Effective Stepwise Anti-inflammatory Treatment for Markedly Disabling Neuropsychiatric Comorbidities: A Case Report

Background: This is the first case report of a stepped novel anti-inflammatory treatment plan for a complicated, markedly disabling neuropsychiatric condition with multiple comorbidities. The treatment consisted of 1) hyperbaric oxygen therapy, 2) combination therapy of infused ketamine applied concurrent with transcranial magnetic stimulation, 3) administration of perispinal etanercept, and finally 4) non-invasive transnasal Sphenopalatine Ganglion block. Methods and findings: The patient was a 34-year-old Caucasian unemployed female who presented with lifelong symptoms of a regulatory disorder of childhood, epilepsy, reflex sympathetic dystrophy, and multiple concussions that ultimately led to marked disability in activities of daily living. Following the sequential treatment, the patient showed marked clinical improvement and progressed from major incapacitation to an independent life, resuming school and taking a parttime job. Indeed, successive improvements occurred after hyperbaric oxygen therapy in the realms of distress tolerance, resilience, and social interaction and then continued after downward titration of oral medications (which required the use of the ketamine/transcranial magnetic stimulation treatment), and further improved after administration of perispinal etanercept. Finally, a Sphenopalatine Ganglion block provided migraine relief. Single-photon emission computer tomography imaging was done before the beginning of treatment, one month later (after hyperbaric oxygen therapy), and at the conclusion of the perispinal etanercept injections. Results from both follow-up SPECT scans validated the clinical impression by showing substantial and additive blood flow increases in previously deficient brain areas. Conclusions: We provide evidence of successful treatment of a disabling neuropsychiatric condition via the sequential application of a novel anti-inflammatory treatment plan including four procedures, all known for their anti-inflammatory effects. The use of functional imaging provided a useful biomarker for the efficacy of this sequential treatment.


Introduction
The treatment and rehabilitation of patients with a history of multiple neuropsychiatric conditions, aggravated by repeated mild traumatic brain injuries and ultimately leading to marked functional disability, is known to be challenging [1,2]. In particular, pre-existing neuropsychiatric problems can become treatment resistant or intractable when the effects of multiple traumatic brain injuries are superimposed. All of these conditions have been shown to induce variable levels of neuroinflammation [3][4][5][6].
We present the very favorable results obtained over a period of over three years, consequent to the administration of some lesser-used methods of anti-inflammatory treatment, in a patient who had previously been intractably ill. The treatments included 1) hyperbaric oxygen therapy (HBOT), 2) combination therapy of infused ketamine concurrent with transcranial magnetic stimulation (TMS), 3) injections of perispinal etanercept (PSE), and 4) non-invasive trans-nasal Sphenopalatine Ganglion (SPG) block. HBOT is believed to have anti-inflammatory effects, reducing the excess of proinflammatory cytokine activation such as TNF-alpha and facilitating improvement by provocation of stem cell activity [7][8][9][10]. The combination therapy of infused ketamine administered concurrent to TMS appears to address the abnormalities in brain circuits found both in treatment resistant depression and treatment resistant central pain [11][12][13][14][15][16]. Additionally, ketamine is known to act as a TNF-alpha inhibitor, thus favoring an anti-inflammatory effect [17]. PSE injections induce tumor necrosis factor (TNF)-alpha modulation directly to the central nervous system and act to normalize the inflammatory response in stroke, traumatic brain injury, and encephalopathic conditions [18][19][20]. The SPG is known to decrease migraine intensity [21] and also to have an anti-inflammatory effect [22]. We thus aimed to provide information about the use of novel anti-inflammatory procedures, in a step-wise approach, for the treatment of a patient with disabling, treatment resistant, neuropsychiatric comorbidities.

