Successful treatment of dermato-neuro syndrome with plasmapheresis

Abstract

Altered mental status can have many causes ranging from emergent intracranial pathologies to more insidious, systemic toxic aetiologies. We report a rare case of dermato-neuro syndrome in a 71-year-old man with a known history of scleromyxoedema. The patient initially presented with encephalopathy which quickly progressed to generalised tonic–clonic seizures and coma. While his presentation fits with other, although rare, cases of dermato-neuro syndrome, it is imperative to rule out lethal, more common causes of altered mentation. Due to the rarity and difficulty in diagnosis of dermato-neuro syndrome, there is a significant debate regarding the optimal management as there are no standardised treatment protocols. In our case, the patient was successfully treated with plasmapheresis resulting in improved neurologic function.

Background

Scleromyxoedema (SM) is a rare, chronic and progressive dermatologic disease characterised by diffuse sclerosis and lichenoid eruption. In 1954, Gottron described a sclerotic and papular form of lichen myxoedematosus, now referred to as SM.¹ Dermatologic manifestations include waxy nodules measuring 2–3 mm in a linear array along the upper trunk and neck, forearms, hands and thighs, which is shown in figure 1.² Fewer than 120 cases have been reported in English language journals. Invariably, patients with SM also have a concomitant monoclonal gammopathy of undetermined significance.³ Dermato-neuro syndrome (DNS) is a rare complication of SM and is characterised by acute onset encephalopathy, often in conjunction with fevers and seizures. There are so few cases that an accurate epidemiology has not been reported and therapy has not been standardised. In this case report, we contribute to a growing body of literature that demonstrates treatment of DNS with plasmapheresis offers a chance at recovery of neurologic function and possible survival.

Figure 1.

Characteristic rash of scleromyxoedema is made up of waxy firm papules in a linear array on the trunk, back and upper extremities.

Case presentation

A 71-year-old man with a history of chronic obstructive pulmonary disease, hypertension, diabetes and SM presented to the hospital with altered mental status of 3-day duration. Of note, at the time of presentation, all treating medical teams were unaware of the SM diagnosis. The encephalopathy began with slight forgetfulness in daily routines but progressed rapidly, leading to inability to follow commands. Dizziness as well as left upper extremity paraesthesia over the past 2 months were also reported by the patient’s wife. According to the family, the patient did not have fever, chills, congestion, headache, neck pain, abdominal pain, chest pain, shortness of breath or trauma. However, the family did report concern for carbon monoxide poisoning as the patient’s car was leaking exhaust into the cabin. In the emergency department, the patient appeared lethargic and oriented only to person, which prompted a consult for the intensive care unit (ICU). While being triaged in the emergency department, the patient developed intermittent, generalised tonic–clonic seizures. He was intubated for airway protection and transferred to the ICU for ventilator dependent respiratory failure, concern for aspiration pneumonia and developing sepsis, worsening encephalopathy of unknown aetiology, as well as new onset seizures. Vital signs were normal on admission; and, apart from the altered mental status, physical examination was largely unremarkable with the exception of multiple, hyperpigmented papules aligned in a linear array on the anterior upper torso and neck (figure 1). Neurology was urgently consulted for new onset seizures; however, at time of evaluation, the seizures had resolved with lorazepam 0.1 mg/kg intravenous and there was no concern for status epilepticus. Levetiracetam was initiated to prevent further seizures and a more thorough investigation was started in the ICU.

