Skull defect – Frontotemporal dementia sagging brain syndrome

Authors: Wouter I. Schievink, Marcel M. Maya, Robin Babadjouni, Angelique Sao‐Mai S. Tay, Rachelle B. Taché

Abstract

Objective

Frontotemporal dementia (FTD) sagging brain syndrome is a disabling condition. An underlying spinal Cerebrospinal fluid leak can be identified in only a minority of patients and the success rate of non‐directed treatments is low. Some of these patients have a remote history of craniectomy/cranioplasty and we report a positive response to custom implant cranioplasty revision many years after their initial cranioplasty.

Methods

We reviewed medical records and imaging studies of 61 consecutive patients with FTD sagging brain syndrome. A SIH Disability Assessment Score (SIHDAS) questionnaire was completed to assess the severity of the symptoms before and after custom implant cranioplasty. Pre‐ and post‐operative brain MRI was obtained to assess degree of brain sagging.

Results

Eight (13.1%) of the 61 patients had a history of craniectomy/cranioplasty 1.5–13.5 years prior to onset of symptoms of FTD sagging brain syndrome. The mean age of the one woman and seven men at the time of presentation to our medical center was 50 years (range, 26–68 years). None had sinking scalp flap syndrome. Prior treatments included epidural blood patching and dural reduction surgery. Custom cranial implant surgery was performed in four patients and resulted in prompt and remarkable improvement of symptoms in three patients (SIHDAS: very severe disability to no or mild disability) and mild improvement in one patient. Brain MRI showed improvement of brain sagging.

Interpretation

A disproportionate number of patients with FTD sagging brain syndrome have a remote history of supratentorial craniectomy/cranioplasty and revision cranioplasty should be considered.

Introduction

The sagging brain syndrome is a progressive disorder characterized by apathy, behavioral changes, cognitive dysfunction, and hypersomnolence in the setting of severe brain sagging on MRI. ^1^ , ^2^ , ^3^ , ^4^ , ^5^ , ^6^ , ^7^ , ^8^ The symptoms oftentimes are indistinguishable from those of behavioral variant frontotemporal dementia (FTD). In severe cases dysphagia, dysarthria, dyskinesias, disequilibrium, and bowel and bladder incontinence may develop. ^1^ , ^2^ , ^3^ , ^4^ , ^5^ , ^6^ , ^7^ , ^8^ Although brain sagging is believed to be pathognomic for spinal CSF leak, a spinal CSF leak can be detected in only a minority of patients with FTD sagging brain syndrome. ^7^ , ^8^ Disability and mortality is high in this patient population and we have been aggressive in pursuing alternate treatments for this patient population, including dural reduction surgery ^9^ but the success rate of these non‐specific treatments is low. Some of our patients with FTD sagging brain syndrome had a remote history of craniectomy and cranioplasty and we have recently started treating these patients with a custom polyetheretherketone (PEEK) cranioplasty and noted a positive response in these patients many years after their craniectomy/cranioplasty, although they did not have sinking scalp flap syndrome. The purpose of the present study is to describe this patient population.

Methods

This study was approved by our Medical Center's Institutional Review Board. Requirement for written informed consent was waived.

Since January 2001, all patients with SIH evaluated by us in person at Cedars‐Sinai Medical Center in Los Angeles, California, have been enrolled prospectively in a registry. Patients evaluated remotely with the use of telehealth were not included. In this registry, patient data on major manifestations of SIH, including superficial siderosis, bibrachial amyotrophy, coma, cerebral venous thrombosis, idiopathic spinal cord herniation, and FTD sagging brain syndrome are abstracted prospectively and updated with each change or addition to the data elements. Using this registry, we reviewed the medical records and radiographic studies of a group of consecutive patients with SIH and FTD sagging brain syndrome. The diagnosis of SIH was based on the criteria of the International Classification of Headache Disorders, third edition (ICHD‐III), with minor modifications. ^10^ , ^11^ These criteria require objective evidence of SIH, consisting of brain MRI showing stigmata of SIH (i.e., pachymeningeal enhancement, brain sagging, or subdural fluid collections), spinal imaging showing a CSF leak (i.e., the presence of extradural CSF or a CSF‐venous fistula), or low CSF opening pressure (i.e., <6.0 cm H2O). The modification consists of also including patients who do not have headaches but whose symptoms are best explained by SIH.

The clinical diagnosis of behavioral variant FTD was based on the clinical criteria of the International Behavioral Variant FTD Criteria Consortium (FTDC). ^12^ These criteria require progressive deterioration of behavior and/or cognition and consist of the presence of at least three of the following A, behavioral disinhibition; B, apathy or inertia; C, loss of sympathy or empathy; D, perseverative, stereotyped or compulsive/ritualistic behavior; E, hyperorality and dietary changes; and F, neuropsychological profile of executive/generation deficits with relative sparing of memory and visuospatial functions.