Methods
A 35-year-old Caucasian unemployed woman presented to our clinic with life-long symptoms of a regulatory disorder of childhood, including dysregulated head pain (of migraineous intensity), stomach pain, parasomnia, panic attacks, and emotional dysregulation. Despite these difficulties, the patient had been able to complete college. Up until age 24, she had not held steady employment, but was actively involved in supporting her church and in other volunteer work.
When the patient was 24 years old, she impacted a tree with her car after having a seizure while driving on the highway. This resulted in a concussion as well as fractures to both of her ankles. Subsequent to that event, the patient was diagnosed by her psychiatrist (not at the present clinic) with generalized anxiety disorder (GAD), secondary insomnia, adjustment disorder with mixed anxious and depressed mood, migraine headaches, and partial epilepsy with impairment of consciousness and progressive worsening of lower extremity pain. The patient was treated with medication and counseling, and continued her part-time work and involvement in churchrelated activities, while continuing to live with her parents.
At 31 years old, while traveling overseas, the patient was subject to another concussion, without loss of consciousness but resulting in a large ecchymosis upon her right forehead. This occurred after a minivan in which the patient had been riding rolled over and she was projected from the lateral bench on one side to the other side of the enclosed vehicle. Upon return home, she consulted with a neurologist for pain, fear, and dull cognition. A computed tomography (CT) scan performed a month later was normal, prompting the neurologist to conclude that any symptoms the patient experienced as a result of the trauma would subside. However, both her neuropsychiatric and pain symptoms worsened, eventually becoming the most severe she had ever experienced. In addition to her previous conditions, the patient began having unusual auditory and visual experiences. She would hear familiar voices giving her advice, see an aura around a person, or see nearby objects as though they were far away from her. Nonetheless, she was not psychotic, meaning she maintained her insight that these perceptual symptoms were unusual. She also developed extreme misophonia and photophobia, and required constant use of noise suppression headphones along with dark sunglasses during her waking hours. The patient described herself as spending the next three years of her life isolated and "completely in the dark," incapable of participating in almost any activity. She was unable to leave her house due to misophonia, head pain of migraineous intensity and lower extremity pain. Indeed, she seldom left her room. Her parents cared for her throughout this time. Her depression worsened substantially, including feelings of severe loneliness.
By the time the patient arrived at our clinic approximately four years after the last accident, she was practically unable to engage in usual daily activities let alone in social events and employment. Her medication history included over 40 types, including antidepressants, anticonvulsants, antianxiety agents, antipsychotics, stimulants, a mood stabilizer (lithium), and pain medication (including Methadone). Her extended-family history was positive for ambulatory depression and high-functioning alcoholism. Her own substance use history was not significant (except for pain medication). Thyroid tests performed by our clinic were normal. Consequently, even though the patient had a history of borderline thyroid levels, hypothalamic hypothyroidism post-concussion was deemed unlikely. Other hormone levels were unremarkable, with the exception of low cortisol. We made the clinical diagnosis of multiple comorbidities including depression, reflex sympathetic dystrophy (RSD), misophonia photophobia, post-concussion syndrome, and auditory and visual perceptual distortions.

