|Year : 2014 | Volume
| Issue : 3 | Page : 187-193
Dyke-Davidoff-Masson syndrome: A study of clinicoradiological variability in hemiplegia, hemiatrophy and epilepsy patients
Amita Bhargava, Bharat Bhushan, Gaurav Kasundra, Khichar Shubhakaran, S Pujar Guruprashad, Banakar Basavaraj
Department of Neurology, Dr. Sampurnanand Medical College, Jodhpur, Rajasthan, India
|Date of Web Publication||17-Aug-2014|
H. No. 21/267 Chopasani Housing Board, Jodhpur - 340 008, Rajasthan
Source of Support: None, Conflict of Interest: None
Context: Clinicoradiological variability expansion in Dyke-Davidoff-Masson syndrome (DDMS) or hemiplegia, hemiatrophy and epilepsy (HHE) patients. Aims: To explore clinicoradiological features, associated abnormalities and refractoriness issues to antiepileptic drugs (AED) on such kind of epilepsy syndrome. Settings and Design: Prospective and retrospective observational hospital based cohort study. Materials and Methods: Thirty-two patients of HHE were enrolled and interviewed. They were divided into 4 groups congenital versus acquired and seizure control group (SCG) versus seizure refractory group (SRG). We used Naranjo adverse drug reaction (ADR) probability scale for analyzed phenytoin and other drugs adverse reaction. All patients underwent clinicoradiological examination, electroencephalograms, magnetic resonance imaging for parenchymal and skeletal changes. Statistical Analysis Used: Fisher's exact and Student's t-test applied for P value. Results: A total of 32 patients (21 males, 11 females) out of 1182 epilepsy patients were enrolled with mean age of 26.84 ± 9.71 (range: 8-42) years. Twenty-eight patients presented with DDMS, three Rasmussen encephalitis and two HHE syndromes. Congenital type and seizure refractory groups were common presentation. Left lateralization with holo-hemispheric atrophy, cerebellar atrophy, calvarial thickening with frontal sinus hyperpneumatization were significant (P < 0.05) magnetic resonance imaging (MRI) findings. Epileptiform activity was concordant to lesion. Phenytoin adverse effects were significantly (P < 0.03) associated with HHE patients. Remarkable findings of our study included cerebral hemispheric plus cerebellar atrophy (28.12%), hippocampal sclerosis (16%), dystonia, hemiparkinsonism, mirror movement and Dandy-Walker syndrome (DWS). Conclusions: DDMS/HHE can present protean clinicoradiological manifestation, cerebellar atrophy, hippocampal sclerosis and phenytoin intolerance may be one of them.
Keywords: Dyke-Davidoff-Masson syndrome, epilepsy, hemiatrophy, hippocampal sclerosis, phenytoin intolerance
|How to cite this article:|
Bhargava A, Bhushan B, Kasundra G, Shubhakaran K, Guruprashad S P, Basavaraj B. Dyke-Davidoff-Masson syndrome: A study of clinicoradiological variability in hemiplegia, hemiatrophy and epilepsy patients. CHRISMED J Health Res 2014;1:187-93
|How to cite this URL:|
Bhargava A, Bhushan B, Kasundra G, Shubhakaran K, Guruprashad S P, Basavaraj B. Dyke-Davidoff-Masson syndrome: A study of clinicoradiological variability in hemiplegia, hemiatrophy and epilepsy patients. CHRISMED J Health Res [serial online] 2014 [cited 2017 Mar 29];1:187-93. Available from: http://www.cjhr.org/text.asp?2014/1/3/187/138895
| Introduction|| |
The key features of Dyke-Davidoff-Masson syndrome (DDMS), hemiatrophy and epilepsy (HHE) syndrome (HHES) Sturge-Weber syndrome, Rasmussen encephalitis (RE), Silver syndrome and hemimegancephaly are HHE. The combination of HHE with mental retardation (MR) and skull changes are known as the DDMS. In their original work, Dyke, Davidoff and Masson described the radiological changes occurring in the skull of nine patients with the clinical diagnosis of "infantile hemiplegia". They observed thickening of the cranial vault on the same side of the cerebral lesion, overdevelopment of the frontal and ethmoid sinuses and air cells of the petrous pyramid of the temporal bone. These compensatory bone changes are the result of precocious unilateral loss of cerebral volume, due to a variety of congenital and acquired pathological processes. 