Investigations

Arterial blood gas analysis failed to demonstrate carbon monoxide poisoning. Complete blood count with differential and complete metabolic panel were normal. HIV testing, thyroid function, respiratory viral panel, heavy metal and drug screen were also negative. Chest X-ray demonstrated mild prominence of the hila bilaterally and diffuse alveolar opacities. Importantly, emergent CT of the head was negative for any acute process. The patient was started on empiric antibiotics and a lumbar puncture was obtained to rule out infectious causes. An elevated opening pressure was observed. The cerebrospinal fluid (CSF) was clear and demonstrated elevated protein of 138 mg/dL and elevated glucose of 109 mg/dL. Cytology demonstrated five white blood cells. Extensive evaluation of the CSF for infectious aetiologies (herpes simplex virus type 1 and 2, syphilis and West Nile Virus), including gram stain, culture and PCR analysis, was negative. An magnetic resonance imaging and magnetic resonance angiography of the brain were obtained and failed to reveal an ischaemic or vascular cause for the patient’s acute deterioration. While awaiting the official read of an extended duration electroencephalogram, the patient’s family shared a copy of the patient’s outpatient dermatology records, which documented a diagnosis of SM. Given this new information and a negative work-up for stroke, infections and seizure, there was a high clinical suspicion for DNS, which is known to be a rare complication of SM. We tested the patient’s serum for a potential M protein. Serum protein electrophoresis indeed revealed an M protein of 0.1 g/dL, with normal levels of free κ of 1.45 mg/dL, λ of 2.53 mg/dL and a ratio of 0.57. Immunoflourescence analysis confirmed immunoglobulin G (IgG) kappa monoclonal gammopathy of 350 mg/dL (normal value: 0 mg/dL). Serum Ig levels of IgG, IgA and IgM were 1590 mg/dL, 183 mg/dL and 21 mg/dL, respectively (normal values: IgG: 751–1560 mg/dL, IgA: 82–453 mg/dL and IgM: 46–304 mg/dL). Urine protein electrophoresis was positive for Bence Jones protein. At this point, a decision was made to use the remaining CSF for protein electrophoresis, which demonstrated a concomitant M spike. Unfortunately, we did not have enough CSF to test for hyperviscosity, which is a reported mechanism of neurologic disease progression.

Treatment

In addition to consulting haematology/oncology, the patient was started on methylprednisolone, 1 g/day and 45 g intravenous immunoglobulin (IVIG) but did not improve over a course of 5 days of treatment. In fact, the patient’s neurologic function seemed to deteriorate further. Haematology initiated treatment with plasmapheresis, using albuminised saline for exchange. After the first session, the patient’s neurologic status markedly improved. He completed a total of 10 sessions of plasmapheresis over a course of 2 weeks with treatment breaks over the weekend. By the completion of the 10th and final session of plasmapheresis, the patient was awake, alert and following commands. His course was complicated by ventilator-associated Pseudomonas aeruginosa pneumonia and the patient was treated with a 10-day course of meropenem.

Outcome and follow-up

The patient continued to improve after treatment with plasmapheresis. On day 35 of the admission, the patient was discharged to a subacute rehabilitation facility. Unfortunately, it was discovered that the patient passed away about 2 months after his discharge from the hospital. At the time of this manuscript, we were unable to reach the patient’s primary care physician to determine the cause of death.

Discussion

SM is a primary cutaneous mucinosis associated with a monoclonal gammopathy. The diagnosis requires a normal thyroid function to exclude lichen myxoedematosus.² The M spike most often associated with scleromyxoedema is IgG with a predominance of λ light chains.⁴ Various extra-dermatologic manifestations of SM include congestive heart failure, heart block, pericardial effusions, obstructive or restrictive lung disease, oesophageal dysmotility, acute kidney injury, polyarticular arthralgias and inflammatory myositis.² DNS is an extremely rare complication of SM. Although there are no formal diagnostic criteria for DNS, all reported cases have presented with mental status changes ranging from aphasia to decreased consciousness. Rongioletti and colleagues followed 30 patients with SM for a mean follow-up of 33.5 months. In this case series, 2 of the 30 patients (7%) developed DNS and died.³ An extensive search of the primary literature to date demonstrates 20 reported cases of DNS. Of these, 15 are in English, which we review here. Four of the 15 cases of DNS, including the seminal report in the literature, presented with the triad of fever, seizures and coma.⁵ Importantly, all other causes of encephalopathy in these cases were ruled out.

The pathophysiology of DNS is poorly understood. Imaging studies of the brain in patients with DNS are normal and brain autopsy has failed to yield definitive answers.⁴ Currently, it is thought that the circulating monoclonal proteins either cause sludging in the central nervous system microcirculation or are able to cross a damaged blood–brain barrier, resulting in encephalopathy.⁴

Patients with SM without DNS have been treated successfully with various therapeutic modalities, including high-dose glucocorticoids, IVIG, multiple myeloma-based therapies, plasmapheresis or a combination of these modalities.⁶ Given the rarity of DNS, formal treatment strategies do not exist; however, patients have had successful recovery after a diagnosis of DNS with various combinations of the above listed treatments for SM. Table 1 is a summary of demographics, presentation, treatments and outcomes in the 15 reported cases of DNS.

