Theophylline can resolve refractory acute negative-pressure hydrocephalus: illustrative case

Abstract

BACKGROUND

Negative-pressure hydrocephalus is characterized by neurological deterioration with ventriculomegaly but negative intracranial pressure (ICP), clinically indistinguishable from acute hydrocephalus with elevated ICP. Subatmospheric CSF drainage, neck wrapping, endoscopic third ventriculostomy (ETV), and shunt placement are treatment methods. Medical therapy remains elusive. The authors describe a patient with refractory negative-pressure hydrocephalus who failed conventional therapies but responded robustly to theophylline.

OBSERVATIONS

A 30-year-old man with traumatic brain injury underwent decompressive hemicraniectomy, cranioplasty, and ventriculoperitoneal shunt placement. He was later rehospitalized for acute hydrocephalus and shunt infection. Surgical revision was complicated by intraventricular hemorrhage with worsening hydrocephalus. An external ventricular drain was inserted, demonstrating negative ICP. Treatment for more than 3 months with subzero drainage, two ETVs, and ventriculopleural shunt placement was unsuccessful. Theophylline was initiated and the ventriculomegaly improved drastically on imaging with increased ICP. He developed status epilepticus, managed medically, with resolution within 5 days. He was discharged with return to his neurological baseline.

LESSONS

Theophylline, a methylxanthine derivate used for obstructive pulmonary disease, can raise ICP in intracranial hypotension. The authors present the first successful case of theophylline for the treatment of refractory acute negative-pressure hydrocephalus. Further studies are warranted to explore the safety and efficacy of theophylline for negative-pressure hydrocephalus.

https://thejns.org/doi/10.3171/CASE2554

Acute low-pressure hydrocephalus (ALPH) or acute negative-pressure hydrocephalus (ANPH) is a subtype of hydrocephalus characterized by ventriculomegaly and symptoms of elevated intracranial pressure (ICP) despite an ICP value less than 5 cm H₂O. It is clinically indistinguishable from hydrocephalus with elevated ICP but presents unique challenges in management given its paradoxical nature and refractoriness to standard surgical interventions. The most common etiologies include hemorrhage, neoplasm, and trauma.¹ The pathophysiology is based on the separation of the intracranial ventricular drainage system from the cortical subarachnoid space (SAS) secondary to either a mechanical obstruction or inflammation of the SAS. This entraps CSF in the cortical SAS, exacerbating ventriculomegaly on CSF diversion due to the pressure gradient between the two CSF compartments without an elevation in ICP.² Decreased cerebral elasticity and increased compliance and iatrogenic sequelae of CSF drainage techniques have also been implicated.^3,4 Goals of management include establishing the diagnosis, reversing any underlying obstruction, draining accumulated CSF, and establishing definitive CSF outflow. This is achieved by subatmospheric CSF diversion via external ventricular drain (EVD) placement or shunt externalization with or without neck wrapping, followed by endoscopic third ventriculostomy (ETV) and/or shunt placement. Other surgical approaches described in the literature for refractory cases include active pumping negative-pressure systems, septum pellucidotomy, and fenestration techniques for loculated CSF.^5–8 Definitive treatment with medical therapy has not been previously described. We present the first successful case of effective medical management with theophylline for surgically refractory ANPH.

Illustrative Case

A 30-year-old male was involved in a helmeted motorcycle accident with an initial Glasgow Coma Scale score of 6 (E1, V1, M6) with an inability to arouse to noxious stimulation, preserved pupillary and gag reflexes, absent corneal and cough reflexes, and withdrawal motor response in all extremities to noxious stimulation. A CT scan of the head demonstrated a 3-mm right frontal parenchymal contusion, a mixed-density 9-mm right acute subdural hematoma with effacement of the right lateral ventricle and an anterior right temporal epidural hematoma with 1 cm of right to left midline shift, a scattered right convexity subarachnoid hemorrhage, and an intraventricular hemorrhage (IVH) in the right occipital horn and fourth ventricle (Fig. 1 left). He underwent a large right fronto-temporo-parietal decompressive hemicraniectomy. He was hospitalized for 6 months, with a clinical course complicated by septic shock, pulmonary embolism, respiratory failure requiring tracheostomy, and percutaneous endoscopic gastrostomy (PEG) tube placement.

FIG. 1.

Left:Axial head CT scan demonstrating the initial traumatic brain injury with a 3-mm right frontal parenchymal contusion, a mixed-density 9-mm right acute subdural hematoma with effacement of the right lateral ventricle, 1 cm of right to left midline shift, a scattered right convexity subarachnoid hemorrhage, and an anterior right temporal epidural hematoma (not seen on image). Right: Axial CT scan showing sunken flap syndrome with increased mass effect from sunken right-sided flap.