Results
A brain SPECT functional imaging with 99m-Tc HMPAO was performed at baseline in our clinic. This is a non-invasive nuclear medicine procedure that can detect functional changes in various gray matter locations. It does so by mapping the blood flow distribution in both cortical and subcortical gray matter areas of the brain. The results are displayed in a two-dimension (2D) and three-dimension (3D) color rendition of relative perfusion maps as well as in a black and white volumetric rendition thresholded at the 65% level [23][24][25][26]. Results from this assessment revealed extensive bilateral hypoperfusion most accentuated in the frontal and temporal lobes (see the upper row of Figure 1). Such bilateral findings on brain SPECT have been seen in various conditions including head trauma without localized impact, where the injuries were caused by a combination of acceleration/ deceleration and rotational forces, even in the absence of magnetic resonance imaging (MRI) findings [27,28]. They have also been seen in long standing depression and various neurotoxic exposures, including iatrogenic ones. A 3 Tesla MRI scan performed shortly after showed normal appearance except for a new 9x6 mm enhancing structure located cephalad from the left internal auditory canal. A special MRI for the auditory canal was performed three weeks later and suggested that the aforementioned signal on the left was likely due to inflammatory changes.
Based on clinical evaluation and on the results of the baseline SPECT, our first line of intervention was to refer the patient for HBOT. She followed a standard protocol consisting of 60-minute treatments administered five days per week over a one-month period at a pressure of 1.5 atmospheres absolute (ATA). She received a total of 40 treatments, which resulted in continuous but slow improvement in the realms of distress tolerance, resilience, and social interaction, including increased ability to leave her home. A second SPECT done a month after the conclusion of HBOT showed improved perfusion in practically every area of the cortex and in some subcortical structures (see the second row and green arrows in Figure 1).
At this point we decided to initiate a medication washout, the main goal being progressive discontinuation of anticonvulsant medications and opioid analgesics. In order to facilitate the opioid washout and improve the patient's chronic pain, a combined TMS/ketamine treatment was started next. It consisted of 21 sessions over a six-month period, as described in our previous publications [16,[29][30][31][32]. Immediately prior to the first combined treatment session, the patient completed two days of rTMS pre-treatment. Each pre-treatment day consisted of four 30-minute sessions of rTMS, with a 45minute resting interval between each session. One hertz TMS was continuously applied, without off cycles, at 115% of the motor threshold, based on three years of observational data from our clinic. The TMS head coil (manufactured by Neotonus, Inc., Marietta, GA, USA) was placed at the midline anteriorly on the patient's scalp. This placement was intended to maximize stimulation of the medial prefrontal area that overlays the anterior cingulate region, which has been implicated in depression and central pain syndromes [11,12].
In each session of the combined treatment, the patient first underwent five minutes of TMS. Intravenous ketamine (Ketalar®, manufactured by Par Sterile Products LLC, Parsippany, NJ, USA) was then administered over a 30-minute span, concurrent to and bracketed within a 40-minute TMS treatment (the patient concluded with five minutes of TMS post infusion). This protocol was repeated 21 times over six months at approximately equal intervals. The ketamine dosage was gradually increased from 25 mg delivered over 30 minutes at the first session to 80 mg delivered over the same period by the last. The ketamine dose adjustment, also previously described [16], was based on the three main factors: 1) the patient's increased tolerance for the experience of infused ketamine, 2) her reduction in symptoms, and 3) a clinical evaluation performed approximately three days after each treatment. The outcome of this treatment was that the patient was able to discontinue most of her medications including the methadone-based analgesia. An electroencephalogram (EEG) performed one year into the washout (once she was free of anticonvulsant medication) was normal.
Improvements started after the first month of the combined TMS/ketamine treatment, and continued to accrue even after the end of the whole series. The patient showed marked improvements in her RSD pain, she was no longer continuously clinically depressed, the unusual auditory and visual experiences subsided, and her energy levels increased. She returned to church activities and started traveling to social functions, for example participating in a wedding in another state. However, she remained emotionally reactive and irritable, and her ability to perform daily activities was still erratic, as she continued to struggle with periodic head pain, anger, and/or episodes of depression, and was cognitively still somehow limited. Therefore, approximately six months after completion of the TMS/ketamine treatment series, another line of intervention was started, namely the PSE injections The patient showed remarkable immediate improvements in cognition, affect, and vocabulary following the first 25 mg PSE injection. Second and third injections of the same dosage were given at approximately one-week intervals to maximize clinical effects.
At the end of the PSE injections, a third SPECT was performed. This scan revealed very significant additional improvements, as shown in the third row of Figure 1.
During the one-year follow-up period after the PSE injections, the patient showed significant improvements in nearly every area of functioning. Her cognition and affect continued to improve, the frequency of her depressive episodes and irritability decreased significantly, and she was able to read, write, and communicate with the alacrity of a graduate student. She was able to regularly engage in daily acts of living and increasingly participated in work, church, and other social activities. Additionally, she regained her driver's license. Particularly noteworthy was the fact that she was asked and agreed to participate in speaking engagements for traumatic brain injury patient audiences.
Finally, eight sessions of non-invasive trans-nasal SPG block were performed to treat persisting head pain. We used a modified protocol based on Candido et al. [34] by administering Marcaine (bupivacaine) 0.5% solution, 0.3 cc in each nare, weekly over two months. This resulted in substantial alleviation of the migraine pain, although some psychosensory features remained.

