Malignant deep brain stimulator withdrawal syndrome

Abstract

Parkinsonism-hyperpyrexia syndrome (PHS) is a neurologic potentially fatal emergency that mimics neuroleptic malignant syndrome. It commonly presents as systemic inflammatory response syndrome, acute onset worsening of muscular rigidity, autonomic instability, hyperpyrexia, confusion, diaphoresis and high creatine phosphokinase. The most common trigger for PHS is reduction or withdrawal of anti-Parkinson’s medications, especially levodopa. It was also reported in a few cases following deep brain stimulation of the subthalamic nucleus surgery shortly after anti-Parkinson’s medications were discontinued. Rare causes of PHS include deep brain stimulator (DBS) malfunction due to battery depletion. To the best of our knowledge, PHS following DBS battery depletion was reported only in three occasions. Here, we report a case of PHS due to DBS battery depletion presented as sepsis and was successfully treated with the administration of dopamine agonists, intravenous fluids and changing the DBS battery.

Background

High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established modality for treating Parkinson’s disease (PD) for more than two decades. Our knowledge about the pathophysiology of PD and the clinical applications for STN DBS is rapidly evolving. Nevertheless, the exact mechanism of action of STN DBS remains an enigma.¹ The common hypothesis is that DBS acts through modulation or disruption of the pattern of neural signalling within targeted regions in the brain: the STN and the internal segment of globus pallidus.^{2 3} The long-term efficacy and safety of DBS are promising, as reported in many recent publications.⁴ Parkinsonism-hyperpyrexia syndrome (PHS) is a life-threatening disorder, commonly reported following withdrawal of anti-Parkinson medications. More rarely, PHS is concomitant with DBS malfunction. In this case report, we describe a novel syndrome of PHS due to DBS battery depletion, which presented as sepsis in our hospital in May 2014.

Case presentation

A 67-year-old woman, previous medical history significant for Hashimoto hypothyroidism, essential hypertension, dementia, major depression and diabetes mellitus. She was diagnosed with PD in 1991. Over the years, her treatment included levodopa/carbidopa and pramipexole, with poor control of her symptoms. In 2007, bilateral STN DBS was implanted, resulting in significant improvement of tremors and motor deficit. Her symptoms were well controlled for the following 7 years; however, the DBS battery was never replaced.

The patient presented to the emergency room (ER) in May 2014 with a 3-day history of high-grade fever (up to 39°C) (figure 1), altered mental status, poor oral intake and low urinary output. On admission, she was febrile 38.5°C, tachycardia at 110 beats/min with elevated blood pressure 180/77 mm Hg; her respiratory rate was 18 breaths/min, with pulse oximetry of 90% in room air. Her physical examination showed a somnolent, diaphoretic and severely dehydrated patient, with mild respiratory distress; neurologic examination demonstrated somnolence with lack of response to painful stimuli. Her breath sounds were diminished in the lung bases. The rest of the physical examination was unremarkable.

Figure 1.

Fever chart in degrees Celsius. Day 1 is the first day of admission. Day 9 (red arrow) represents time of increasing her levodopa dose. Day 17 (blue arrow) is when her IPG Impulse Generator was replaced. On day 23, she was sent to rehabilitation.

Laboratory tests were remarkable for acute prerenal failure with creatinine 123 µmol/L, hypernatraemia 157 mmol/L, elevated creatine kinase at 1015 U/L, leucocytosis 12 600/µL with a C reactive protein (CRP) of 1.6 mg/dL. A chest X-ray demonstrated atelectasis in the lung bases. Lumbar puncture ruled out central nervous system (CNS) infection, with normal cell count and negative viral PCR and cerebrospinal fluids (CSF) cultures. After blood, sputum, urinary and stool cultures were obtained, the patient was started on an antibiotics for possible pulmonary infection. Due to continued fevers and decreased consciousness, she underwent a whole-body CT that failed to localise a possible source of infection. Serology for cytomegalovirus (CMV) and Epstein-Barr Virus (EBV), respiratory viral swab and all other cultures came back negative. The patient’s Thyroid Stimulating Hormone (TSH), calcium, ammonia, liver enzymes and vitamin B₁₂ levels were all within normal limits. She completed a course of antibiotics and thiamine with no improvement.