He was discharged to a skilled nursing facility and readmitted with sunken flap syndrome (Fig. 1 right) with increased mass effect manifesting as headaches. He underwent cranioplasty but subsequently developed positive-pressure hydrocephalus requiring ventriculoperitoneal shunt (VPS) placement with a Certas (Codman) valve. At discharge, he was awake and alert, able to state his name, answer simple questions, and follow simple commands in the midline and on his right side, with left-sided hemiparesis. His tracheostomy was decannulated and his PEG tube removed.

Three months later, he presented to the emergency department with urinary retention, confusion, and abdominal pain with interval enlargement of the left frontal lateral ventricular horn (Fig. 2 left). His VPS was tapped and significant resistance encountered, raising concern for proximal shunt failure. Aspirated CSF demonstrated growth of gram-positive cocci. He was started on ceftriaxone 3 g daily and ampicillin 3 g every 4 hours and was taken to the operating room (OR) for removal of his shunt on posthospital day (PHD) 4. During surgery, no resistance was noted when removing the catheter. Postoperatively, the patient was lethargic, nonverbal, and minimally withdrawing to pain. A CT scan demonstrated extensive IVH of his lateral, third, and fourth ventricles (Fig. 2 right). He was transferred to the neuro-ICU and reintubated, and an EVD was placed. CSF drainage was limited with ICPs less than 5 mm Hg. The EVD was set to −8 cm H₂O with a drainage goal of 10 mL/hr.

FIG. 2.

Left: Preoperative axial head CT scan obtained after the patient presented with acute hydrocephalus in the setting of an infected VPS. Right: Axial head CT scan obtained after removal of the infected VPS, showing extensive IVH and worsening hydrocephalus.

Over the next 3 weeks, he was extubated, his IVH cleared with intraventricular tissue plasminogen activator, and his antibiotics were narrowed based on CSF culture growth for Enterococcus faecalis. His ICP, however, remained in the range of −5 to +10 mm Hg, and his EVD could not be weaned. On the contrary, he developed worsening ventriculomegaly despite forced hourly drainage for a minimum goal of 10–20 mL/hr.

On PHD 25, the EVD was replaced with a valveless right occipital ventriculopleural shunt with ongoing negative-pressure drainage. The following day his examination declined and repeat head CT demonstrated further enlargement of his ventricles and bifrontal pneumocephalus. Because the new shunt was not providing adequate drainage, a right EVD was placed and set at −10 cm H₂O with a goal drainage of 15 mL/hr, again requiring forced drainage. During this time, his ICP dropped as low as −21 mm Hg without exceeding +2 mm Hg. His examination waxed and waned. At best, he was awake, oriented to person, answering a few simple questions, following commands intermittently, and moving all extremities against gravity, more briskly on the right side as per his baseline. He developed a persistent fever without a clear source, and workup on PHD 43 revealed pneumoperitoneum on abdomen and pelvis CT scans. He underwent exploratory laparoscopy with externalization of the right ventriculopleural shunt. Staphylococcus haemolyticus was cultured from the CSF from his EVD and pleural shunt. On PHD 47, the externalized shunt was removed and a new right frontal EVD was placed.

Over the next few days, his EVD was maintained at −5 cm H₂O, with a minimum drainage goal of 10 mL/hr requiring ongoing forced drainage with ICP as low as −12 mm Hg. He became more lethargic, and a head CT scan showed grossly unchanged ventricles with air trapped within the left lateral ventricle frontal horn (Fig. 3A and B). His EVD was set as low as −30 cm H₂O for forced ventricular reduction with a maximum ICP of −10 mm Hg. The ventricular size eventually reduced compared to weeks prior but still was larger than his prehospital baseline (Fig. 3C). The EVD was gradually raised to −10 cm H₂O, which was maintained for the following week.

FIG. 3.

A: Axial head CT scan obtained after removal of a ventriculopleural shunt and placement of a new right frontal EVD with air trapped in the left frontal ventricular horn. B: Axial CT scan showing persistent enlarged ventricular system and entrapped air in the left frontal ventricular horn despite the EVD being set to −5 cm H₂O. C: Axial CT scan showing improvement in hydrocephalus and reduction of entrapped air in the left frontal ventricular horn with EVD adjusted to −25 cm H₂O.

