Persistence and regredience of intraspinal fluid collection determine symptom control in intracranial hypotension syndrome

Intracranial hypotension syndrome (IHS) is a consequence of cerebrospinal fluid (CSF) hypovolemia, caused by spontaneous or (micro-)traumatic CSF leakage into extra-arachnoidal and extradural spinal spaces [1]. The estimated annual incidence is 5 per 100,000 with a midlife peak and a female predominance [2]. The diagnostic criteria are (A) any headache fulfilling criteria B through D with (B) low CSF pressure (< 60 mmH₂0) and/or evidence of CSF leakage on imaging; (C) headache has developed in temporal relation to the low CSF pressure or CSF leakage or has led to its discovery (D) not better accounted for by another ICHD-3 diagnosis (Headache Classification Committee of the International Headache Society 2013). The overall spectrum of symptoms besides headaches is more diverse and commonly includes photophobia, dizziness, and tinnitus. Neurocognitive decline and brainstem ischemias have also been reported [3, 4].

In the case of chronic IHS, the headache may change from an initial postural character with severe headaches while standing into a milder and constant bilateral throbbing without clear orthostatic features [5]. This is important since it adds to the obscure nature of the disease and makes clinical observation more difficult. Although generally considered to be benign, especially chronic IHS may lead to secondary complications, such as cerebral sinus thrombosis and superficial siderosis (SS) [6], with potentially irreversible damage and in some cases even lethal consequences [7, 8]. These long-term sequels further expand the spectrum of symptoms that can be associated with an underlying chronic IHS pathology.

A variety of possible causes for the development of IHS exist including iatrogenic after surgery [9, 10]. In the past, a large proportion of IHS cases were considered to be idiopathic, since no clear etiology could be identified. In recent years, it has been suggested that microspurs and meningeal diverticula might explain many of those cases [11]. Independent of etiology spinal leakage leads to a common final path with CSF hypovolemia and extra-arachnoidal or extradural spinal fluid collection. First-line treatment is usually conservative, i.e., bedrest, head-down position, and administration of caffeine or theophylline, speculating on spontaneous closure of the leak over time. The next or alternative step is the application of repetitive blood patches without guidance. In cases of an identified leakage, CT-guided blood patches are performed [12, 13]. Moreover, an operative closure by administration of fibrin glue or a suture can be pursued.

The increased application of MRI frequently identifies not only supratentorial pathologies associated with IHS like subdural hematoma or the enhancement of the meninges but also an intraspinal fluid collection (ISFC) [14]. This fluid is hypothesized to be the accumulated leaked CSF. The exact anatomic compartment, in which spinal fluid collects, is sometimes difficult to assess and may vary from case to case. Both subdural and extradural extravasations of fluids have been described before [5]. In this study, the more general term ISFC is used to avoid confusion. In cases of chronic IHS with ISFC, the development of a SS is thought to be a serious complication. Hence, failure in leakage closure and ISFC resorption may lead to irreversible structural lesions of the central nervous system. The efficacy of the blood patches or surgery was often correlated to the reversal of cerebral abnormalities [15, 16]; however, more recently spinal alterations have become the focus of attention as well [17, 18]. The aim of the following study was to clarify the association of clinical disease activity with regard to persistence or regression of ISFC in chronic IHS and to study long-term sequels with regard to the occurrence of a cerebral hemosiderosis. We postulated that spinal MRI is a necessary and effective tool to monitor disease activity.

Ten patients were examined and included in our data analysis. The eleventh patient underwent radiological follow-up examination, stated to be free of symptoms, but did not attend neurological follow-up examination. Since he did not comply with the study protocol, he had to be excluded. Of those participating in the study, four were female and six male (medium age 51.1 years). Median time from therapy to follow-up was 3 years (Q1 2 years, Q3 6 years).

