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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Arch Neurol. Author manuscript; available in PMC 2010 August 11.
Published in final edited form as:
PMCID: PMC2922039
NIHMSID: NIHMS223237

Subdural Fluid Collections in Patients with Infantile Neuronal Ceroid Lipofuscinosis

Sondra W. Levin, M.D.,1,2,Ж§ Eva H. Baker, M.D., Ph.D.,3,§ Andrea Gropman, M.D.,4 Zenaide Quezado, M.D.,5 Ning Miao, M.D.,5 Zhongjian Zhang, M.D., Ph.D.,1 Alice Jollands, M.D.,6 Matteo Di Capua, M.D.,7 Rafael Caruso, M.D.,8 and Anil B. Mukherjee, M.D., Ph.D.*,1

Abstract

Objective

To describe subdural fluid collections on magnetic resonance imaging (MRI) as part of the natural history of infantile neuronal ceroid lipofuscinosis.

Design

Case series

Setting

Program on Developmental Endocrinology and Genetics, The Clinical Center, The National Institutes of Health, Bethesda, Maryland.

Results

During an ongoing bench-to-bedside clinical investigation, MRI examinations led to the incidental discovery of subdural fluid collections in four of nine patients with INCL. No particular event (such as trauma) or change in symptoms was linked to this finding, which was already in the chronic phase when discovered. Of the four patients, one was followed for 7 years, two for 4 years and a fourth patient was followed for 2.5 years. Over time, these collections remained stable or decreased in size.

Conclusion

Recognition that subdural fluid collections are part of the INCL disease process may obviate the necessity of additional workup as well as therapeutic interventions in these chronically sick children.

Introduction

Mutations in eight different genes cause neuronal ceroid lipofuscinoses (NCLs), the most common (1 in 12,500 births) neurodegenerative storage disorders of childhood.1-4 Infantile form of NCL or INCL, the most lethal disease among all the NCLs, is caused by mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene.5 PPT1 catalyzes the cleavage of thioester linkages in S-acylated proteins facilitating their recycling or degradation. The lack of thioesterase activity due to PPT1 mutation causes the accumulation of s-acylated proteins (ceroids) leading to INCL pathogenesis. Children afflicted with this disease are normal at birth, but by two years of age they undergo complete retinal degeneration and by age four brain activities become undetectable. Currently, there is no treatment for INCL and it remains a uniformly fatal disease. Our laboratory studies indicated that cysteamine and N-acetylcysteine facilitate the removal of ceroids from cultured cells from INCL patients.6 A bench-to-bedside clinical protocol was initiated to determine whether cysteamine bitartrate (cystagon) alone or in combination with N-acetylcysteine (mucomyst) is beneficial for patients with INCL.

REPORT OF CASES

Protocol and patients

The clinical protocol was approved by the Institutional Review Board (IRB) of the Eunice Shriver Kennedy National Institute of Child Health and Human Development (NICHD) at the National Institutes of Health (NIH). To date 9 patients with INCL (carrying the most lethal mutations in the PPT1 gene) were admitted to this protocol study and followed for up to 7 years.

Patient INCL-1

This patient entered the NIH protocol at age 25 months. As part of our ongoing evaluation, all patients in this protocol underwent head MRI examination, which included standard clinical images: T1-weighted, T2*-weighted, FLAIR, diffusion-weighted, and T2 gradient echo image. Brain MRI of this patient at age 25 months demonstrated diffuse brain atrophy (Figure 1a). At age 31 months, extensive chronic subdural fluid collections, located adjacent to the frontal lobes and adjacent to the occipital lobes, were discovered (Figure 1b); the occipital collections contained layering blood products. At age 34 months, surgical drainage of the fluid collections was performed at another institution. At age 38 months, brain MRI showed that the occipital fluid collections were slightly smaller, while the frontal fluid collections were similar in size and there were new blood products in the left frontal fluid collection (Figure 1c). Over the course of the next 5 years, these collections gradually became smaller, with evidence of further bleeding episodes in the left occipital collection between 63 and 74 months (Figure 1d&e), and again between 74 and 84 months (Figure 1e&f) of age. Bridging vessels (Figure 1g) that are the likely source of the hemorrhages, as well as the simultaneous presence of subdural hemorrhages of varying ages (Figure 1h) can be readily visualized.

Figure 1
Progression of subdural fluid collections in patient INCL-1. The images are serial T2 weighted images of the same image plane through the lateral ventricles. Subdural fluid collections developed between age 25 months (a) and age 31 months (b). Layering ...

PATIENTS INCL-2 AND INCL-3

These two patients (fraternal twins) were enrolled in the protocol at age 27 months. Over four years of follow-up, both of these patients demonstrated ongoing albeit slow developmental regression and progressive cortical atrophy. At 45 months INCL-2's brain MRI showed a small extradural fluid collection adjacent to the left frontal lobe and an even smaller collection adjacent to the right frontal lobe (Figure 2a). The collections showed evidence of blood products (Figure 2b and 2c). The subdural fluid collections became smaller over the following 2 years. For INCL-3, bilateral parietal subdural collections were discovered at age 71 months (Figure 2d). Both collections contained blood products (Figure 2e and 2f)

Figure 2
Progression of subdural fluid collections in patient INCL-2 and INCL3. a) Serial T2-weighted images (ages 36, 45, 59, and 71 months) of the same image plane show that the subdural collections appear at age 45 months. b) FLAIR image at age 59 months shows ...