On PHD 70, the patient was taken back to the OR for placement of a right ventriculoatrial shunt and right frontal ETV. During the ETV, the third ventricle floor was noted not to be pulsating, likely secondary to negative ICP. Although ventricular caliber improved, a persistent large collection of air on the left frontal horn remained (Fig. 4 left) for which a left frontal EVD was placed and a left frontal endoscopic exploration and repeat ETV were completed on PHD 76. No membranes were observed with significant improvement of the air collection on subsequent CT (Fig. 4 right).

FIG. 4.

Left: Axial CT scan showing persistent pneumoventricle of the left lateral ventricular frontal horn despite right ventriculoatrial shunt placement and ETV. Right: Axial CT scan showing improvement in left lateral frontal horn pneumoventricle after placement of a new left frontal EVD and repeat ETV.

His EVD was weaned to 0 cm H₂O with forced drainage oscillating between a minimum of 10 and 15 mL/hr to meet the drainage goal. Ventricular caliber did not improve, and over the next 2 weeks, a drainage rate of 15–20 mL/hr was targeted by lowering the drain to whatever negative pressure achieved that goal, although not through forced drainage. The drain’s height was adjusted hourly to allow spontaneous CSF flow by either raising or lowering it by 2 cm H₂O. The ICP during this period oscillated between −19 and +3 mm Hg.

Neither of these strategies succeeded. The patient’s ventriculomegaly had worsened (Fig. 5 left) by PHD 99, and he was taken to the OR for conversion of his right ventriculoatrial shunt to a ventriculopleural shunt. His left EVD was kept at a height of −10 cm H₂O. He remained lethargic on examination.

FIG. 5.

Left: Axial head CT scan obtained on day 99 of hospitalization, showing persistent hydrocephalus and IVH despite multiple interventions for ANPH. Right: Axial head CT scan obtained on day 105 of hospitalization, 4 hours after the second dose of theophylline was administered, showing drastic reduction in ventriculomegaly to almost slit-like ventricles.

The case was presented to several experts around the country, but no additional definitive management strategies were proposed. A review of the medical literature identified a single case in which theophylline increased ICP in a woman with chronic low-pressure hydrocephalus.⁹ After discussion with the neuro-ICU team and pharmacy, it was planned to administer theophylline 200 mg twice a day via PEG tube. Oral caffeine 200 mg twice a day was administered first for 48 hours, as theophylline was not available on formulary, but this did not result in any clinical or radiographic change in the patient’s neurological status.

Two doses of theophylline 200 mg twice a day were administered starting on PHD 104. Shortly after the first dose, the left EVD drained spontaneously at −18 cm H₂O without forced drainage. A head CT scan obtained 4 hours after the second dose demonstrated complete collapse of the ventricles to an almost slit-like appearance, a dramatic change from the previous 2 months (Fig. 5 right). As the patient only received two doses of theophylline, no drug levels were measured.

Shortly after the CT study, however, the patient developed focal seizures with intermittent left-sided head, face, and hand twitching as well as right arm and trunk flexion with associated eye opening and blinking that persisted despite maintenance Vimpat 100 mg twice a day and 8 mg of Ativan administration, with progression to status epilepticus. He was intubated for airway protection, started on a dexmedetomidine drip, and placed on continuous EEG monitoring, demonstrating right-sided centrotemporal electrographic seizures with continuous interictal lateralized periodic discharges. Theophylline was stopped, and levetiracetam 2 g twice a day, phenytoin 100 mg every 8 hours, and zonisamide 100 mg twice a day were sequentially added to his antiepileptic regimen. Status epilepticus resolved in 5 days, and his seizure frequency declined to the point of clinical and electrographic resolution, with only rare right frontal interictal discharges prior to discontinuation of continuous EEG monitoring. His examination significantly improved: even while intubated, he was awake, alert, and able to follow simple commands.

CT demonstrated sustained hydrocephalus improvement, and his EVD drainage goal was decreased to 7 mL/hr, the lowest since admission. He was extubated 1 day later with his EVD at −5 cm H₂O and no drainage. The EVD was removed the following day (PHD 111), and he was transferred to the floor 2 days later.

Over the next 45 days, he made progressive recovery and serial CT studies demonstrated persistently small, slit-like ventricles. He was ultimately discharged to a facility on PHD 150, at which time he was confused but conversant, eating a puree diet, and moving all extremities with almost full strength. He remained on levetiracetam and lacosamide on discharge.

Informed Consent

The necessary informed consent was obtained in this study.

