Clinical Reasoning: A 45-year-old man with progressive insomnia and psychiatric and motor symptoms

Section 1

A 45-year-old right-handed hypertensive man presented with a 6-month history of worsening neuropsychiatric symptoms, abnormal movements, and weight loss. He was hallucinating, apathetic, and having severe insomnia (total sleep duration of 1–2 hours/night). During sleep, his wife noted labored and sonorous breathing. Six months before admission, he led a healthy and active lifestyle.

In the weeks preceding admission, the patient developed short-term memory loss, confabulation, and complete lack of insight to his symptoms. Weekly, he was working at least 40 hours as a public works employee plus 20 hours as a mechanic. He consumed nearly 4 cans/day of beer and had prior tobacco exposure (15 pack-years, quit 14 years prior to presentation). Family history was notable for Parkinson disease (PD).

On examination, pulse oximetry was 98.9%, heart rate was 94 beats per minute, blood pressure was 161/89 mm Hg, and respiratory rate was 18 breaths per minute. Systemic examination revealed a thin, middle-aged man in no acute distress. Neurologic examination was notable for binocular diplopia (worst on midline and right gaze), postural tremor, whole body akathisia, multifocal and asynchronous myoclonic jerks, and choreiform movements of the legs while in a sitting position. An exaggerated startle response, progressive deficits in executive function and visuospatial skills, and involuntary chewing were also present (video 1).

Section 2

The symptoms and signs in this vignette point to a process likely involving the bilateral frontotemporal lobes and the basal ganglia. In cases of diffuse cortical and subcortical dysfunction, infections such as syphilis, neuroborreliosis, and HIV should be considered.

Progressive clinical worsening may suggest a degenerative process such as frontotemporal dementia or prion diseases. PD, Alzheimer disease, and Lewy body disorders are less likely at this age and also less likely to exhibit a rapid progression. Although less common, autoimmune encephalitis, hereditary and acquired leukoencephalopathies, paraneoplastic syndromes, and vitamin deficiencies are also possible. Acute toxicity and substance-induced disorders should be ruled out. In this setting, empiric treatment for Wernicke and Korsakoff encephalopathy is appropriate.

A complete blood count and comprehensive metabolic panel including liver profile were significant for a sodium level of 122 mEq/L. Tests for reversible causes of dementia including thyroid function tests, vitamin B₁ and B₁₂ levels, HIV and syphilis screening, ammonia, and urine toxicologic screen were negative.

The likely culprit of the patient's hyponatremia was syndrome of inappropriate antidiuretic hormone secretion, as he was euvolemic, with normal urine osmolality, and had urine sodium >20 mEq/L. Brain MRI without gadolinium revealed no parenchymal abnormalities, normal ventricular size and configuration, and no restricted diffusion. FDG-PET revealed asymmetric hypometabolism in the left thalamus. EEG was normal except for rudimentary sleep structures, which can be found in healthy patients but may also indicate thalamocortical dysfunction.

CSF analysis showed normal levels of protein and glucose, an erythrocyte count of 21, and no pleocytosis. The immunoglobulin G index was elevated at 696 mg/L. Fungal and bacterial cultures were negative, as were serologies for cytomegalovirus, varicella-zoster virus, Epstein-Barr virus, herpes simplex virus, and Lyme disease. Protein analysis of Aβ42/total tau index and phosphorylated tau were 0.46 and 18.75, respectively, with the former consistent with Alzheimer disease, but the latter not. Analysis of 14-3-3 was indeterminate and tau protein was negative.

Section 3

In the setting of serum anti-VGKC, hyponatremia, and neuropsychiatric syndrome, autoimmune neuromyotonia (Morvan syndrome) with superimposed limbic encephalitis was considered. Thus, initial treatment included pulse dose methylprednisolone and IV immunoglobulin.

Clinical deterioration ensued with decreased verbal output, increasing agitation, and profound dysautonomia (diaphoresis, pallor alternating with facial flushing, tachycardia, and wide body temperature fluctuations). Four weeks after therapy initiation, plasmapheresis was employed without response. The patient developed profound central hypoventilation, requiring mechanical ventilation, ultimately requiring tracheostomy and gastrostomy tube placement.

Section 4

Given the lack of response to initial immunotherapy, treatment should be individualized. Despite the absence of prospective and randomized trials, rituximab and cyclophosphamide can be considered in autoimmune encephalitis.¹ A complete course of rituximab followed, without clinical improvement despite appropriate depletion of B-cell lines on flow cytometry (video 2).

During the subsequent 5 weeks, worsened hypercapneic respiratory failure requiring mechanical ventilation and sepsis ensued. Repeat MRI showed global cerebral atrophy (figure e-1, doi.org/10.5061/dryad.2hm3d5g).

Section 5

Proper genetic counseling prior to testing is paramount when a genetic disease is suspected. In FFI, genetic testing may have implications in life and family planning given its autosomal dominance with high penetrance. Upfront discussions with family and surrogates (if minor or incapacitated individuals) are essential. In these cases, surrogates should consider deferring genetic testing until adulthood, as FFI is an adult-onset condition with no therapeutic options (figure).

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Figure Family genetic pedigree

This Polish American family had no history of presenile neurodegenerative disorders in the maternal lineage, but evaluation of the paternal lineage was complicated by early mortality in the proband's father from cancer and estrangement from the remaining family. There was no known consanguinity. Of the proband's 3 full siblings, a brother declined genetic screening and his children were not tested. One sister (coincidentally severely disabled due to profound congenital insensitivity to pain) tested negative and another clinically normal sister in her 40s was found to share the mutation observed in the proband. The proband's children underwent screening: none have the fatal familial insomnia (FFI) mutation. Regarding the sister who shares the mutation, 2 of her children were tested: the youngest child has the mutation and is asymptomatic; the oldest child tested negative.