If sequence of seizure, hemiplegia followed by epilepsy occurred irrespective of etiology, it has been considered as HHE syndrome. Several factors might contribute to the pathogenesis of HH/HHE syndrome: 1. prolonged febrile seizure, in which inflammation may worsen the level of cell injury; 2. inflammation and prolonged ictal activity that act on blood-brain-barrier permeability; 3. predisposing factors facilitating prolonged seizure such as genetic factors or focal epileptogenic lesion. However, these factors cannot explain the elective involvement of an entire hemisphere. 
If chronic progressive, intractable seizure, hemiplegia and cognitive decline present without skull change, a diagnosis of RE is made. Progressive means that at least two sequential clinical examination or magnetic resonance imaging (MRI) studies are required to meet the respective criteria. To indicate clinical progression, each of these examinations must document a neurological deficit, and this must increase over time. To indicate progressive hemiatrophy, each of these MRI must show hemiatrophy, and this must increase over time. 
Sturge-Weber syndrome is a congenital malformation in which fetal cortical veins fail to develop normally. Although there is a clinical overlap with DDMS, the characteristic port-wine stain is a distinguishing feature. The imaging features, which are sequelae of progressive venous occlusion and chronic venous ischemia, are most often unilateral. They include progressive cortical atrophy and characteristic tram track calcification, enlarged ipsilateral choroid plexus and extensive pial enhancement. As the condition progresses there is compensatory thickening of the calvarium and hyperpneumatization of paranasal sinuses. 
Hemimegancephaly is a congenital malformation in which defective cellular organization and neuronal migration results in hamartomatous overgrowth of a hemisphere. Patients typically present with intractable seizures in the first year of life and go on to develop progressive contralateral hemiparesis. Imaging features include an enlarged dysplastic hemisphere, an enlarged ipsilateral ventricle with straightened and pointed frontal horn, contralateral displacement of the posterior falx and an enlarged thickened hemicranium. ,
Due to dearth of studies regarding clinicoradiological characteristics, refractoriness of seizures to the AED and hypothesized unveil protean hidden presentation of HHE patients we contemplated this study.
Aims and objective
The aims of study were to assess clinicoradiological presentation, refractoriness with therapy, severity of mental retardation with effect of AED, electroencephalography (EEG) changes and associated unusual presentation in DDMS/HHE patients. Although some anecdotal case reports have mentioned these issues but it has not been highlighted by any study on HHE till date.
| Materials and Methods|| |
This was a non-randomized, prospective and retrospective, observational cohort study conducted between September 2012 and January 2014 in the department of Neurology at Dr. S. N. Medical College, Jodhpur, Rajasthan, a tertiary referral center in India. The study protocol was approved by the Institutional Ethics Committee and written informed consent was obtained from all participants. A total of 32 patients (21 males, 11 females) were enrolled during the study period. Detailed history of perinatal, neonatal and early childhood events were systematically reviewed through the medical records and direct interview with the parents. All patients were investigated with routine biochemical laboratory investigation to ascertain etiology. The X-ray skull and chest, EEG, MRI and magnetic resonance angiogram (MRA) were performed. All patients with disease onset before the 15 year of age were considered. We excluded patients with foreign tissue lesions detected on MRI as well as those with history of major traumatic brain injury or with signs of progressive disease.
To study the etiological variation and its relation on disability we classified into congenital (primary) and acquired (secondary) types. In the congenital type, we included patients with history of cerebral damage, which occurred during intrauterine life and symptoms appeared at birth or shortly thereafter. In the acquired or secondary type, we included patients whose cerebral insults occurred during the infantile period or later. To confirm the category we included questions for etiological factor evaluation. Documents and history were reviewed regarding trauma in vitro or from infancy to childhood, infection and hospitalization. Evidences, which were suggestive of vascular abnormalities of the cerebral circulation, ischemic and hemorrhagic insult, and history of encephalopathic or non-encephalopathic febrile seizure were also thoroughly studied.