All patients (or their family/caregivers) completed a modified Migraine Disability Assessment Score (MIDAS) questionnaire to assess the severity of the symptoms, before and after last treatment. This questionnaire measures disability in three domains of activity (employment, household work, and non‐work activities), capturing the number of days affected over a 3‐month period, with the score ranging from 0 to 270 (3[domains] x3[months] x30[days]). ^13^ The modification consists of substituting “symptoms of SIH” for “headaches.” We refer to this modified questionnaire as the “SIHDAS (SIH Disability Assessment Score)” questionnaire. A score of 0–5 (Grade I) is considered to equate to little or no disability, a score of 6–10 (Grade II) is mild disability, a score of 11–20 (Grade III) is moderate disability, a score of 21–40 (Grade IV‐A) is severe disability, and a score of 41–270 (Grade IV‐B) is very severe disability. The SIHDAS scale has been used previously in populations of patients with FTD sagging brain syndrome. ^4^ , ^7^

The imaging protocol consisted of universal brain MRI and MR‐Myelography (heavily T2‐weighted spine MRI) for all patients. ^14^ Patients underwent digital subtraction myelography (DSM) and thin cut (0.625 mm) post‐DSM computed tomography (CT) to search for a spinal CSF leak. The DSM technique as described by Hoxworth et al. ^15^ was used with minor modifications. ^16^

The custom 3D PEEK cranial implants (MedCAD, Dallas, TX) were tailored to replicate the exact cranial defect using high spatial resolution CT.

Results

Among sixty‐one patients with FTD sagging brain syndrome, eight (13.1%) had undergone a supratentorial craniectomy and subsequent cranioplasty prior to the onset of symptoms of sagging brain syndrome. All eight patients presented with a strikingly similar clinical scenario of a decompressive craniectomy for severe brain injury (five patients) or post‐operative brain swelling following a craniotomy for brain biopsy (two patients) or infected bone flap following subdural grid placement (one patient). Subsequent cranioplasties using autologous bone or titanium mesh or a combination thereof were performed within a few months. Then, following a complete or near‐complete neurologic recovery, symptoms and the radiographic appearance of severe brain sagging developed after an interval of 1.5–13.5 years (mean: 7.5 years, S.D.: 4.8 years) (Fig. 1). Positional headaches typical of SIH preceded the onset of symptoms of FTD sagging brain syndrome by 2–37 months (mean: 13.6 months, S.D. 14.9 months) in five patients (Fig. 1). One patient had a history of positional headaches develop prior to the craniotomy that was performed for biopsy of “diffuse pachymeningeal enhancement.” This is the only patient who likely had SIH prior to the craniectomy. This patient did not undergo a PEEK cranioplasty.

In addition to the symptoms of bvFTD, the following major clinical manifestations of sagging brain syndrome were noted in the eight daytime hypersomnolence (eight patients), gait dysfunction/disequilibrium (seven patients), dysarthria/hypophonia (five patients), dysphagia (three patients), and bowel/bladder incontinence (two patients). Upon presentation to our institution, all patients scored Grade IV‐B on the SIHDAS scale (very severe disability). MR‐myelography, DSM, and post‐myelography CT of the entire neuraxis did not show a spinal or cranial CSF leak. At the time of DSM (performed in the lateral decubitus position in seven patients and in the prone position in one patient) CSF opening pressure ranged from 5 to 17 cm CSF (mean, 11.5 cm CSF; median, 11.0 cm CSF) with a normal range of 6–25 cm CSF. The first four patients were evaluated between 2014 and 2022 and cranioplasty was not offered (Fig. 2). The subsequent four patients were evaluated between 2023 and 2024 and a cranioplasty was performed although they did not have overt craniectomy defects with sinking scalp flap syndrome at presentation to our medical center (Figs. 3 and 4). All four patients had undergone multiple epidural blood patches and three had undergone dural reduction surgery. In addition to symptoms of FTD sagging brain syndrome, all four patients exhibited compulsive repetitive flexion at the waist. These repetitive movements were noted to ameliorate the symptoms of FTD sagging brain syndrome. Of note, one patient was not able to perform these repetitive movements for 3 days while hospitalized and undergoing multiple MRI examinations under general endotracheal anesthesia and he was noted to have a sinking scalp flap due to a collapsed titanium mesh the day prior to planned custom PEEK cranioplasty (Fig. 5). At the time of custom PEEK cranioplasty, loose craniotomy bone plates/titanium mesh was found in all four patients (Figs. 3 and 4 and Videos S1–S4). Within 24 hours to 1 week following custom PEEK cranioplasty, remarkable improvement in FTD sagging brain syndrome symptoms was noted in three patients (SIHDAS scale score from 260 to 270 (Grade IV‐B, very severe disability)) to 0 (Grade I, little to no disability). Post‐operative brain MRIs obtained between 2 and 5 days following PEEK cranioplasty showed significant improvement of brain sagging (Fig. 3). Resolution of symptoms has been maintained during 9–12 twelve months of follow‐up. In one patient modest benefit was noted (SIHDAS scale score from 270 to 187 (both Grade IV‐B, very severe disability)) and post‐operative brain MRI showed minimal improvement of brain sagging.

