41-Year-Old Male with Sub-Acute Encephalopathy, Seizures, and End Stage Renal Disease: A Unifying Diagnosis and Response to Therapy

Abstract

We describe a case of a 41-year-old male with a history of end-stage renal disease, hypertension, epilepsy, ischemic stroke, and traumatic brain injury transferred to our tertiary care center for subacute, progressive cognitive impairment. He was found to have disproportionate brain atrophy, focal seizures, and refractory hypertension. Given suspicion for an underlying genetic etiology, a genetic panel for progressive renal disease was sent, revealing two known pathogenic variants in a gene for a cobalamin metabolism disorder, Cobalamin C deficiency. He was started on targeted metabolic supplementation with subsequent improvement in his cognition. Our case highlights the crucial need to expand diagnostic workup to include genetic and metabolic causes in patients with neurologic disease, atypical features, relevant family history and multi-organ dysfunction.

Case Presentation

A 41-year-old male with a history of end-stage renal disease, hypertension, epilepsy, ischemic stroke, and traumatic brain injury (TBI) was transferred to our tertiary center for further evaluation of refractory seizures and subacute progressive cognitive impairment. Although the patient suffered from TBI at age 27, his family reported minimal cognitive and behavioral concerns after the insult. He had finished high school with no concerns and was employed throughout his adulthood. The patient’s chronic kidney disease (CKD) had been diagnosed around age 27, with rapid progression to stage 4 CKD by age 34. Kidney disease was attributed to hypertension, with possible contributions from non-obstructive nephrolithiasis and cocaine use. He first developed seizures at age 36 and was treated with levetiracetam and lacosamide. Magnetic Resonance Imaging (MRI) of the brain at that time demonstrated global atrophy disproportionate to age. At age 39, he suffered a left corona radiata ischemic stroke and was started on aspirin. Family history revelated end-stage renal disease of unknown etiology at various ages of diagnoses in both sides of his family and late-onset dementia in the paternal grandmother. His reported cocaine use was transient with no recent history of drug use.

A few months prior to admission to our tertiary care center, he began having refractory seizures and encephalopathy which were associated with progressive decline in kidney function attributed to acute tubular necrosis and rhabdomyolysis, including one admission with transient hematuria. Ultrasound demonstrated progressive bilateral kidney atrophy and he was undergoing transplant evaluation and consideration of dialysis initiation.

Upon discharge home, he began to showcase behavioral changes characterized by social withdrawal and impulsivity. One month later, he was admitted for progressive encephalopathy and dialysis was initiated to treat any contribution of uremia to his cognitive changes. Other symptoms at the time included weight loss, fatigue, breakthrough seizures, and a progressive inability to care for himself.

Despite dialysis and correction of metabolic abnormalities, his cognitive symptoms worsened. His speech was progressively limited, and he developed irregular repetitive movements of his upper extremities. Levetiracetam was uptitrated empirically, but mental status continued to decline, prompting presentation to an outside hospital after he was found incontinent of urine and diffusely tremulous. He was ultimately transferred to our institution for further management.

Initial examination revealed a depressed mental status with a blank stare, inability to follow commands, and language limited to his name. Cranial nerves, motor exam and reflexes were otherwise intact.

Encephalopathy has a broad differential which includes infection, toxic and vascular processes, trauma, autoimmune/inflammatory conditions, seizures, metabolic/genetic, neoplastic, and neurodegenerative diseases. Etiologies particularly worthy of consideration in this patient include seizures, metabolic disturbances, toxins, neurodegenerative and vascular causes. The patient’s personal and family history of kidney disease, behavioral changes and brain atrophy out of proportion to his age prompt consideration of genetic etiologies. The patient’s brain atrophy on MRI at a young age together with a strong family history early onset renal disease raises concern for the possibility of a neurodegenerative process and provides sufficient evidence for investigation into neurodegenerative and genetic causes of his presentation. Next steps to narrow the differential diagnosis for neurohospitalists should include repeat brain imaging, continuous electroencephalogram (EEG), toxic/metabolic testing, and cerebrospinal fluid (CSF) analysis.

MRI brain with and without contrast revealed global atrophy progressed compared to 2018 (Figure 1). EEG showed diffuse global slowing and several clinical and subclinical parasagittal seizures.

Figure 1.