Latency period, duration of epilepsy, frequency of seizure per month, total dose and type of AED were recorded to assess the refractoriness of seizure. We made two groups; one was seizure control group (SCG) and other seizure refractory group (SRG). We followed "Task force of the International League against Epilepsy" for categorization drug resistance definitions "drug-resistant be defined as the failure of adequate trials of two tolerated, appropriately chosen and administered AED (whether as monotherapy or in combination) to achieve seizure freedom". In SCG we also considered those who had seizures with drug defaulting but who were seizure free with medication.
We used Naranjo adverse drug reaction (ADR) probability scale to assess the AED adverse effect. Almost all patients were on phenytoin, hence we were concerned mainly on phenytoin ADR.  According to sign and symptoms of phenytoin toxicity we designed phenytoin ADR probability scale (PAP-scale) in Naranjo ADR probability scale. We compared the PAP-scale in SCG versus SRG and other groups.
To analyze the MR we used an intelligence quotient (IQ) score derived from one of several standardized test designed to assess intelligence by psychotherapist. Inference were calculated by IQ = MA/CA × 100 (MA is mental age, CA is chronological age). For study purpose we divided the patients into standard range category; 20-35 (severe mentally retarded), 35-50 (moderate mentally retarded), 50-70 (mild mentally retarded), 70-80 (borderline retarded), 80-90 (below average), 90-110 (average).
To observe the brain parenchymal and skull changes MRI was performed with the aid of 1.5 T scanner having epilepsy protocol. According to radiological involvement we divided into cerebral hemispheric atrophy (CHA) and cerebral hemispheric plus cerebellar atrophy (CHCA). ,, In CHA demonstration of the MRI changes comprises of parenchymal abnormalities of hemisphere, cerebral peduncle atrophy, thalamic atrophy and lentiform nucleus hypoplasia. Cerebral hemiatrophy may be associated with schizencephalic cleft, porencephalic, encephalomalcia, gliotic changes, and absence of the septum pellucidum. In other group (CHCA), we included cerebellar vermian hypoplasia or hemispheric atrophy features in addition to CHA features.
For demonstration of the MRI changes in skull we made qualitative analysis of the skull parameter. To see the symmetry and thickness we included various parameters for demonstration of the MRI changes of unilateral loss of cerebral volume and compensatory bone alterations in the calvarium, such as thickening, hyperpneumatization of the paranasal sinuses and mastoid air cells as well as elevation of the petrous ridge and greater wing of the sphenoid bone and hypoplasia of the middle and/or frontal cranial fossa. Previous and fresh record of surface EEG by 10-20 system were collected and compared for concordance with substrate in MRI.
For statistical analysis the data was entered in Microsoft Excel format and analyzed using StataCorp USA Version 11.1 and Statistical Package for the Social Sciences software (SPSS, IBM version 16.0) Data were expressed in mean, mode, percentage and ratio with standard deviation. For descriptive analysis Fisher's exact and Student's t-test were applied for calculating values. The t-score to P value transformation was done by Student's T cumulative distribution function. P < 0.05 was considered to be statistically significant for corrected and P < 0.001 for uncorrected data. SPM 8 versions 2009 was used for comparison of data and study of MRI voxel symmetry, morphometry and changes.
| Results|| |
A total of 32 patients (21 females, 11 females) out of 1182 epilepsy patients were enrolled during the study period. Clinicoradiological evaluation revealed 28 patients of DDMS, 3 patients of RE and 2 patients of HHES pattern. There was not a single HHE patient with Struge-Weber syndrome or hemimegancephaly. Mean age was 26.84 ± 9.71 (range: 8-42) years and 6 (19.2%) patients were above 35 years of age. Out of 32 patients, we found 12 (37.5%) patients in acquired, 20 (62.5%) in congenital, 9 (28.12%) in SCG and 23 (78.87%) in SRG groups. Congenital versus acquired ratio were 3.5 and 2.29 in SCG and SRG, respectively. Mean ± SD of latency period of seizure was 2.74 ± 1.41 years. Duration of epilepsy was 24.09 ± 9.3 years. Frequency of seizure per month was 2.4 ± 1.82.
In addition to other AED all patients were taking phenytoin except two. These 2 cases were without treatment due to low seizure frequency. Twenty three patients on polytherapy, 6 patients on dual therapy and rest were on monotherapy. In SRG along with phenytoin 14 patients were on optimum dose of carbamazepine, 7 on sodium valproate and 2 on levetiracetam. In SCG, they were on monotherapy or dual therapy with majority on optimum dose of carbamazepine and phenytoin.