Discussion

Observations

Since its first identification in 1994, ANPH continues to pose ongoing diagnostic and management challenges given the fundamental paradox of acute hydrocephalus in the setting of negative ICP.³ Common symptoms include decreased level of consciousness, headache, nausea, vomiting, cranial nerve deficits, and gait disturbance—similar to hydrocephalus with raised ICP.

Several conditions or procedures can cause ANPH, including subarachnoid hemorrhage, IVH, lumbar puncture, CSF leakage, meningitis, posterior fossa tumors, congenital aqueductal stenosis, spinal arachnoid cysts, cranial radiotherapy, hemispherectomy, extensive brain infarction, and normal pressure hydrocephalus.^10,11 A case series and systematic review of 195 patients highlighted the most common etiologies in the adult and pediatric populations: hemorrhage, neoplasm, and trauma. Hemorrhage and trauma accounted for most of the cases in adults (46% and 23%, respectively), with infection accounting for 4.9% of cases. Neoplasm was the most commonly identified etiology in the pediatric group (74%). While ANPH occurred in the majority without any preceding CSF-related procedure, it was diagnosed in 16% of adult and 36% of the pediatric patients after a CSF-related surgery. Furthermore, ANPH was diagnosed in 31% of pediatric and 4% of adult patients after a lumbar puncture.^1,7 In a case series of 39 patients with ALPH or ANPH from a single hospital, 46.15% were complicated by intracranial infections, of which 87.5% were specifically in the ANPH subset compared to 35.48% of ALPH.¹²

The pathophysiology of ANPH is multifactorial. One theory suggests a functional disconnection of the ventricular system from the cortical SAS from either mechanical obstruction or SAS inflammation.² This compartmentalizes CSF to the cortical SAS, which, when drained, exacerbates ventricular expansion without a concomitant rise in ICP, also described as the “transmantle pressure theory.”¹³ Another theory postulates an alteration in the brain’s viscoelastic properties and turgor via reduced extracellular fluid content, resulting in diminished cerebral elasticity or increased compliance secondary to the underlying pathology.^3,10 This has been corroborated in a case of low-pressure hydrocephalus using MR elastography demonstrating significantly low tissue elasticity.¹¹ The glymphatic system is another emerging factor in certain etiologies of ANPH such as aneurysmal subarachnoid hemorrhage, given the role of meningeal lymphatic vessels in clearing erythrocytes from the CSF to the cervical lymph nodes, CSF reentry, and increased expression of aquaporin-4 at the blood-brain barrier and blood-CSF interface as well as the role of CSF drainage in improving blood flow and normalizing the extracellular environment.^11,14

The mainstay of managing ANPH remains establishing a diagnosis, stabilizing the patient, and establishing definitive treatment.^1,15 Because initial ICP may be elevated or normal, initially serial 1-hour ICP checks are recommended following shunt externalization or placement of an EVD. Once low or negative ICP is confirmed, aggressive measures must be undertaken to reduce the ventricular size, including large-volume aspiration of 30–50 mL of CSF and subsequent drainage of 10–15 mL/hr, with a willingness to lower drainage settings to less than zero to meet this target. Blood patch; Trendelenburg positioning; neck, chest, and/or abdominal binding to inhibit venous return and increase cerebral venous blood volume; 5% dextrose infusion to achieve hyponatremia of 130–135 mEq/L to replete brain volume; and increasing PaCO₂ to greater than 40 mm Hg to increase cerebral perfusion have all been suggested in refractory cases.^10,11,16 Once stabilized, definitive treatment must be established around one or a combination of the following: weaning the EVD, ETV, and/or ventricular shunt placement. A procedure is required in 80% of pediatric and 99% of adult patients with ANPH.

Generally, obstructive pathologies are more amenable to ETV success compared with inflammatory etiologies. If ETV is not an option, shunt placement must be considered. It is the most commonly reported definitive treatment in two-thirds of all reported cases.¹ An active pumping system with catheter modifications, fenestration of loculated hydrocephalus, and septum pellucidotomy in the setting of shunt revisions have been described for refractory cases such as ours.^5–7

Despite following this approach with aggressive subzero drainage, multiple shunt revisions, and two ETVs, no sustained improvement in ventricular size was achieved in our patient. Although ANPH is considered a surgical disease, our experience in this case and other chronic conditions associated with low ICP suggests that there may be a larger role for medical management. A Cochrane systematic review of 13 randomized clinical trials evaluating the role of eight drugs in the management of post–dural puncture headache (PDPH), with a total of 479 participants, found that caffeine effectively decreased the incidence and need for additional medications for managing PDPH symptoms and that theophylline effectively relieved pain better than placebo or conventional treatment alone.¹⁷ Similarly, in a patient with prolonged refractory headache with associated appearance of an Arnold-Chiari type I malformation and low CSF pressure confirmed by CT cisternomyelography with a CSF leak at the C2 vertebral level, symptomatic relief and resolution of the apparent Arnold-Chiari malformation was only achieved with long-term theophylline administration.¹⁸