Figure 1
Single-photon emission computed tomography (SPECT) imaging results. The color code indicates the level of blood flow, which in turn is proportional to the metabolism level. This enables the detection of hyper or hypo functioning areas: from lowest levels (blue hues) to highest levels (white and black surrounded by white). The black and white display is a volumetric rendition at a standardized threshold level for all three studies. The baseline SPECT shows extensive areas of marked hemispheric underperfusion (top row). There was progressive improvement after hyperbaric oxygen treatment (HBOT) in multiple locations, as highlighted by the green arrows (middle row). The final scan, completed after the series injections of perispinal etanercept (PSE) (bottom row), shows overall marked improvement (increased perfusion) in the whole cortex including in the orbito-frontal and apico-mesial temporal areas, bilaterally. There is also increased relative perfusion in the putamen bilaterally and in the mid thalamus. In addition there are now several localized areas of hyperperfusion in each hemisphere as well as in the posterior cingulate/precuneus area.

Discussion
The sequence of events in this very difficult case point to the fact that, besides commonly used medication and rehabilitation therapy, there are additional therapeutic means that should be considered in the treatment of complex neuropsychiatric cases, especially when complicated by multiple traumatic brain injuries. The chronic problems our patient presented with since childhood, i.e., regulatory disorder of childhood [35] followed by affective disorder, partial epilepsy, RSD pain, and multiple traumatic brain injuries, are known to have neuro-inflammation in common [3][4][5][6]. The use of HBOT, although well documented, is still considered controversial by some. Recent publications have reported variable outcomes in great part because of using protocols that differ significantly in depth, duration, frequency and number of sessions [36][37][38]. It appears that HBOT can be effective in decreasing chronic inflammation in the brain by reducing pro-inflammatory cytokine activation and through provocation of stem cell activity [7][8][9][10]. The repeat brain SPECT indicated the valuable contribution of this technique as a functional imaging biomarker.
The combination therapy of TMS/ketamine infusion has been recently patented and successfully applied in a variety of conditions involving various treatment-resistant neuropsychiatric disorders, including pain and depression [16,[29][30][31][32]39,40]. In the present case, this brought the patient to a higher functional level in part due to the fact that it enabled a drastic cut in the number and amount of drugs she was taking. Nonetheless, this was still short of adequate independence in, or better tolerance for, daily activities. Therefore, the decision was made to start PSE. This technique works in part by inducing TNF-alpha modulation directly to the central nervous system, thus normalizing the inflammatory response [18][19][20]33]. The subsequent clinical amelioration and marked improvement on the SPECT functional imaging validated this decision. Finally, the patient's persisting head pain was addressed by the non-invasive SPG block [21,22,34].
The long follow-up the present study showed an additional benefit of the stepwise anti-inflammatory treatment, namely that it prevented the recurrence of the patient's main symptoms of depression, RSD pain, cognitive deficits, and allodynic head pain with misophonia.

Conclusion
When faced with complex, chronic neuropsychiatric conditions aggravated by multiple traumatic brain injuries, it may be beneficial to go beyond the more common medication and rehabilitation procedures, adding one or more of the novel forms of anti-inflammatory treatment outlined above. Our findings may be of particular interest given that depression and pain can be inextricably linked, exacerbating each other and thus becoming very difficult to treat, especially in the context of added multiple traumatic brain injuries. This vicious cycle appears to have been successfully interrupted, and recurrence of future symptoms avoided, by the sequence of novel therapeutic interventions. The use of Brain SPECT functional imaging, in this context, provided a useful biomarker for confirmation of the therapeutic benefit of this sequential anti-inflammatory treatment.