Spinal imaging has become an essential part in the diagnosis and therapy of IHS [22]. Identification and localization of the CSF leak(s) may be difficult and influenced by the flow character in the leakage (low flow versus high flow). Different myelographic techniques (fast or ultra-fast CT myelography, digital subtraction myelography) were developed to overcome this problem [19, 20]. Spinal MRI can demonstrate various secondary spinal manifestations of IHS like ISFCs, dilated veins, and dural enhancement [2]. Supratentorial changes, as, for example, subdural hygromas, that are usually included into follow-up examination to ascertain regression are increasingly complemented by spinal imaging as well [18]. Since repeated or chronic microbleeds in IHS cases with an associated ISFC can lead to complications like SS [23] with potentially irreversible neurological deficits, spinal imaging rightfully deserves our attention. It has been theorized that drag caused by intracranial hypotension leads to an engorgement of intradural veins causing the subsequent microbleeds [24] and accumulation of hemosiderin on the brain surface and its subpial layers [25, 26] resulting in a cytotoxic effect through free iron and hydroxyl radicals [27]. Etiology of SS may vary with traumas, arteriovenous malformations, and tumors being among others [6]. However, in about half of the patients, no etiology is identified [28]. It is in these cases one has to be aware of the possibility of an underlying chronic IHS, which may be identified by the diagnosis of an ISFC. In cases #2 (Fig. 2) and #10, the leak persisted despite of the regression of orthostatic headache and led over a period of 15 and 8 years, respectively, to the development of a SS with debilitating symptoms like among others gait ataxia and hypacusis. Case #2 demonstrated SS of significant extent affecting frontal, sulcal, occipital, and intrathecal structures possibly due to the long time course disease progression was not stopped.

Not every leak seems to be accompanied by classical symptoms of IHS. Case #5 (Fig. 3), which originally demonstrated a recurrent leak at level L4/5 following facet infiltration, showed an extensive intraspinal fluid collection at the time of follow-up. However, the initial symptoms of IHS had ceased, and the patient presented himself free of complaints. A possible explanation is the development of a new equilibrium between the different spinal compartments and the surrounding connective tissue preventing further spreading while the leak itself remains unclosed. According to the Kelly-Monroe doctrine, the space within the central nervous system is limited. If one of the containing elements therein—blood, liquor, and brain parenchyma—increases in volume, the others must decrease. Through an extradural extension of liquor, this above-mentioned principle may be compensated and clinical symptoms may not be manifested. This may add to the variable and inconclusive clinical picture of chronic IHS and emphasizes the need for neuroradiological control examinations (Fig. 3).

To our knowledge, this is the first study analyzing a long-term follow-up of IHS. In our cohort of patients, the median time interval from therapy to follow-up exam was 3 years. While this might be too short for reliably detecting SS, it can identify a recurrent or not regressing ISFC as described in case #5. It is of interest to note that both cases with SS had a particularly long time interval from therapy to follow-up. This indicates that complications of chronic IHS can manifest themselves even more than a decade after diagnosis. Figure 4 proposes a decision tree to be used in case of IHS. If an ISFC accompanies the diagnosis of an IHS, spinal follow-up examination is always recommended regardless of symptom control or regression. In our diagram, we propose an examination interval after therapy of 6 months to ascertain reduction of the ISFC. When no neuroradiological signs are present, the opaque nature of the clinical appearance of chronic IHS can make diagnosis difficult. In this case, a diagnostic reevaluation should take place in order not to miss possible treatable other causes for the complaints. In patients free of ISFC and without symptoms, no disease activity is to be expected.

The study was not designed to determine the incidence of an ISFC in patients with IHS. However, our retrospective analysis of patients with chronic IHS in our institution suggests that an ISFC can be found in a significant percentage of cases.

The protocol of spinal examinations should encompass T1 and T2 spin echo sequences for demonstration of intraspinal fluid collections. While the T2 spin echo sequence is effective in showing the dural sac, the T1 sequence is sensitive to the extradural fluid collection itself and useful to differentiate from epidural fat. A T2* or SWI sequence should be chosen to detect more sensitively possible cases of SS [29]. Another GRE sequence T2-Trufi can reduce the impact of field inhomogeneities caused by motion for an improved visualization of CSF.

Limitations of our study were its single-center design and the varying post-therapeutic follow-up intervals. The low number of patients recruited is problematic, although results were statistically highly significant. Further investigations could help improve both patient care and our understanding of a still insufficiently comprehended disease. Our data shows that persistence and dynamic of intraspinal fluid collections were predictive of chronic IHS-associated symptoms. All patients with a resolved fluid collection were free of symptoms on follow-up, while apart from one exception (case #5), all patients with persistent fluid collections suffered from ongoing complaints attributable to IHS disease. It can therefore be postulated that in case of successful closure of a leak, the intraspinal fluid is gradually absorbed and that the hypothesis of that spinal MRI is a valid tool for monitoring disease activity in IHS is true. It even seems more reliable than clinical examination since disease activity is often opaque and unspecific. It should routinely be used not only in the diagnosis of IHS but also in follow-up examinations. This is recommended not only for patients with ongoing chronic IHS symptoms but also for asymptomatic patients in order not to miss treatment opportunities and to prevent irreversible long term sequelae such as SS.