Due to lack of a similar reported cases in the literature, unfamiliarity with this presentation among the medical team, and given no history of neuroleptics administration or withdrawal of dopaminergic medications prior to the onset of symptoms. It was not until day 9 postadmission that the diagnosis of PHS was made, after the patient continued to have non-resolving high fever, severe muscular rigidity, altered mental status, autonomic instability (hypertension up to 180/90 and tachycardia between 110 and 125 beats/min) and elevated creatine kinase (CK) to 1615 U/L. Subsequently, the patient was treated with intravenous fluids, acetaminophen and ice packs; levodopa dose was tripled, with no clinical improvement. Yet, transient resolution of fever was noted before it spiked again 2 days later (figure 1). Considering the unsatisfactory results of conservative management, lack of clinical improvement and given that the estimated DBS battery life is between 3 and 5 years, DBS withdrawal syndrome due to battery depletion was suspected. However, the Implantable Pulse Generator (IPG) replacement was not accomplished until day 17 of admission due to lack of similar reported cases and unavailability of supportive evidences in the literature. A few hours later following successful IPG replacement, clinical improvement was documented. After 1 day post IPG replacement, there was no more fever (figure 1) or autonomic instability; CK, white blood cell (WBC) count, creatinine level and CRP all normalised. The patient’s rigidity and mental status improved to full recovery until discharge.

Outcome and follow-up

During the course of admission, the patient continued to have non-resolving high fever, altered mental status and autonomic instability. CK level increased to 1615 U/L. After a delayed diagnosis of malignant DBS withdrawal syndrome due to battery depletion was made, she underwent successful IPG replacement with subsequent dramatic clinical improvement, as documented by rapid resolution of fever (figure 1), normalisation of CK, WBC count, creatinine and CRP levels. Full recovery with normal mental status was documented on discharge.

Discussion

PHS is a medical emergency described in patients with PD. This syndrome was first shown in a PD patient in 1981 after discontinuation of his anti-Parkinson’s medications even though no neuroleptics were prescribed.⁵ It is not uncommon to misdiagnose PHS because of the overlapping symptoms with advanced PD and sepsis. The classic presentation include muscle rigidity, tremors, rapidly evolving fever, autonomic instability, reduced mental status, diaphoresis, elevated CRP, high CK due to rhabdomyolysis and increase in WBC counts.⁶ The exact pathogenesis behind the development of PHS remains unclear. A growing body of evidence suggests acute reduction of neurotransmission in the hypothalamus, nigrostriatal system and mesocortical dopaminergic system contributing to the development of PHS.⁷ Complications of PHS include aspiration pneumonia, renal failure due to rhabdomyolysis, disseminated intravascular coagulation and venous thromboembolism. In addition, patients may develop a potentially fatal CNS; hypodopaminergic crisis within hours to days. Supportive management and reinitiation of dopaminergic medications are the core stones of treatment.^{7 8}

The most common trigger for PHS is withdrawal of anti-Parkinson’s medications, especially levodopa. Due to ultra-short half-life of levodopa, sudden withdrawal of dopaminergic medications during the perioperative period may cause PHS.^9–15 Additional triggers reported in the PD patient include prescription of neuroleptic medication, infection, dehydration and excessive hot weather.^{16 17}

Cases of PHS reportedly associated with acute DBS withdrawal are summarised in table 1.

Table 1.

Reported cases with DBS withdrawal syndrome (all patients had subthalamic nucleus DBS)

Report	A/S/YOD	PDD/DBSD	Treatment	Laboratory results	Cause of DBS failure	DBS restoration	Outcome
Chyong-jy et al 18	69/M/2017	16/9	↑Levodopa	↑CK (1250 IU/L)	Battery depletion	Battery was replaced	Recovery
			Conservative	↑WBC (12.1 x 109/L)
			Bromocriptine
			Dantrolene
Artusi et al 19	63/M/2015	18/5	↑Levodopa	↑CK (2820 U/L)	Battery depletion	IPG was reimplanted	Recovery
			Conservative	↑CRP (50.1 mg/L)
				↑WBC (10.0 x 109/L)
Reuter et al 22	75/M/2014	19/9	↑Levodopa	–	IPG infection	IPG was not reimplanted	Death
			IV Amantadine
			Conservative
Reuter et al 22	74/M/2014	24/10	↑Levodopa	–	IPG infection	IPG was not reimplanted	Death
			Intravenous amantadine
			Conservative
Reuter et al 22	52/M/2013	20/8	↑Levodopa	–	IPG infection	IPG was reimplanted	Recovery
			Intravenous amantadine
			Apomorphine
			Conservative
Neuneier et al 20	77/M/2013	18/5	↑Levodopa	↑CK (1642 U/L)	Battery depletion	Late IPG reimplantation	Death
			Intravenous amantadine	↑CRP (50 mg/L)
			Conservative
Kadowaki et al 21	60/M/–	17/8	Conservative	↑CK (1878 U/L)	DBS switched off	DBS switched on	Recovery
				↑CRP (10.3 mg/L)
				↑WBC (12.6 x 109/L)
Our case	67/F/2014	23/7	↑Levodopa	↑ CK (1615 U/L)	Battery depletion	Battery was replaced	Recovery
			Pramipexole	↑ CRP (10.6 mg/L)
			Conservative	↑WBC (16.5 x 109/L)