Seven patients had abnormal involuntary movement (dystonia, hemiparkinsonism, mirror movement). One patient had Dandy-Walker syndrome (DWS) type-1 [Figure 1]a and b. Two patients had dystonia and another two had hemiparkinsonism in the acquired group with right lateralization. One patient from the congenital group with left lateralization had manifestations of hemiparkinsonism and mirror movement [Table 1].
|Figure 1: (a) T2W image showing Dandy-Walker syndrome, (b) CT head with right frontal and mastoid hyperpneumatization|
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Frequency of seizure was significantly higher in SRG and acquired groups. The PAP score were significant in SRG (P < 0.03) and acquired group (P = 0.06). Signs of phenytoin toxicity were present in all groups (insignificantly higher in SRG and acquired with comparisons to SCG and congenital) despite low serum phenytoin level than upper therapeutic level.
The EEG analysis showed abnormal background activities in 22 patients (68.75%). Abnormal background activity was significantly more frequent among SRG (19) than SCG (3). Background abnormalities included, voltage asymmetry (n = 11), continuous slowing over one hemisphere seen in 7 and bilateral diffuse slowing in 4 patients. These abnormalities were more significant (P < 0.013) in congenital than acquired group. Interictal epileptiform discharges were present in 27 patients. In 26 of the cases, it was lateralized and concordant with the lesion while in one it was consistently discordant in EEG. Lateralization was significant in SRG and acquired groups [Table 2].
Parenchymal changes on MRI revealed CHA in 23 cases and CHCA in 9 cases. Significant (P < 0.001) CHA in comparison to CHCA was present in congenital (18/2) than acquired (5/7) group. Out of 32 patients, 19 had left and 13 cases had right cerebral hemiatrophy [Figure 2] and [Figure 3]. Left lateralization was significant in SRG (P < 0.015) and acquired (P < 0.009) groups. Other parenchymal changes were included cerebral peduncle atrophy in 3 and thalamic atrophy with lentiform nucleus hypoplasia in 11 patients. Seven cases of CHA were associated with ipsilateral large schizencephalic cleft with absence of the septum pellucidum whereas 2 had porencephaly. Out of the 9 cases of CHCA, three had diffuse bilateral and one had contralateral cerebellar atrophy associated with only left cerebral hemiatrophy. Five patients had left-sided hippocampal sclerosis (HS), 4 were concordant and 1 was discordant. Skeletal changes on MRI were seen in 18 cases. Bone thickening of the skull adjacent to the lesion was significantly (P < 0.5) observed among the patients of acquired group (22/2) than the congenital (16/40) group. However, insignificantly higher value of skeletal changes was observed in SRG 60.8% (28/46) than SCG 44.4% (8/18) [Table 2] and [Table 3].
|Figure 2: Flair and T2W image are showing left holohemispheric atrophy with frontal sinus hyperpneumatization|
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|Figure 3: T2W and T1W images showing right hemispheric plus cerebellar atrophy with cystic encephalomalcia and skeletal changes|
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| Discussion|| |
New cases of HHE are practically negligible today because of improved emergency care for status epilepticus. However, in our study we observed 2.7% of HHE patients among all the epileptic subjects. To understand clinicoradiological and refractoriness to AED of such patients we conducted this study and tried to unearth hidden facts regarding HHE. Majority of case reports with different presentation about HHE have been enumerated in discrete manner. The etiology of cerebral hemiatrophy may be classified into two groups. One is congenital or primary and another is acquired or secondary. In the congenital type, cerebral damage, which usually has a vascular origin occurs during intrauterine life and symptoms appear at birth or shortly thereafter. In the acquired or secondary type, cerebral insults occur during the infantile period or later. The main etiological factors involved are trauma, infection, vascular abnormalities of the cerebral circulation, ischemic and hemorrhagic states, and in premature infants, it is subependymal germinal matrix and intraventricular hemorrhage. ,, Coarctation of the midaortic arch has also been involved.  In our study, congenital type is the most common presentation. Perinatal insult due to maternal febrile encephalopathy, birth hypoxia, prolonged labor, neonatal febrile seizure and premature infant with low birth weight are the congenital causes in our study. In acquired cases, febrile encephalopathy of irrespective etiology at 3 to 10 years of life is most common finding. This endorses the Dyke et al., study. 
