Adult Hydrocephalus

Adult hydrocephalus comprise a family of disorders characterized by a cerebrospinal fluid dynamic disturbance and a shared core symptomatology. Idiopathic normal pressure hydrocephalus (iNPH) has gained an increasing scientific attention over the past decades and is the most studied type of adult hydrocephalus. While knowledge of iNPH have accumulated and expanded, literature is still meagre in other, more uncommon adult hydrocephalus. In this focused review, we describe the most important advances in the literature on natural course, outcomes, quality of life and health economics with a focus on iNPH, the type of adult hydrocephalus where substantial research data exist.

Key points

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The natural course of idiopathic normal pressure hydrocephalus (iNPH), is progression of disease and poorer outcome over time. Shunt surgery should, therefore, be performed without delay.
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Clinical short- and long-term outcomes after shunt surgery in iNPH are favorable. Surgery also improves symptoms in other forms of adult hydrocephalus.
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Quality of life is reduced in patients with iNPH but significant improvements are generally seen after surgery.
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Shunt surgery for iNPH is a very cost-effective treatment.

Abbreviations

CHiA	chronic hydrocephalus in adults
CI	confidence interval
CSF	cerebrospinal fluid
CT	computed tomography
EQ5D	EURO-QoL 5 dimensions
HI	healthy individuals
HRQoL	health-related quality of life
iNPH	idiopathic normal pressure hydrocephalus
iNPHGS	iNPH grading scale
mo	months
mRS	modified Rankin scale
PROMs	patient-reported outcome measures
QOL	quality of life
RCTs	randomized controlled trials
SSVD	subcortical small vessel disease
y	years

Introduction

Adult hydrocephalus comprises a family of disorders characterized by a cerebrospinal fluid (CSF) dynamic disturbance and a shared core symptomatology. Adult hydrocephalus can be either acute or chronic. Acute forms exhibit a rapid onset of symptoms and urgent need of intervention and are often caused by an obstruction within the CSF pathways and related to an identifiable external cause. In chronic hydrocephalus in adults (CHiA), progression of symptoms is slow and gradual, and diagnosis often delayed: patients typically present with symptom duration of years. The terminology of CHiA is confusing and inappropriate with many proposed terms, several of which represent the same condition. Based on a review of the literature, a new classification of CHiA was recently proposed describing 6 different entities. Importantly, this study concluded that symptoms in CHiA are age-dependent, younger patients often showing pressure-related symptoms (eg, headache, nausea, and visual symptoms) in addition to the classic Hakim tetrad (gait/balance, cognition, and urinary incontinence), whereas older patients exhibit Hakim symptoms alone.

Idiopathic normal pressure hydrocephalus (iNPH) is, by far, the most common form of CHiA. During the last decades, iNPH has gained increasing awareness, with a rapidly increasing annual number of articles presenting iNPH research. The scientific progress has led to a better understanding of iNPH and the consequences this condition means for patients and society. It has gradually become evident that iNPH is a common condition with reported prevalence figures of 2% to 4% in individuals aged over 65 years, increasing with increasing age. ^, A recent study found a prevalence of iNPH of 1.5% in 70 year olds, another 3.5% showing radiological features of iNPH without fulfilling clinical criteria. This makes iNPH, the only truly treatable dementia, second to Alzheimer’s disease possibly the most common. The recent understanding of the natural course of iNPH and the importance of treating iNPH without delay and the fact that shunt surgery is a very cost-effective treatment clearly points at the necessity of giving these patients priority in the allocation of health care resources. ^,

We would like to point out that the topics covered in this review are not or very meagerly reported in the literature in acute adult hydrocephalus or most forms of CHiA. Among adult hydrocephalus forms, data on natural history, quality of life, and health economics are only available for iNPH, and outcomes are only described in numerous reports and in large series of patients with iNPH. Therefore, this article will focus on iNPH and on other adult hydrocephalus forms only where reliable data are available.