Conservative treatment refers to intravenous fluids +/− (antipyretic, antibiotics, cooling measures, sedatives, eg, benzodiazepines).

A, age; CK creatine kinase; CRP, C reactive protein; DBS, deep brain stimulator; DBSD, DBS duration at PHS onset; PDD, Parkinson’s disease duration; PHS, Parkinson-hyperpyrexia syndrome; S, sex; WBC, white blood cell; YOD, year of diagnosis.

Chyong-jy et al ¹⁸ reported a patient with a history of PD for 16 years, who developed PHS during preoperative assessment for planned DBS battery replacement, which was consequently postponed on account of suspected sepsis. Following significant clinical deterioration despite broad-spectrum antibiotic administration, and the failure to identify a source of sepsis, PHS was suspected. Treatment of dantrolene and bromocriptine was commenced, as well as intense supportive care, and the dose of dopaminergic medications was increased. As a result of the failure of conservative management, the DBS battery was replaced with subsequent recovery. Artusi et al ¹⁹ described a 63-year-old man with long-standing advanced PD with suspected PHS due to DBS battery depletion, showing gradual clinical and laboratory improvement after IPG replacement. Neuneier et al ²⁰ reported a case of fatal PHS in a patient with advanced PD, who developed withdrawal syndrome a few days after battery depletion. IPG replacement was postponed in this case, due to risk of bleeding on account of concomitant antiplatelet administration, resulting in the death of the patient with disseminated intravascular coagulation (DIC) and multiorgan failure. Kadowaki et al ²¹ described a PD patient with recurrent PHS following several attempts of discontinuing STN-DBS to improve psychiatric complications (manic symptoms). Reuter et al ²² published three cases with PHS after the removal of DBS implant, due to hardware-related infection. Fatal outcomes were reported in patients who had no IPG replacement despite an increase in the dose of levodopa. In our reported case, we came to the conclusion on account of the knowledge that battery efficiency depletes within a specific time frame and replacement is advised regularly, as is the exclusion of possible diagnosis, which would explain presenting symptoms. PHS was suspected despite a lack of previous reported cases. Initial treatment involved the increase of levodopa dose, administration of intravenous fluids, as well as pramipexole, with no clinical improvement in a patient with advanced PD and long-term STN stimulation. It was only after IPG replacement that the patient began to show signs of recovery.

The exact mechanism by which DBS influences neurotransmission in the brain has yet to be determined. As seen in other reported cases, as well as in our case, dopaminergic transmission may have been enhanced during the patient’s STN DBS stimulation; therefore, abrupt cessation of DBS results in a rebound effect with PHS development. In this scenario, patients were not responsive to conservative treatment using intravenous fluids and an increase in the dosage of dopaminergic medications. On the contrary, patients responded to the restoration of STN stimulation after replacing the IPG, suggesting possible different mechanisms of action in the nigral pathways for the DBS versus oral dopaminergics. As a result, sudden withdrawal of DBS, independent of changes in dopaminergic therapy, may induce PHS, deeming dopaminergic therapy in these cases ineffective. Possible risk factors for life-threatening DBS withdrawal syndrome may include long-standing PD (mean is 19.3 years, table 1), prolonged DBS stimulation (mean is 7.6 years, table 1) and old age (mean is 67.1 years, table 1). An optimal prognosis can be achieved with high index of suspicion and immediate DBS restoration, while delayed restoration or failure to restore DBS activity can result in fatal outcomes.

Learning points.

• Malignant deep brain stimulation (DBS) withdrawal syndrome is a rare disease, which happens exclusively in patients with advanced Parkinson’s disease as a result of abrupt cession of DBS activity.

• It has a hypothesised different mechanism of action, in comparison with dopaminergic medication.

• Treatment by augmenting the dopaminergic medications should be considered temporary, while immediate DBS restoration is considered the definitive treatment, preventing an otherwise fatal outcome.