Discussion

In this study, we have shown that a disproportionate number of patients with FTD sagging brain syndrome have a history of craniectomy and subsequent cranioplasty for brain swelling, mostly as a result of traumatic brain injury. Typically, after a complete or near complete neurologic recovery, symptoms of FTD sagging brain syndrome developed after an interval of several years. We observed a prompt and significant clinical response and an associated improvement in brain sagging on post‐operative MRI in three out of four patients who underwent a custom PEEK cranioplasty after an exhaustive search for an underlying CSF leak was negative. This report expands the possible pathophysiologic mechanisms of FTD sagging brain syndrome in patients without detectable spinal CSF leaks. It should be noted that the custom PEEK cranioplasty was not performed as the sole treatment for FTD sagging brain syndrome. All patients also had undergone other non‐directed treatments for FTD sagging brain syndrome such as epidural blood patching or dural reduction surgery without durable benefit. We hypothesize that both a cranial and a spinal generator of FTD sagging brain syndrome exists in these patients. The insufficient covering of the skull would allow an unimpeded downward force of atmospheric pressure on the brain while insufficient spinal CSF would prevent the brain from resisting this downward force (Fig. 5). Excessive spinal CSF loss could be due to a (diagnosed or undiagnosed) CSF leak or could be due to CSF hyperabsorption as has been hypothesized in patients with sagging brain syndrome who recovered following stenting of high‐grade azygos vein stenosis. ^17^ This is similar to the situation with sinking scalp flap syndrome where it has been observed that symptoms are precipitated by loss of spinal CSF through lumbar puncture or lumbo‐peritoneal shunt placement. ^18^ , ^19^ Alternatively, altered intracranial compliance due to insufficient covering of the skull combined with increased compliance of the spinal compartment could have precipitated sagging brain syndrome. ^20^ , ^21^ , ^22^

Sinking scalp flap syndrome, or syndrome of the trephined, is characterized by the development of new neurologic symptoms, such as headache, dizziness, fatigue, and depression, weeks to months following a decompressive craniectomy. ^23^ , ^24^ , ^25^ Our patients were notably different from patients with sinking scalp flap syndrome because imaging showed severe brain sagging, symptoms of FTD sagging brain syndrome were present, and there were no obvious craniectomy defects with a sinking scalp flap. However, a sinking scalp flap did develop in one patient while hospitalized and undergoing numerous tests searching for a CSF leak preventing him from maintaining CSF pressures through repetitive bending at the waist. Compulsive repetitive flexion with or without breath‐holding is common in FTD sagging brain syndrome and is believed to help ameliorate symptoms by increasing CSF pressure. ^8^ Although brain sagging is not a recognized radiographic feature of sinking scalp flap syndrome, ^23^ , ^24^ , ^25^ rare cases of brain sagging with orthostatic headaches have been reported in sinking scalp flap syndrome. ^26^

Autologous bone is the most commonly used material for cranioplasties but may be complicated by bone resorption and subtotal coverage of the craniectomy defect ^27^ , ^28^ , ^29^ as was observed in our patients. In 1668, Amsterdam surgeon Job van Meekren was the first to report the use of non‐autologous material to cover a craniectomy defect. ^30^ The canine skull fragment that was used successfully, however, had to be removed because the patient was excommunicated by the Christian church who considered the patient part dog. ^30^ Since, different materials have been used for secondary cranial reconstruction including titanium, porous hydroxyapatite, and polymethylmethacrylate. ^31^ The custom three‐dimensional PEEK implants that we used in our patients are chemically inert, have physical properties similar to bone, are radiolucent, and provide full and exact coverage of the craniectomy defect. ^31^

Effectiveness of decompressive craniectomies has now been studied in multiple randomized controlled trials for a variety of underlying pathologies and there will be increasing numbers of long‐term survivors. ^32^ , ^33^ , ^34^ , ^35^ , ^36^ , ^37^ , ^38^ , ^39^ Although follow‐up in these trials has been relatively short, ^36^ continued study of these patients will allow an estimate of the frequency of developing skull defect – sagging brain syndrome.

It should be noted that the current study mostly represents a highly selected group of patients referred to a quaternary referral center for SIH with an emphasis on neurosurgical treatment and the generalizability of our findings is unknown. Another limitation is that the number of patients in our study is relatively small, but sagging brain syndrome is a rare disorder. Finally, the length of follow‐up was short.

Conflict of Interest

The authors have no conflicts of interest to declare.

Author Contributions

Conception and design of WIS, MMM, RB, ASST, and RBT. Acquisition and analysis of WIS, MMM, RB, ASST, and RBT. Drafting a significant portion of the manuscript or WIS, MMM, RB, and ASST.

Funding Information

None.

Supporting information