Progression of global brain atrophy from 2018 to 2022. (A) Coronal T2 image from MR examination in 2018, age 39, at the level of the hippocampal bodies demonstrates no significant brain volume loss. No structural lesion for the patient’s epilepsy is present. (B) Coronal T2 image from MR examination in 2022, age 41, at the level of the hippocampal bodies demonstrates enlarging ventricles and sulci compatible with global volume loss, which has markedly progressed compared to 2018. The hippocampi are normal bilaterally.

Complete blood count, comprehensive metabolic panel, levetiracetam level, plasma glucose, ammonia, thiamine, thyroid stimulating hormone (TSH), thyroxine 4 (T4) and vitamin B12 were normal except for baseline abnormalities from end-stage renal disease (ESRD) which corrected with hemodialysis. Erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP) were mildly elevated at 19 and 7.2, respectively. Serum testing for human immunodeficiency virus (HIV) and rapid plasma reagin (RPR) were negative. CSF demonstrated opening pressure 18 cm H₂O, 0 WBCs, 59 RBCs, glucose 56 mg/dL and protein 87 mg/dL. Oligoclonal bands were negative in the CSF and IgG index was elevated at .7.

The presence of clinical and subclinical seizures on EEG provide a highly likely contributor to the patient’s recent cognitive symptoms. An immediate next step should be to escalate antiepileptic therapy and evaluate its effect on seizure burden and neurological exam with continuous EEG.

Our results thus far suggest that uremia, electrolyte abnormalities such as hyponatremia, and central nervous system inflammation are less likely to be drivers of the patient’s encephalopathy. Nevertheless, the modest elevation in CSF IgG index is worthy of further diagnostic evaluation with dedicated autoantibody testing and an expanded serum autoimmune workup.

The progression of global brain atrophy on MRI is somewhat intriguing. One possible explanation for this finding is that the patient has been suffering longstanding subclinical seizures that have gradually caused progressive brain atrophy. However, in the absence of discrete episodes suggestive of seizure in his clinical history, neurohospitalists must also be aware of and consider potential neurodegenerative and/or genetically driven processes.

Expanded serum inflammatory workup as well as serum and CSF autoimmune and paraneoplastic autoantibody testing, including anti-Ma and anti-Ta antibodies, was unremarkable, with the exception of a low positive ANA titer (1:80). Levetiracetam was discontinued due to the possible neuropsychiatric side effects of the drug in the light of his reduced renal clearance. ¹ He was started on valproic acid with an interval increase in doses, which successfully stopped his seizures.

In the following days, the patient improved cognitively but continued to have poor insight, judgment, and neuropsychiatric symptoms characterized by aggression and emotional lability. His speech was limited, except in the context of demanding food.

Initial therapeutic approach involved a number of concurrent interventions to help address likely drivers of his encephalopathy; however, the patient had failed to improve to baseline mental status despite the team addressing his seizures and renal-related electrolyte disturbances and uremias. The most likely explanation is the presence of an as-yet undiagnosed neurologic process that is responsible for cognitive dysfunction and possibly seizures. It is not uncommon for neurohospitalists to encounter cases of an acute or subacute on chronic process and the urgency of continued inpatient workup needs to be considered. In our case, given the relative acute deterioration, grave disability, and the level of impairment of symptoms to his daily living—further workup was indicated prior to discharge and the differential diagnosis should be expanded to include other neurologic contributors to cognitive dysfunction.

The patient’s brain atrophy on MRI at a young age together with a strong family history of early onset renal disease raises concern for the possibility of a neurodegenerative process and provides sufficient evidence for investigation into neurodegenerative and genetic causes of his presentation.

Conditions that cause both chronic encephalopathy and end stage renal disease could include Fabry disease, Niemann-Pick Type C disease, and various Neuronal Ceroid Lipofuscinoses (NCL).

With support from nephrology consultation, a renal disease panel and NCL testing were sent. The genetic panel revealed that the patient was a carrier for biallelic pathogenic variants in MMACHC (c.352del and c.482G>A), consistent with Cobalamin C (CblC) deficiency. Despite a normal Vitamin B12 level and normal folate, he was found to have markedly elevated homocysteine of 228 μmol/L (RR < 11.4) and methylmalonic acid of 531 μmol/L (RR < .41), consistent with CblC deficiency.

Treatment was initiated by the metabolic service in line with published guidelines for this disorder and consisted of high dose IM hydroxocobalamin (2 mg per day), betaine anhydrous 5 mg three times daily to assist remethylation of homocysteine to methionine, folinic acid 5 mg twice daily, and levocarnitine 500 mg IV or by mouth twice daily. ² Aspirin 81 mg orally once a day was continued for secondary prevention of stroke. He continued these medications on discharge. The goal of the treatment is to decrease homocysteine levels below 50 μmol/L to reduce stroke risk. The methylmalonyl-CoA and methionine levels should also improve with this treatment therapy. The patient’s cognitive symptoms slowly improved in parallel with improved homocysteine values, which remained above normal but below 50 μmol/L.