Natural history of idiopathic normal pressure hydrocephalus

The way that normal pressure hydrocephalus was discovered by the Colombian neurosurgeon Salomon Hakim was by showing that hydrocephalus is, in fact, treatable by CSF diversion also in a situation without an increased intracranial pressure. This means that there are no historically examined cohorts conveying information on the natural history of the condition. Randomizing patients to none or delayed treatment is ethically questionable. In the literature, what can be found on this topic, are reports of patients who for different reasons were not offered or who declined surgery, who had to wait for a longer time period for surgery, or who had their treatment delayed according to protocol in a randomized controlled study. An overview of studies reporting results for patients with iNPH who were followed up and re-examined after a period without surgery is presented in Table 1 .

The first 4 studies on that list (Savolainen, Eide, Pfisterer, and Brean ) reported follow-up data on patients who were not thought to benefit from shunt surgery, based on specific hydrodynamic measurement criteria, constituting a confounder when regarding these patients as iNPH. However, there is no general consensus about those specific criteria, and they were not included in the 2005 international diagnostic guidelines for iNPH. The next 2 studies (Scollato and Razay ) followed patients who declined surgery; a possible confounder as they might have been either less prone to take surgical risks due to less severe symptoms or due to extensive comorbidities entailing higher surgical risks. Less severe symptomatology was seen in the patients who declined surgery in the study by Todisco and colleagues ; the study unveiled how these patients’ gait and continence scores successively deteriorated. The study by Razay and colleagues also included 4 patients who were selected for shunt surgery but surgery was delayed due to a waiting list situation, a method that was also applied in our own study of 33 patients. The collected evidence from these studies is that on a group level, iNPH symptoms progress over time.

Four randomized controlled trials (RCTs) on shunting in iNPH have been published, where patients were randomized to 3 or in 1 case 4 months delayed active treatment, further reviewed in later section. The studies by Tisell, Toma and Luciano with a total of 23 patients in the placebo-arms reported no negative effect of that wait. The study by Kazui reported that out of 42 patients, 7 deteriorated in their modified Rankin scale (mRS) score, 34 were unchanged, and 2 improved. All 4 studies showed improvements in the active treatment arms. At longer follow-up, there was no difference between the groups, that is, remaining functional impairments in those with 3 to 4 months delayed treatment was not shown.

The only study that investigated whether a longer delay in shunt surgery would result in a less beneficial outcome was our natural history study from 2013. The design was to compare a consecutively included cohort of patients who had waited at least 6 months when they were scheduled for surgery, to all other equally clinically evaluated patients in our database who had surgery within 3 months from the surgical decision. This resulted in a cohort of 33 patients who had waited up to 24 months—median 13 months—for surgery, compared to 69 patients with only median 0.3 months’ wait. Both groups had the same level of functional impairment when they were referred for shunt surgery. The renewed clinical evaluation that was performed in close proximity to the delayed surgery showed significant deteriorations in gait, balance, neuropsychology, and functional level as measured by the mRS. In spite of the deterioration, a remaining reversibility was shown by improvements after surgery. Regrettably, when comparing the 3 months’ postsurgical outcomes to the outcome of the group operated without delay, the 33 patients with delayed surgery had poorer outcomes ( Fig. 1 ). A follow-up study showed that mortality was higher in patients with delayed surgery, with an adjusted hazard ratio of 2.57 (95% confidence interval [CI]: 1.13–5.83). The results indicate that the natural history of iNPH is symptom progression over time and that the symptoms are only partially reversible with more pronounced residual symptoms and higher mortality in patients who were left to deteriorate before shunt surgery. The same effect was seen in another Swedish retrospective study where longer waiting time for surgery was a negative predictor of postsurgical outcome in 273 patients with iNPH.

Studies on a longer term of untreated iNPH are hardly conceivable. A population-based study on older persons in our city where 1235 persons were prospectively examined with computed tomography (CT) of the brain and clinical examinations made a retrospective diagnosis of untreated probable iNPH in 24 persons. After a median follow-up time of 11.5 years, mortality was shown to be clearly increased in these 24 persons, with an adjusted hazard ratio of 3.8 (95% CI: 2.4–5.8).