Table 1.

Where multiple presentations, treatments and outcomes exist for a single patient, each course is delineated by a number

Age (years)	Gender	Presentation	Treatment	Outcome	Reference
60	M	Seizure, fever, coma	MP+PP	Resolution	5
41	M	Flu-like symptoms, seizure, coma Flu-like symptoms, fever	Extracorporeal phototherapy Family refused IVIG and CP	Resolution Hospice	7
39	F	Flu-like symptoms	IVIG and Dex	Resolution	8
56	M	Lethargy, mental slowing, seizures	Bortezomib and Dex	Resolution	9
45	F	Flu-like symptoms, dysarthria, coma	Pred+PP, then melphalan+IVIG	Resolution	10
40	F	Confusion and coma during pregnancy	IVIG+PP	Resolution, loss of fetus	11
39	M	Confusion, seizure Fever, seizure, coma	PP+Dex IVIG, CP, Dex, melphalan, ASCT	Resolution with recurrence Resolution	12
52	F	Confusion, agitation, seizures	IVIG+MP	Resolution	13
60	M	Fever, malaise, confusion, positive influenza test	Oseltamivir	Resolution	14
50	M	Flu-like symptoms, confusion	GC +PP, IVIG	Resolution	15
50	F	Fever, seizure, coma	PP	Cardiac arrest and death on day 2 of PP	4
50	F	Fever, seizure, coma	Antibiotics for bacterial pneumonia	Died prior to initiation of treatment	16
50	M	Acute, self-limited confusion Fever, aphasia, confusion Confusion, seizure Skin manifestations Confusion, seizure, diagnosed with AL amyloidosis Psychomotor slowing, pneumonia	No treatment No treatment No treatment MP Melphalan, Dex Antibiotics for pneumonia and sepsis	Resolution Resolution Death from sepsis	17
59	F	Fever, malaise, myalgia, coma	GC+PP, then IVIG	Resolution	18
62	F	Fever, headache	IVIG, maintenance thalidomide	Resolution	19

ASCT, autologous stem cell transplant; CP, cyclophosphamide; Dex, dexamethasone; GC, glucocorticoids; IVIG, intravenous immunoglobulin; MP, methylprednisolone; PP, plasmapheresis.

When multiple treatment modalities have been used, it is difficult to determine if a second-line or third-line treatment was successful in their own right, or required the previous treatments. In the 15 cases of DNS reported in English language journals, 46% of patients received plasmapheresis at some point during their treatment. Of the patients who received plasmapheresis at any point, 86% experienced a resolution of symptoms; one of the patients died from unrelated complications during treatment. Similar to the 15 DNS patients reviewed here, our patient ultimately required multiple modalities of treatment. High-dose glucocorticoids and IVIG were not effective. After a single session of plasmapheresis, however, our patient demonstrated noticeable improvement. Indeed, after all 10 sessions, our patient was awake, alert and following commands.

Despite the lack of formal treatment strategies, our case supports the importance of initiating treatment in a patient presenting with altered mental status, a history of SM and exclusion of other aetiologies for encephalopathy. Furthermore, our case helps to support the evidence that treatments targeting the monoclonal gammopathy, such as plasmapheresis, offer a chance of survival in DNS.

Learning points.

• Life-threatening aetiologies must be promptly ruled out when assessing a patient with altered mental status.

• A comprehensive physical examination is a crucial aspect of developing a differential diagnosis, especially when common aetiologies have been ruled out.

• SM is a rare, chronic and progressive dermatologic disease characterised by diffuse sclerosis and lichenoid eruption, which can progress to the lethal complication of DNS.

• High clinical suspicion of DNS should be suspected in a patient with a known history of SM, monoclonal gammopathy or suspicious skin lesions resembling SM and presenting with altered mental status, seizures, fever or coma.

• Treatment with plasmapheresis, glucocorticoids, intravenous immunoglobulin or a combination should be considered if there is clinical suspicion for DNS, as this can potentially reverse neurologic decline.