PATIENT INCL-4

Patient INCL-4 entered the NIH protocol at age 29 months. At this time the brain MRI showed progressive brain atrophy, and at age 49 months a follow-up brain MRI revealed subdural fluid collections adjacent to the left cerebral hemisphere (Figure 3a and 3b) as well as anterior to the tip of the right temporal lobe. Signal on the FLAIR images (Figure 3c) suggested that blood breakdown products were probably present in the left hemisphere fluid collection, although hemosiderin was not detected. At age 58 months, follow-up brain MRI showed hemosiderin deposition in the right temporal fluid collection (implying interval hemorrhage) and significant decrease in size of the left hemisphere fluid collection (Figure 3d). In all four patients, no traumatic events or any abrupt changes in clinical status corresponding to the development of any of the fluid collections were noted. No mass effect was noted for any of the fluid collections in any of the patients.

Figure 3
Progression of subdural fluid collections in patient INCL-4. The subdural collection appears between age 36 months (a) and age 49 months (b) (arrows), and is less prominent at age 58 months (d). FLAIR image at age 49 months (c) shows that the fluid does ...

COMMENT

The NCLs as a group are the most common (1 in 12.500 births) neurodegenerative storage disorders of childhood.1-4 The infantile form of NCL, caused by mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene,5 is the most devastating form of this disease. The clinical symptoms of INCL include irritability, progressive visual loss leading to complete blindness, seizures, and psychomotor deterioration that finally progresses to a vegetative state followed by death.1-4 Pathological findings include severe and progressive brain atrophy and the presence of autofluorescent storage material in both neuronal and other cell types.1-4 While the clinical manifestations of all types of NCLs are quite similar, the age of onset is variable. Thus, on the basis of age of onset, cellular ultrastructure, and the composition of the storage material, NCLs are classified into four major subtypes: infantile (INCL), late-infantile (LNCL), juvenile (JNCL), and adult types.1-4, 7-9 Recent reports indicate that mutations of at least eight different genes underlie the various forms of NCLs known to date.1-4

During the course of an ongoing clinical study to evaluate whether cystagon and mucomyst are beneficial for patients with INCL, 4 out of 9 patients were found to have subdural fluid collections. Previously, postmortem pathological analysis of brains from INCL patients have shown the presence of gelatinous subdural collections10 and these findings were correlated with MRI studies of INCL patients11. Moreover, the results of MRI studies on 18 patients with late infantile NCL (LINCL), which is caused by mutations in the tripeptidyl peptidase-1 (TPP1) gene and manifests a slower disease progression than INCL, have also been reported.12 However, subdural fluid collections in these patients were not specifically noted. Our results are consistent with those of the earlier reports.10, 11 Since 4 out of 9 patients in our protocol had subdural fluid collections, we wondered whether cystagon and mucomyst may have induced this abnormality. However, this possibility appears unlikely because: (a) despite the fact that cystagon has been used for many years in the treatment of cystinosis, subdural effusions have not been reported, and the only significant side effects of oral cystagon use are GI irritability and halitosis;13 (b) mucomyst (N-acetylcysteine) also has a long history of safe and effective use as a mucolytic agent, in the management of acetaminophen toxicity as well as contrast-induced nephropathy,14 but subdural fluid collections have not been reported; and (c) subdural fluid collections have been observed previously during pathological examinations of postmortem brains of untreated INCL patients10 and in MRI studies,11 although the specific PPT1 mutations in these patients were not known; therefore, it could not have been ascertained whether these patients carried the lethal PPT1 mutations as in the current patient population.

Similar subdural fluid collections have also been reported in other progressive diseases with associated cerebral atrophy. For example, patients with Menkes disease, a neurodegenerative disorder of copper metabolism, also develop subdural fluid collections.15 In this disease severe cortical and cerebeller atrophy are associated with abnormal cerebral vasculature, which may be one of the predisposing factors for the subdural fluid collections. However, marked cerebral atrophy and tearing of bridging veins as the brain recedes from the dura are also felt to account for this phenomenon16.Subdural fluid collections as early on as in the neonatal period have been demonstrated on CT in infantile olivopontocerebellar atrophy, a rare congenital disorder characterized by failure to thrive and neurological impairment.17 Glutaric aciduria type 1 is also a rare neurometabolic disorder that can present in the first years of life with chronic subdural hematomas that mimic nonaccidental trauma.18 Hermansky-Pudlak syndrome, manifested by oculocutaneous albinism, a storage pool deficiency, lysosomal accumulation of ceroid lipofuscin and bleeding tendency has also been associated with subdural fluid collections and retinal hemorrhages.19, 20

The prevailing theory for the formation of such subdural collections is shearing of cortical veins that become more vulnerable as cerebral atrophy progresses. Most of these disorders stand in stark contrast to reports of pediatric subdural hematomas occurring as a result of non-accidental brain trauma. These patients often present with acute onset of neurological symptoms. Additional supportive findings include retinal hemorrhages and occult fractures on radiological survey.21 Associated parenchymal injury may provide evidence for underlying traumatic brain injury.22 None of the INCL patients in our protocol presented with acute neurological symptoms or changes in their neurological status, and MRI findings were coincidental. The recognition that subdural fluid collections in INCL develop as a consequence of the disease process may prevent unnecessary additional investigation and intervention in these chronically ill children.

Acknowledgements

This research was supported in full by the intramural program of the NICHD, NIH. We thank the families of the patients for consenting their children to participate in this clinical study. We also thank the referring physicians, medical and nursing staff of the Mark Hatfield Clinical Research Center of the NIH for their support in conducting this study. We also thank Mr. Lance Johnston, Executive Director, Batten Disease Support and Research Association, for his continued support in making the patients’ families aware of our ongoing clinical protocol.

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