The clearest evidence for theophylline raising ICP comes from a single case report of a patient with Chiari malformation, syringomyelia, and both a ligated ventriculoperitoneal shunt and an intact syringopleural shunt with progressive syringomyelia and enlargement of her third and fourth ventricles. She underwent placement of a ventriculothecal shunt to equilibrate her two CSF compartments, 2 weeks after which she developed bilateral hygromas with symptoms suggestive of intracranial hypotension. Her reservoir was exchanged for a telemetric intracranial sensor reservoir, which demonstrated negative ICP as low as −16.78 mm Hg. She started oral theophylline 200 mg twice a day for 3 months, and this successfully increased her ICP over several weeks. Brain MRI demonstrated resolution of the subdural effusions, and her headaches and nausea resolved.⁹ This case was the basis for the administration of theophylline in our patient.

Lessons

Theophylline is a competitive, nonselective phosphodiesterase inhibitor, increasing intracellular cyclic AMP (cAMP), potentiating the effects of cAMP-stimulating drugs such as catecholamines, and inhibiting the synthesis of pro-inflammatory mediators such as tumor necrosis factor–alpha and leukotrienes. In the skeletal and cardiac muscle, it acts to release calcium from the sarcolemma. In the brain, theophylline acts as a stimulant via an adenosine receptor competitive antagonism. It reduces accumulation of cAMP by antagonizing the actions of endogenous adenosine, a stimulator of cAMP accumulation.¹⁹ Its affect on ICP is not well understood, possibly mediated by adenosine antagonism, cerebral vasoconstriction, and venous outflow resistance.²⁰ Increased CSF production may also be a contributory factor.^18,21 Theophylline has classically been used to treat asthma and chronic obstructive pulmonary disease, although less commonly now given its narrow therapeutic index necessitating drug level monitoring and its adverse effect profile. This includes tachycardia, restlessness, tremor, nausea, vomiting, and seizures.²² Our patient developed focal seizures that progressed to status epilepticus 4 hours after starting theophylline. Although he did not have a history of seizures, his recent severe traumatic brain injury placed him at high risk for epilepsy.

This is the first reported case of successful medical treatment of acute, refractory negative-pressure hydrocephalus with theophylline. Although our experience represents a single case, it validates and adds to a growing body of literature supporting the role of theophylline and related methylxanthine derivatives in augmenting low ICP states and potentially reversing their underlying pathogenesis.

ANPH is a rare but difficult disease to diagnose and manage requiring novel approaches to ensure optimal outcomes. In our patient, 4 months of aggressive CSF diversion at subatmospheric pressures with numerous EVDs, shunts, and ETVs did not improve his ANPH and his ICP remained persistently below zero. After two doses of theophylline, he experienced robust and sustained physiologic, radiographic, and clinical improvement. This case supports that a trial of theophylline may be warranted in cases of refractory ANPH and larger-scale studies are warranted to study the safety and efficacy of theophylline in this setting.

Acknowledgments

The authors thank Alan Balu, MS, for his contributions to this paper.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Mamelak, Quintero-Consuegra, Ryan, Vargas, Garcia, Rejali. Acquisition of data: Salam, Quintero-Consuegra, Ryan, Vargas, Garcia, Rejali, Babadjouni. Analysis and interpretation of data: Mamelak, Salam, Quintero-Consuegra, Vargas, Babadjouni. Drafting the article: Salam, Quintero-Consuegra, Ryan, Vargas, Garcia, Wong, Babadjouni. Critically revising the article: Mamelak, Salam, Quintero-Consuegra, Vargas, Garcia, Babadjouni. Reviewed submitted version of manuscript: Mamelak, Salam, Ryan, Babadjouni. Approved the final version of the manuscript on behalf of all authors: Mamelak. Administrative/technical/material support: Salam, Babadjouni. Study supervision: Mamelak.

Supplemental Information

Previous Presentations

Presented in part as an electronic poster at the Annual Meeting of American Association of Neurological Surgeons, Boston, MA, April 25–28, 2025.

Correspondence

Adam N. Mamelak: Cedars-Sinai Medical Center, Los Angeles, CA. adam.mamelak@cshs.org.