Although the pathogenesis is not well characterized, the chronic progressive nature of symptoms agrees with that the disease process likely begins several years prior to presentation, that is, that the natural history includes a preclinical phase. Population-based studies with cohorts of older persons screened with CT or MRI of the brain indicate that the presenting feature of iNPH is ventricular enlargement before symptoms develop. These cohort studies, several of which were performed in Japan, as well as the one from Sweden cited earlier, found subsets of persons with hydrocephalic ventricular enlargement without symptoms. At follow-up, some of these had progressed to iNPH, while other remained asymptomatic. Proportions of persons with hydrocephalic ventricular enlargement who develop iNPH range in those studies from 25% to 62.5% in 3 to 16 years. It is not understood either why or when persons with this radiological finding develop coherent symptoms or if all would develop hydrocephalic symptoms if they live long enough—or if compensatory mechanisms can, in some instances, be sufficient to avoid functional impairments.

Table 1

Overview of studies where results from follow-up of untreated patients with idiopathic normal pressure hydrocephalus were reported

First Author, Publication Year	N	Follow-up	Reason not to Operate	Results
Savolainen et al, 2002	26	12 mo	Not fulfilling specific criteria	65% deteriorated in gait, 15% improved
Eide et al, 2006	15	12 mo	Not fulfilling specific criteria	Deteriorated on group level
Pfisterer et al, 2007	37	7.2 y	Not fulfilling specific criteria	25% deteriorated in gait, 55% in cognition
Brean et al, 2008	12	12 mo	Not fulfilling specific criteria	“Unchanged or worse”
Scollato et al, 2008	9	20 mo	Declined surgery	All deteriorated: 6 in gait, 9 in urinary, 8 in cognition
Razay et al, 2009	14	3–4 mo	10 declined, 4 on waiting-list	9 deteriorated in global rating
Andrén et al, 2013	33	13 mo	Left on waiting list	55% deteriorated in iNPH scale
Todisco et al, 2020	34	12 mo	Declined	Deterioration in gait and continence

Abbreviations: mo, months; mRS, modified Rankin scale; N, number of untreated patients; y, years.

Clinical outcomes

For many decades, the positive effects of CSF diversion in adult patients with hydrocephalus have been evident to clinicians seeing these patients, which have formed the foundation for treatment protocols over the years. The publication of the hallmark studies by Hakim and colleagues ^, describing iNPH as a treatable disorder further raised the interest in treating patients. Earlier, short-term and long-term outcomes in iNPH have sometimes been debated, or the effect of shunt surgery even questioned related to the lack of evidence from RCTs, considered the highest level of evidence for a treatment. One reason for the small number of available RCTs on outcome in comparison with the high number of clinical studies is probably the ethical aspect: with an established treatment that is continuously showing favorable results, it is more difficult to cancel or postpone treatment from an ethical point of view, especially given the natural course of iNPH. This paragraph will start by outlining results of RCTs followed by a more extensive review of the most relevant literature on outcomes with a focus on iNPH.

In a recent Cochrane review, Pearce and colleagues identified 4 RCTs reporting on the effect of shunt surgery in iNPH, as mentioned earlier (Tisell 2011, Kazui 2015, Toma 2016, and Luciano 2023 ) and based on the review concluded that there is moderate-certainty evidence that CSF-shunting likely improves gait speed and disability in iNPH, a result mainly explained by the lack of RCT data. Kazui and colleagues reported on outcome after lumboperitoneal shunt surgery in an immediate versus a 3 month postponed group concluding that lumboperitoneal shunt surgery might be beneficial for patients with iNPH. The most recent RCT by Luciano and colleagues found that in a small group of patients, there was a trend suggesting that gait velocity improves more in an open shunt group than in a placebo group with shunt setting at a high opening pressure. In the RCT by Tisell and colleagues from our center, exploring shunt effectiveness in patients with iNPH with extensive small vessel disease white matter changes, comparing open shunt versus ligated shunt with sham operations to ensure blinding of patients, the study was terminated in advance for ethical reasons due to the very favorable results of treatment ( Fig. 2 ). In the aggregate, RCTs show favorable outcome of shunt surgery iNPH for primary endpoints, however, without providing data to support a more extensive understanding of the spectrum of outcomes in short-term or long-term perspectives.