responded well to Divalproex and Sertraline and is maintaining well. The comparative details of the cases can be found in Table 1.

Discussion

There is marked heterogeneity in the clinical picture of megalencephalic leukoencephalopathy with subcortical cysts. The age at onset of symptoms ranges from birth to 25 years, with a median age at onset of 6 months.[7] The patient who presented to us at 33 years of age was surprisingly well preserved. The most consistent feature is macrocephaly which has been demonstrated in all the genetically proven cases.[457] The macrocephaly is usually present at birth and after the first year follows the normal growth pattern. It remains several centimeters above the normal throughout life. Seizures may be partial or generalized. They are usually well controlled with one or two drugs and uncontrolled epilepsy is unusual. Seizures have been reported in half of the patients (49%) by Singhal et al.[78] and six of eight patients by Van der Knaap et al.[2] Mental retardation and cognitive regression is reported to be mild, though late progression may be noted.[7] Significant disability due to motor as well as cognitive and language impairment was present in only one of our patients. The presentation of case 4 is unique as depression has not been reported in literature to the best of our knowledge. The mild course with near-normal motor and cognition functioning at 34 years of age is also remarkable. The most important clue to the diagnosis is the radiological picture. The extensive white-matter changes in the brain with temporal subcortical cysts, sparing of the deeper structures have been considered the MRI hallmarks of the disorder. Subcortical cysts are present in the anterior temporal region most commonly and often in the frontoparietal region. Later, MRI may only reveal cerebral atrophy. The size and number of the cysts may increase over time. The frontal involvement is variable and so is the cerebellar involvement. The MRI features of our patients are characteristic of megalencephalic leukoencephalopathy with subcortical cysts. Two of our patients had posterior subcortical cysts as well.

Though Alexander disease, Canavan disease, and Glutaric aciduria have been considered as differential diagnosis of megalencephalic leukoencephalopathy with subcortical cysts,[7] these conditions are quite unlikely to have such a mild clinical course. None of these conditions have subcortical cysts on MRI and all of these involve basal ganglia unlike megalencephalic leukoencephalopathy with subcortical cysts. Indian reports emphasize the existence of this disorder more commonly among a certain community belonging to Haryana state. Three of our patients were from the same community.

Conclusion

We report four cases of megalencephalic leukoencephalopathy with subcortical cysts with some usual and a few unusual features such as neuropsychiatric features in one and seizures in all four patients. One of our patients was not from the predisposed ethnicity and this highlights that the possibility of MLC should not be limited to these families in India. We believe that characteristic MRI features, large head size, ethnicity, pyramidal and cerebellar features, with a discrepantly mild clinical course are the key to diagnosing this disease in practice.