If the genetic panel was inconclusive, the next step would have been to investigate for possible neurodegenerative disease through a CSF analysis for Alzheimer’s amyloid/tau ratio and additional functional imaging.

Discussion

Methylmalonic aciduria and homocystinuria, CblC type (OMIM #277400), is an autosomal recessive cobalamin (vitamin B12) metabolism disorder. ² Biallelic pathogenic variants in the MMACHC gene result in decreased production of the two cofactors derived from B12: adenosylcobalamin - a cofactor for methylmalonyl-CoA mutase, and methylcobalamin - a cofactor for methionine synthase (Figure 2). This results in increased methylmalonic acid, and increased homocysteine, respectively, the latter due to an impairment of the remethylation of homocysteine (Hcy) to methionine (Met) by methionine synthase. Biochemical markers for the disease include elevated methylmalonic acid and homocysteine, in the presence of normal folate and B12 serum levels.

Figure 2.

Intracellular cobalamin metabolism. Intracellularly, the Cobalamin-Transcobalamin complex is taken up by lysosomes and transcobalamin (TC) is cleaved. After lysosomal release, the exact form of cobalamin (Cbl) is unclear (indicated by Cbl-?). In the cytoplasm, the MMACHC gene has a role in the conversion of cobalamin into two active coenzyme derivatives: methylcobalamin and adenosylcobalamin. Adenosylcobalamin is required for the activity of the mitochondrial enzyme, methylmalonyl-CoA mutase (MMA mutase), which converts methylmalonyl-CoA to succinyl-CoA. In the cytoplasm, methylcobalamin is required for the activity of the cytoplasmic enzyme, methionine synthase (MS), which converts homocysteine to methionine.

CblC deficiency typically presents as a pediatric early-onset disease in 88% of all cases. ³ Late-onset disease is historically applied to patients who have symptoms after age 4. Early-onset vs late-onset disease correlates with the genotype of affected patients. Our patient carried biallelic pathogenic variants of the MMACHC gene, c.352del and c.482G>A, associated with a late-onset presentation.^4,5 Neurohospitalists must be aware of late-onset vitamin responsive diseases as presentation manifests in any decade of life with neuropsychiatric symptoms (personality changes, confusion/disorientation), progressive encephalopathy, cerebral atrophy, ataxia, dysarthria, myelopathy, kidney failure, optic nerve atrophy, and thromboembolic events due to hyperhomocysteinemia. ⁶ Imaging findings include cerebral atrophy and deep white matter loss. ²

Our patient had unexplained early-onset hypertension and an extensive family history of chronic kidney disease. Seizures, cerebral atrophy, and ischemic stroke manifested 4 years before encephalopathic symptoms. This presentation is consistent with other reports of similar pattern of deterioration in CblC disease: an initial period of normal development followed by psychomotor delay and ultimately abrupt deterioration that may be fatal. ² Progressive kidney failure and hypertension as seen in this patient are common renal manifestations of CblC deficiency. This patient did not have a kidney biopsy, but findings would typically include a thrombotic microangiopathy. ⁷ Questioning the etiology of nonspecific kidney disease in the setting of minimal antecedent comorbidities is an important step in the evaluation of patients with uncertain diagnoses and presentations.

Diagnostic clues that favored a genetic diagnosis in our patient included young age, personal and family history of kidney disease, and progressive brain atrophy. While CblC deficiency is one of the most common conditions affecting cobalamin processing, the late-onset type is very rare, with some studies reporting less than 150 cases to date. ⁷ Neurohospitalists typically encounter neurologic disease in its most acute presentation, but in this patient and in others, it is paramount to also appreciate any chronic progressive underlying symptoms in order to best understand an acute presentation. CblC deficiency is one of many neurogenetic diseases with a response to vitamin supplementation. ⁶ Additionally, restoration of methylation capacity with the recommended treatment may reverse acute clinical signs of CblC deficiency. ² Neurohospitalists should be versed in considering these entities given that many are treatable and have the potential for acute presentations with unexpected phenotypes. In addition, it should be remembered that some metabolic therapies are important to initiate on an urgent basis to avoid permanent neurologic damage.

ORCID iD

Tameena Wais https://orcid.org/0009-0000-0786-0642