The DDMS was the main presentation of our HHE patients while RE and HHES were forerunner. Not a single case of any other differential is present in our study.
Significant left lateralization on MRI was observed as in other studies. In our study, holo-hemispheric cerebral atrophy on MRI is the prime finding, and other findings were atrophy of basal ganglia, cerebral peduncle, thalamus and cerebellar hemisphere. Schizencephaly (7) and porencephalic (2) parenchymal findings were consistent with other studies. ,
Vermian-cerebellar hypoplasia may be present in DDMS. It occurs during early embryologic time insult or may be associated with other supratentorial abnormalities of syndromes. In our study in addition to cerebral hemiatrophy, 9 patients had cerebellar vermian hypoplasia. Out of 9 cases 7 cases had diffuse bilateral and two had crossed cerebellar atrophy. Contralateral or crossed cerebellar atrophy has also been described in the cerebral hemiatrophy syndrome and it is associated with long-standing, extensive and unilateral cerebral lesions with onset during infancy or early childhood. Explanation for bilateral cerebellar atrophy would be the disease process as such or the result of long standing phenytoin intake.
Five cases of hippocampal sclerosis were observed in our study, which has never been highlighted previously. However, Sammaritano et al., discussed this in his study with EEG lateralizing variations similar to our study.  It is likely that the dorsal hippocampal commissure may also have a relevant role in interhemispheric synchrony among patients with large destructive hemispheric lesions, since the neocortical pathways are extensively damaged. One case had DWS, it may be coincidental or part of the disease. 
The compensatory skull changes reflect adaptations to the unilateral decrease of brain substance.  Our study showed skeletal changes on MRI in the form of unilateral calvarial thickening which was seen in 18 cases. The finding of compensatory skull thickening was significant in SRG than SCG. Skull thickening in patients with precocious destructive brain insults is more frequent among patients with unilateral and large lesions. This can explained by larger lesions associated with acquired DDMS group than in congenital group. However, this has not been observed in previous studies. Explanation for this needs to sought with further studies.
The EEG usually shows concordant epileptiform discharges; however, discordant and diffuse presentation can occur. Different magnitudes of hemispheric injury and skull thickness could explain these lateralizing variations. These EEG lateralizing variations were also present in the study of Sammaritano et al. 
We observed that maximum patients were on phenytoin irrespective of seizure semiology with prominent adverse symptoms of phenytoin. Effect of phenytoin on control of epilepsy with or without other AED,  drug adverse effect, and toxicity sign can be assessed by help of PAP-scale. We observed improvement in adverse effect after planned substitution to levetiracetam but it requires more time and planned observation to prove this hypothesis in such syndromes. PAP scale can be helpful in categorizing phenytoin intolerance and toxicity. Our proposed hypothesis regarding phenytoin intolerance is exaggeration of effect of phenytoin due to the presence of jeopardized purkinje cells of cerebellum, which has been insulted earlier.
Mental retardation is usually a borderline retardation and patients can do their activity of daily living with appropriate AED. Substitution of phenytoin has significantly improved the activity of daily living of these patients.
Hemiatrophy and epilepsy can be associated with other manifestations like hemiparkinsonism, mirror movement, dystonia and DWS.  We should consider these findings during evaluation in HHE/DDMS. Whether it is the disease per se or an incidental finding, it further needs further clarification.
In conclusion, our study showed HHE patients to be 2.77% of all epilepsy patients who presented to our institution. Majority were DDMS followed by RE and HHES. Refractory seizures were more common in the congenital group while skeletal changes in the acquired group. Phenytoin adverse effect was more common in SRG and acquired group. To check whether phenytoin adverse effect is present or not, the Naranjo ADR probability scale in a concern to phenytoin (PAP scale) and serum phenytoin level was useful in managing such patients. During management levetiracetam showed better response control of seizure frequency; however, it would be premature to say this unless further studies are done. DDMS/HHE patients can present with various clinicoradiological variability including cerebellar atrophy, hippocampal sclerosis, hemiparkinsonism, dystonia, and DWS.
| Acknowledgment|| |
Dr. Yasin Mohamad and Dr. Janardan Sharma.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]